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Review

Can We Treat Neuroinflammation in Alzheimer’s Disease?

by
Sandra Sánchez-Sarasúa
†,
Iván Fernández-Pérez
†,
Verónica Espinosa-Fernández
,
Ana María Sánchez-Pérez
* and
Juan Carlos Ledesma
*
Neurobiotechnology Group, Department of Medicine, Health Science Faculty, Universitat Jaume I, 12071 Castellón, Spain
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(22), 8751; https://doi.org/10.3390/ijms21228751
Submission received: 3 November 2020 / Revised: 13 November 2020 / Accepted: 16 November 2020 / Published: 19 November 2020
(This article belongs to the Special Issue Old and New Players in Inflammatory Disorders as Tools for Prevention, Diagnosis, and Treatment)
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Abstract

:
Alzheimer’s disease (AD), considered the most common type of dementia, is characterized by a progressive loss of memory, visuospatial, language and complex cognitive abilities. In addition, patients often show comorbid depression and aggressiveness. Aging is the major factor contributing to AD; however, the initial cause that triggers the disease is yet unknown. Scientific evidence demonstrates that AD, especially the late onset of AD, is not the result of a single event, but rather it appears because of a combination of risk elements with the lack of protective ones. A major risk factor underlying the disease is neuroinflammation, which can be activated by different situations, including chronic pathogenic infections, prolonged stress and metabolic syndrome. Consequently, many therapeutic strategies against AD have been designed to reduce neuro-inflammation, with very promising results improving cognitive function in preclinical models of the disease. The literature is massive; thus, in this review we will revise the translational evidence of these early strategies focusing in anti-diabetic and anti-inflammatory molecules and discuss their therapeutic application in humans. Furthermore, we review the preclinical and clinical data of nutraceutical application against AD symptoms. Finally, we introduce new players underlying neuroinflammation in AD: the activity of the endocannabinoid system and the intestinal microbiota as neuroprotectors. This review highlights the importance of a broad multimodal approach to treat successfully the neuroinflammation underlying AD.

1. Introduction

Alzheimer’s disease (AD) is the most common type of dementia, and is characterized by a progressive loss of memory, visuospatial and complex cognitive abilities, such as language and reasoning, which ultimately lead to a total inability to perform any type of daily activity [1,2]. Oftentimes, the patient presents comorbid psychopathologies, including depression, psychosis, anxiety, aggressive and antisocial behavior. Histologically, AD has been traditionally characterized by the appearance of neurofibrillary tangles (NFTs) and amyloid plaques [3]. NFTs are the intracellular aggregation of hyperphosphorylated Tau, a microtubule-associated protein that provides axonal cytoskeleton stability. Under pathological conditions (e.g., neuroinflammation and insulin resistance), Tau undergoes hyperphosphorylation, and consequently, conformational changes that reduce its affinity for microtubules [3], leading to neurodegeneration [4]. Misfolded Tau can spread via migration to neighbor healthy neurons, worsening the condition [4,5]. Senile amyloid plaques are formed by amyloid β (Aβ) peptide accumulation [6]. The old amyloid hypothesis to explain AD postulates that soluble Aβ oligomers, and Aβ deposits in plaques, together with NFTs are ultimately responsible for neuronal death.
Aβ-peptide is generated from the amyloid protein precursor (APP) proteolysis. APP is a transmembrane glycoprotein expressed in a wide variety of cells and located on chromosome 21 (21q21.3, in mammals) and it undergoes proteolysis by secretases in two possible pathways (see Figure 1). The amyloidogenic pathway starts by the action of the β-site APP-cleaving enzyme 1 secretase (BACE 1), followed by the action of the γ-secretase (presenilin). This sequential cleavage releases different lengths of Aβ peptides (39–42aa), depending on γ-secretase action. Long peptides (Aβ42) are more prone to aggregation. The non-amyloidogenic pathway starts by the α-secretase action followed, as above, by γ-secretase, where no pathological peptides are generated. In healthy conditions, both pathways would compete in APP proteolysis [7], and the clearance of amyloid products is carried out by microglia, the resident brain macrophages. An imbalance between the formation and clearance of Aβ peptides results in their aggregation and accumulation in amyloid plaques [8].
Soluble Aβ oligomers can also be neurotoxic, since they induce intracellular oxidative stress and synaptic dysfunction [9,10] through the aberrant interaction with numerous receptors (NMDA, AMPA, acetylcholine, insulin, BDNF and receptors for advanced glycosylation end products; for a review, see [6]). Since deposition of Aβs in amyloid plaques have been observed in other dementias and in non-demented aged people, it is nowadays only considered a specific AD hallmark if it is observed in addition to other signs, such as NFTs, neurodegeneration, insulin resistance and neuroinflammation [11,12]. Importantly, inflammation and insulin resistance start the pathological process years before the appearance of AD’s first clinical symptoms [13,14,15].

2. Neuroinflammation in AD

Neuroinflammation is a process regulated by brain resident macrophages, the microglia cells, which are required to recognize and eliminate any toxic component in the central nervous system (CNS) (for a review, see [16]). Microglia has a high capacity for mobility, and they can switch between two different phenotypes, M1 and M2, characterized by a different morphology and cytokine profile. The M2 phenotype is the resting type that actively monitors the brain in healthy conditions [17]. The switch to M1 begins with the recognition of the pathogen-associated molecular patterns (PAMPs) or the damage-associated molecular patterns (DAMPS) by the pattern recognition receptors (PRRs). This includes the ‘toll-like receptors’ (TLRs) in microglia membrane (both plasma and endosomal membrane), cytoplasmic NOD-like receptors (NLR), intracellular retinoic acid-inducible gene-I-like receptors and transmembrane C-type lectin receptors (for a review, see [18]). PAMPS and DAMPS range from bacterial wall components, the lipopolysaccharides (LPS) and virus capsid proteins, to debris released by dying cells and Aβ oligomers [19]. The activation of this system, the so-called inflammasome, initiates the inflammatory cascade, which results in the secretion of several pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukins 1β, 6 and 18 (IL-1β, IL-6 and IL-18, respectively). Pro-inflammatory cytokines purpose is to orchestrate the neutralization and elimination of toxic molecules and/or cellular debris. In normal conditions, once the toxic stimuli have been cleared, microglia swifts to the anti-inflammatory (M1) phenotype and secretes anti-inflammatory cytokines such as interleukins 4, 10 and 18 (IL-4, IL-10 and IL-18, respectively), brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF), whose role is to terminate the innate immune response and contribute to restore the synaptic function. However, under pathological conditions, microglia cells do not go back to their resting state, thus causing a chronic inflammation process, with the overproduction of pro-inflammatory cytokines and reduction of neuroprotective factors that in sustained situations become highly toxic, leading to neurodegeneration [20].
Therefore, the chronic neuroimmune system activation underlies the initiation and progression in many dementias, and surely, is involved in the late onset of AD [21,22,23]. Not only Aβ activates the microglia [24], but also misfolded Tau interaction with microglia triggers inflammation [25]. The elimination of the microglial receptor, NLR family pyrin domain containing 3 (NLRP3) has shown to reduce brain Aβ levels in rodent models of AD [26,27]; since then, NLRP3 inflammasome has been deeply studied and characterized in AD [28,29]. In addition to the neurological symptoms, neuroinflammation also underlies the psychiatric signs associated with AD, and for that reason, targeting neuroinflammation has also been proposed to treat those comorbid disturbances [30].
According to the neuroinflammation hypothesis underlying AD, there is a lower incidence of AD among users of chronic non-steroidal anti-inflammatory molecules (NSAIDs) [31,32]. NSAIDs inhibit mostly the cyclooxygenase (COX) activity, which synthesizes prostaglandin (PG) from arachidonic acid. At least two isoforms have been described, COX-1 and 2. COX-1 is expressed constitutively; in contrast, COX-2 is induced by inflammation and cellular stress, increasing PG production [33]. Anti-inflammatory compounds, inhibiting COX activity, Naproxen and Celecoxib have been tested in clinical trials against AD. Naproxen, a non-selective COX inhibitor was administered (220 mg/twice day for two years) to 195 pre-symptomatic AD subjects (aged 55+) with a familial history of AD. The progression of the disease was evaluated with the Alzheimer’s Progression Score (APS). Naproxen reduced the rate of the APS, though not significantly [34]. Celecoxib, a selective COX-2 inhibitor, was administrated (200 mg/twice day for 2 years) in 677 pre-symptomatic subjects (70+) with at least one first-degree relative with AD. No improvement in the cognitive symptoms in the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) in the AD patients compared to the placebo group was found [35]. None of these clinical trials analyzed inflammation biomarkers; therefore, these studies cannot test the neuro-inflammation hypothesis underlying AD progression. In addition, these clinical data would shift the focus to different inflammation pathways, other than the COX-PG pathway.
Furthermore, the specific TNF-α inhibitor, Etanercept, was evaluated in a small group of 41 AD patients (55+) with mild to severe AD (SMMSE score between 10 and 27), to test its anti-inflammatory effect and subsequent improvement of cognitive function. The weekly 50 mg subcutaneous administration was well tolerated; however, after 24 weeks of treatment, Etanercept did not show significant beneficial effects in cognition, behavior, systemic cytokine levels or global function compared to the placebo-treated group [36]. The failure of this clinical trial involves many factors, including insulin resistance [37]; thus, inhibiting specifically the TNF-α action may not be sufficient to counteract the inflammasome activity, and hence, to effectively prevent disease, perhaps due to the short period of time of assays,. In Table 1, the clinical studies testing anti-inflammatory molecules with potential therapeutic value for Alzheimer disease treatment are presented.

3. Targeting Insulin Resistance to Treat AD

The late onset of AD is strongly associated with insulin resistance; in fact, AD has been often recognized as Type 3 diabetes [38]. Several situations can bring about insulin resistance: metabolic syndrome caused by high fat diet, sedentarism, obesity, genetic predisposition and neuroinflammation [39]. Insulin resistance increases Tau aberrant phosphorylation, the expression of APP and the formation of Aβ oligomers and its deposition. In addition, insulin resistance augments oxidative and endoplasmic reticulum stress, mitochondrial dysfunction and pro-inflammatory cascades [40]. Not surprisingly, Type 2 Diabetes mellitus (T2DM) has been associated with cognitive impairment [41].
For this reason, administration of intranasal (IN) insulin has been considered as a potential therapeutic strategy against AD. A systematic review on this strategy concluded that whereas IN insulin administration showed improvement in verbal memory and story recall, it was not effective on other aspects of cognition. Interestingly, the authors conclude that the treatment is affected by the Apoe4 isoform, where Apoe4 (–) patients displayed more benefits compared to Apoe4 (+) patients. This systematic review concluded that current data do not demonstrate that IN insulin can be used as a treatment for dementia of AD or mild cognitive impairment (MCI), although it is very safe, not interfering with systemic glucose levels. Most importantly, these data support that proper stratification by disease stage, Apoe4 carrier status and different types of insulin must be considered for a better therapeutic effect [42].
In Insulin resistance situations, the administration of insulin is not effective in the long term; thus, other treatments have been developed instead to enhance the insulin sensitivity, rather than overload the system with insulin. These strategies include the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). AMPK activation inhibits the mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70S6K) activity [43]. The mTOR/p70S6K pathway is activated by insulin and phosphorylates the insulin receptor substate 1 (IRS1) on serine residues as a negative feedback loop to reduce insulin signaling [44,45] (see Figure 2). Interestingly, AMPK activity displays an anti-inflammatory effect, decreasing inflammatory cells proliferation and their adhesion to the blood vessel endothelium. AMPK activity also reduces amyloidogenesis, Tau hyperphosphorylation and the activation of autophagic degradation [43]. In agreement with this, a pilot study in non-diabetic subjects (aged 55–80 years) diagnosed with MCI, Metformin (an AMPK activator) administration, ameliorated learning, memory and attentional abilities, evaluated by the Paired Associates Learning (PAL) scale and DMS Percent Correct Simultaneous. Despite the improvement in behavior, no changes in the cerebrospinal fluid (CSF) of Aβ42, and total or phosphorylated Tau levels were found [46], further suggesting the idea that the amyloid hypothesis does not accurately explain AD.
Milk-derived proteins have also been proposed as possible antioxidant and anti-inflammatory compounds, given their capability to reduce insulin resistance. For example, lactoferrin (a multifunctional iron-binding glycoprotein) administration increases insulin sensitivity in adipose tissue explants from obese subjects [47,48]. Indeed, Lactoferrin antioxidant function is highly dependent on its iron binding capacity [49]. In metabolic syndromes, iron accumulation is considered an important factor underlying insulin resistance and oxidative stress; accordingly, iron-chelators have a positive effect ameliorating the physiopathology of obesity. Lactoferrin therapeutic potential against AD was demonstrated in a pilot study with AD patients. Short-term administration of lactoferrin (250 mg/day for three months) reduced serum oxidative levels and neuroinflammatory markers, and regulated neurotransmitters serum levels concomitant with improved cognitive performance, compared to control [50].
Moreover, deficiency in micronutrients such as vitamin B12 (critical for mental health [51]) has been associated with insulin resistance [51,52,53]. Interestingly, combined treatment of folic acid and vitamin B12 has been shown to improve AD cognitive performance in a randomized trial of 240 patients diagnosed with MCI for 6 months, concomitant with a reduction in serum inflammatory markers [54]. Additionally, Vitamin B12 in combination with anti-psychotic drugs (Risperidone and Quetiapine) reduced blood levels of the pro-inflammatory cytokines IL-8 and TNF-α and augmented the expression of the anti-inflammatory cytokine TGF-β, compared to non-treated AD patients [55]. The same medication formulation was tested in psychotic patients for the expression of the Cluster of Differentiation 68 (CD68), a protein expressed by monocytes and macrophages that has been shown to correlate positively with psychotic symptoms in AD patients. This treatment reduced CD68 expression [56], and therefore, has been proposed as a good strategy against AD. In addition, CD68 has been shown to bind and internalize oxidized Low-Density Lipoprotein (oxLDL), a cholesterol carrier [57], suggesting a relationship of CS68 with intracellular lipid accumulation and atherogenesis.
In this line of research, pharmacological treatments used to treat other diseases, such as hypertension (i.e., calcium channel blockers) [58,59] or hypercholesterolemia (i.e., statins) [60,61], were postulated as therapeutic agents against AD, given their alleged anti-inflammatory and insulin sensitizing properties. The results from a randomized clinical trial demonstrated that, for instance, the calcium channel blocker nilvadipine has no beneficial effects in a clinical trial against treating AD [62]. On the other hand, statins’ potential therapeutic effect against Alzheimer seems controversial. Simvastatin has been shown to improve memory deficits only at higher doses (80 mg/daily for 18 months) in small groups of patients (50+) [63]; lower doses in larger groups, even though they were efficient in lowering lipid levels, did not ameliorate memory performance [64]. Another statin has been evaluated, artovastatin. In an 18 months clinical trial in dyslipidemic patients, although artovastatin effectively corrected dyslipidemia and inflammatory markers, cognitive function was not evaluated in the study [65]; furthermore, a randomized clinical trial demonstrated no beneficial effects of artovastatin treatment on AD patients’ symptoms [66]. These data conclude that although there is a promising therapeutic evidence in correcting dyslipidemia with statins treatment in AD, more studies are needed to establish their therapeutic applications in AD patients.
Taken together, all the clinical data presented in this section (Table 2) suggest that targeting insulin resistance is a promising strategy to fight AD; however, longer longitudinal studies and larger cohort studies with stratified patients will provide a better profile of successful treatment.

4. Nutraceuticals as a Treatment of AD

In the last years, several molecules isolated from plants, also known as nutraceuticals, have been proposed as useful tools for ameliorating cognitive functions and reducing neuroinflammation in animal models of AD.
Because of its anti-oxidant and anti-inflammatory properties, polyphenol compounds belong to the most investigated nutraceuticals to treat human pathologies. Among them, curcumin (the active component of Curcuma longa, or turmeric) is traditionally prescribed in Ayruvedic medicine [68], given its remarkably anti-inflammatory effect [69,70,71]. Despite the preclinical studies providing promising results, there is still no clear evidence of its application to AD patients. One study showed improvement in cognitive function when administered to older population compared to control group [72]. However, when it was tested in a clinical trial with AD patients, the study could not evaluate its efficacy, since the control group did not show a decline in cognitive function during the time of the study [73]. Thus, further testing needs to be carried out before concluding the beneficial effect of curcumin on human AD patients.
Resveratrol (RV), a polyphenol no flavonoid found in fruits, including nuts, berries and grape skin, is a Sirtuin activator, stimulates cell survival and prevents apoptosis, neuroinflammation and oxidative stress [74,75]. In clinical studies, RV administration (up to 1 g/twice day orally for 52 weeks to 119 patients diagnosed with mild to moderate AD), was found to reduce CSF and plasma inflammatory markers and Aβ42, together with a reduced decline in mini-mental status examination (MMSE), and ADCS-ADL scores [76,77]. Hence, RV based therapy holds a very promising strategy to treat AD symptoms.
Other polyphenols have also been shown to obtain promising results in preclinical models of AD. Among them: Epigallocatechin gallate (EGCG) (green tea) is an α-secretase activity inhibitor [78,79]; Ferulic acid, found in grains, fruits, and vegetables, has been tested alone [80] or in combination with EGCC [81]; Silibinin (herb milk thistle; Silybum marianum) [82]; Apigenin, found in vegetables, fruits, herbs and plant-based beverages [83,84]; Puerarin, a Chinese herbal medicine [85,86]. Nevertheless, to our knowledge, in spite of the therapeutic potential of these compounds, they have not been tested in human patients.
Polyunsaturated fatty acids (PUFAs) (contained in blue fish and vegetables such as corn, soybeans, sunflowers, pumpkins, walnuts and others) have been postulated to have a protective role against dementia [87,88]. In contrast to PUFAs, Palmitoylethanolamide (PEA), a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, exacerbates oxidative stress and amyloid burden in AD mouse models [89,90]. However, despite the promising results in preclinical models, the multidomain clinical trial MAPT study showed that PUFA supplementation had no significant effects on cognitive decline over three years in elderly people with memory complaints [91]. Another nutraceutical commonly used as a herbal medicine and food supplement given its anti-inflammatory properties is ginsenoside (ginseng saponin) [92]. Ginsenosides are amphipathic compounds, acting as partial agonists of steroid hormone receptors, regulating metabolism and inflammation [93]. In a pilot study with 40 patients diagnosed with moderate AD, Ginseng administration (1.5–4 g/day) for 12 to 24 weeks was reported to improve cognitive function [94]. Lycopene (carotene, a pigment of red and pink fruits) has anti-inflammatory, neuroprotective and antioxidant properties, in a preclinical mouse model of AD [95]. Interestingly, their levels, together with another antioxidant molecule, were found to be reduced in demented patient’s plasma levels [96]. It is, thus, accepted that the reduction of these protective factors contributes to the disease.
Other phytohormones, such as Abscisic acid (ABA), has been demonstrated to have antiglucemic effects in patients with type 2 diabetes [97]. ABA has been shown to have neuroprotective properties through its interaction with Lanthionine synthetase C-like protein 2 (LANC-2) [98] and PPAR-γ [99,100]. In addition, we have demonstrated that ABA can improve memory in an animal model of AD, reducing neuroinflammatory markers and restoring insulin-mediating molecule expression [101,102,103]. To our knowledge, ABA has not yet been tested in clinical trials.
In summary, there is a large amount of evidence indicating that nutrition and/or supplementation with nutraceuticals with anti-diabetic and anti-inflammatory properties might be a good option to avoid AD progression (see Table 3). However, longer studies with stratified human patients must be conducted to establish the therapeutic application.

5. Targeting the Endocannabinoid System in Preclinical Models of AD

The endocannabinoid system (ECS) is a lipid-based signaling mechanism involved in the control of neuronal and brain immune function, acting as a natural defense mechanism against pathological conditions [104]. The ECS has gained attention in AD research based on reports over the last two decades demonstrating the potential of cannabinoids to target Aβ and Tau metabolism, inflammation, mitochondrial dysfunction and excitotoxicity [105].
The ECS is composed of the G-protein-coupled cannabinoid 1 and 2 receptors (CB1 and CB2, respectively), their respective endogenous ligands N-arachidonil-ethanolamine (AEA) and 2-arachidonilglycerol (2-AG), the ligand synthesizing enzymes N-acyl-phosphatidylethanolamine (NAPE) for AEA, and 1,2-diacylglycerol lipase α (DAGLα) for 2-AG and the ligand degrading enzymes fatty acid amide hydrolase (FAAH) for AEA and monoacylglycerol lipase (MAGL) for 2-AG [106,107].
CB1 receptors are highly expressed in the central nervous system (CNS). Data regarding the participation of the CB1 in AD are somewhat conflicting [108]. Either a reduction in the number of CB1, particularly in the frontal cortex, or no changes have been reported in AD patients [109]. In contrast, cerebral CB2 expression is sparse under normal conditions, but after specific insults (i.e., neuroinflammation), its expression augments in neurons, M1 pro-inflammatory microglia and astrocytes. CB2 cannot be detected in resting microglia, the so-called M2 phenotype [110], and the CB2 activity in M1 is postulated to facilitate M1 switch into M2 phenotype, thus initiating the anti-inflammatory and immunosuppressive responses [111]. In humans, brains from patients with AD revealed that CB2 is selectively overexpressed in cells associated to Aβ-enriched neuritic plaques and correlating with the concentrations of Aβ [112,113,114]. Activation of CB2 facilitates the removal of Aβ from frozen tissue sections of patients with AD [113]. These and other studies suggest that aiding the CB2 receptor activity could have a therapeutic potential in AD (see Figure 3).
In agreement with this hypothesis, selective synthetic CB2 agonists (JWH-15, JWH-133 and HU-308) can reduce pro-inflammatory cytokines in rodent models of AD [110,115,116]. Similar results are found with JZL184, a synthetic inhibitor of MAGL (the degrading enzyme of the CB2 ligand 2-AG) in a mouse model of AD [117].
The major natural exogenous cannabinoids are delta-9-THC (THC) and cannabidiol (CBD), mainly found in the plant Cannabis sativa. The THC is agonist of CB1, and has psychotropic effects, in AD patients, THC has been evaluated to treat neuropsychiatric symptoms in a randomized trial, 24 subjects were administered THC (1.5 mg/three times day) for three weeks. Although well tolerated, it had no effect on Neuropsychiatric Inventory (NPI). The authors conclude that longer treatment and well-tolerated higher doses may offer better results [67]. In contrast to THC, CBD is a non-psychoactive cannabinoid. In cellular studies, CBD reduced Aβ production and improved cell viability by inducing APP ubiquitination [118,119]. In rodent models of AD, CBD administration reduced Tau hyperphosphorylation, and significantly attenuate neuroinflammation, improving cognitive function [120,121]. Although, to our knowledge, the potential therapeutic effect of CB2 have not yet been tested in AD patients, this is now considered a promising therapeutic target in AD, given their participation in inflammatory regulation and also given the crosstalk between acetylcholine transmission and endocannabinoid function that has been revealed recently [122].

6. Gut Microbiota, Neuroinflammation and AD

The microbiota of the gastrointestinal tract is becoming increasingly relevant in the study of neuroinflammatory diseases, such as AD. The gut microbiota (GM) is composed of a complex ecosystem where mainly bacteria, but also fungi, archaea and viruses, reside in a symbiotic balance. The main phyla of bacteria encountered in healthy human GM are Firmicutes and Bacteroidetes (90%), and the remaining 10% contains Actinobacteria, Proteobacteria, Fusobacteria and Verrucomicrobia [123,124]. However, the composition of the microbiota varies intra-individually depending on the enterotype, body mass index, lifestyle, exercise frequency, ethnicity, age, diet and cultural habits [125].
A growing body of evidence supports that the GM maintains a close relationship with the activity of the CNS, though the microbiota-gut-brain axis. This bidirectional communication system connects the GM and CNS via the neural, immune, metabolic and endocrine pathways. The brain can influence the GM through the autonomic nervous system (noradrenaline and acetylcholine) and the hypothalamic-pituitary-adrenal axis (cortisol), controlling intestinal motility, acid and bicarbonate production, intestinal permeability and mucosal immune response. The autonomic system is in close contract with the enteric nervous system [126], which synthesizes a great number of neurotransmitters; in fact, many authors refer to GM as “The second brain” (for a review, see [127,128]). The immune and enterochromaffin cells also modulate the GM though other signaling molecules [129,130]. The alteration of these parameters can lead to changes in the composition of GM [129,130].
In turn, the metabolites and neurotransmitters (short-chain fatty acids, catecholamines, norepinephrine, 5-HT, GABA and acetylcholine and histamine, dynorphin and cytokines) synthesized in the GM can regulate CNS activity. Moreover, GM have been shown to influence the maturation, differentiation and activation of the brain immune system [131,132]. Furthermore, GM activity can also influence the blood brain barrier (BBB) permeability [133,134].
A very recent line of research postulates that the GM, by influencing the brain neuroinflammatory status, could participate in the pathogenesis of several neurodegenerative diseases, such as AD. Thus, the dysbiosis of the GM has been associated with the onset and progression of AD, in both animal models and human patients [132,135,136]. In general, in the microbiota of AD patients, the concentrations of Firmicutes and Actinobacteria are reduced, and the levels of Bacteroidetes are increased, compared to healthy subjects [137]. Bacteroidetes are gram-negative bacteria that generate lipopolysaccharides (LPS), and several species of bacteria such as Escherichia Coli, Salmonella enterica, Salmonella typhimurium, Bacillus subtilis, Mycobacterium tuberculosis and Staphylococcus aureus, which produce amyloid peptides in the gut [138]. The dysbiosis of the GM leads to an overproduction of LPS and amyloids in the gut that causes an increased permeability of both the intestinal and BBB [139]. In addition, LPS and amyloid peptides stimulate the epithelium immune cells triggering the innate immune response [140]. As a result, GM dysbiosis facilitates the penetration of pro-inflammatory molecules across the epithelium barrier into the bloodstream, from where they can reach the CNS, thereby contributing to the chronic neuroinflammation state [141,142].
Furthermore, higher levels of LPS have been found surrounding β-amyloid plaques in the brains of AD patients compared to healthy individuals [143].
It is well known that the food habits are a determining factor in the composition of the microbiota. Thus, the consumption of a varied diet rich in fiber, such as a Mediterranean diet (MD), has been shown to maintain the balance and diversity within the intestinal microbiome. A recent study in mice reveals that the administration of an MD to obese mice prevents GM dysbiosis, preserved colonic mucus barrier and reduced systemic and neuroinflammation, improving synaptic plasticity and cognitive function [144]. Moreover, in humans, adhering to an MD confers anti-inflammatory and positive regulatory properties to the microbiota and ameliorates its metabolic profile [145]. Importantly, an MD decreases the expression of some AD’s biomarkers (Tau-p181 and Aβ42) in the CSF of subjects with MCI [146]. Hence, maintaining a healthy microbiota by the habitual ingestion of a fiber-rich diet prevents neuroinflammation. Therefore, it is postulated that a healthy nutrition would ameliorate AD’s symptoms and possibly prevent AD progression. According to these premises, MD as an intervention strategy against AD has been tested in a six-year clinical trial with over 500 patients, aged 55–80. Although in this study no neuroinflammatory markers were found, the results in memory tasks were very promising [147].
The administration of probiotics and prebiotics has been propounded as another possible treatment to restore altered GM in AD patients. Probiotics are commonly bacteria, such as Lactobacillus and Bifidobacterium, that help fiber digestion, produce vitamins and contribute to a healthy immune system activity [148]. Several reports show that the oral ingestion of different probiotics reduces the content of pro-inflammatory cytokines in the brain and Aβ load, and improves cognitive function in murine models of AD [149,150]. In humans, a randomized double-blind placebo-controlled trial demonstrated that probiotic Bifidobacterium breve A1 intake decreases memory disturbances in elderly people with memory complaints but not dementia [151].
Prebiotics are also food components that improve the balance of healthy bacteria. Similar to probiotics, distinct rodent models of AD treated with prebiotics (such as fructo-oligosaccharides and inulin) exhibit a GM amelioration, concomitant with a decrease in Aβ deposition, neurodegeneration and oxidative stress and an improvement in neurotransmitter secretion and cognitive abilities [152,153,154]. It is important to remark that the therapeutic effects derived from the modulation of the microbiota by the administration of pro- and prebiotics in AD from all these studies have been linked to a reduction in neuroinflammation.
Another strategy to reverse microbiota dysbiosis in AD is fecal microbiota transplant (FMT). In animal models, two studies have reported that FMT from WT to transgenic mice, recovers GM dysbiosis, while reducing neuroinflammation and enhancing synaptic plasticity together with a decrease in cognitive deficits, in an APP/PSEN mice model [155] and in an ADLPAPT mice model [156].
Overall, alterations in the GM are beginning to be considered as a pathophysiological mechanism in AD. GM dysbiosis heightens the permeability of the intestinal epithelial barrier and the BBB, and consequently increases the neuroinflammatory state of the organism, thereby aggravating the symptomatology of AD. In fact, some authors point out that GM dysfunction should be one of the main origins of the pathology. In this way, the restoration and maintenance of a healthy microbiota could play a key role in the prevention and treatment of AD (see Table 4). Although specific trials evaluating GM in AD have not yet been published, it is safe to assume that the consumption of a balanced diet high in fiber and low in fat and the use of pro/prebiotics will contribute to reduce neuroinflammation in AD, and therefore, aid in ameliorating its neurological and neuropsychiatric symptoms.

7. Conclusions

Neuroinflammation and insulin resistance are considered major neuropathological events underlying the onset and progression of AD; therefore, multiple strategies that target these processes have been developed to effectively treat this disease. In the current review, we have revised some of the latest preclinical and clinical studies targeting inflammation in AD, either directly with anti-inflammatory drugs or indirectly, improving insulin signaling.
A recent metanalysis has reviewed the results of dietary supplementation in clinical trials against AD. The results indicate that there may be an improvement in cognitive function in AD, particularly in early stages, but indicate that the effect of most dietary interventions on cognition in AD patients remains inconclusive [157]. Finally, a multidomain intervention with exercise and diet are the main strategies that showed very promising results in preventing cognitive decline in 2654 people at risk [158] (see Table 5). Again, it is not known whether this outcome would be obtained in already-diagnosed AD patients. Taking together all clinical studies revised, we conclude that strategies targeting neuroinflammation together with insulin resistance have, finally, demonstrated to be a promising therapeutic potential in AD, especially at early stages. However, many molecules have produced inconclusive results, and other methods, such as promoting neuroprotection via CB2 boosting or restoring GM, are still at the preclinical stage. In addition, patient’s stratification seems to be crucial to determine best treatment. The definite cure for AD does not exist yet; however, targeting neuroinflammation may be a path worth pursuing.

Author Contributions

S.S.-S., I.F.-P. and V.E.-F. wrote different chapters. J.C.L. and A.M.S.-P. designed and corrected the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This work has been funded by Plan Propi UJI-B2018-01 to AMSP. Predoctoral fellowship from Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital ACIF/2016/250 to SSS.

Conflicts of Interest

Authors disclose no conflict of interest.

Abbreviations

2-AG2-arachidonilglycerol
5-HT5-hydroxytryptamine (serotonin)
AβAmyloid beta
ABAAbscisic acid
ADAlzheimer’s disease
ADAS-CogAlzheimer disease assessment scale–cognitive
ADAPTAlzheimer’s disease anti-inflammatory prevention trial
ADCS-ADLAlzheimer’s disease cooperative study-activities of daily living
AEAN-arachidonil-ethanolamine
AMPKAdenosine monophosphate-activated protein kinase
APPAmyloid protein precursor
APSAlzheimer progression score
AVLAuditory Verbal Learning Test
BACE1β-site APP-cleaving enzyme 1 secretase
BADLSBristol Activities of Daily Living Scale;
BBBBlood brain barrier
BDNFBrain-derived neurotrophic factor
CB1G-protein-coupled cannabinoid 1 receptor
CB2G-protein-coupled cannabinoid 2 receptor
CBDCannabidiol
CCRCambridge Contextual Reading Test
CD68Cluster of Differentiation 68
CDTClock Drawing Test
CGI-IClinical Global Impression-improvement
CNCategory naming test
CNSCentral nervous system
COXCyclooxygenase
COWAControlled Oral Word Association Test
CSFCerebrospinal fluid
DAGLαDiacylglycerol Lipase alpha
DAMPsDamage-associated molecular patterns
DMSDelayed Matching to Sample
DSSDigit Symbol Substitution
ECSEndocannabinoid system
EGCGEpigallocatechin gallate
FAAHFatty acid amide hydrolase
FMTFecal microbiota transplant
GABAGamma-aminobutyric acid
GMGut microbiota
IFN-γInterferon gamma
IL-1βInterleukin 1 beta
INIntranasal
IRS1Insulin receptor substate 1
LanCL2Lanthionine synthetase C-like protein 2
LDLLow density lipoprotein
LPSLipopolysaccharides
MAGLMonoacylglycerol lipase
MAPTMultiDomain Alzheimer preventive trial
MCIMild cognitive impairment
MDMediterranean diet
MMSEMini-mental state examination
MoCAMontreal Cognitive Assessment
mTORMammalian target of rapamycin
NAPEN-acyl-phosphatidylethanolamine
NTBNeuropsychological Test Battery
NTBNeuropsychological Test Battery NFTs Neurofibrillary tangles
NGFNerve growth factor
NLRNOD-like receptors
NLRP3NLR family pyrin domain containing 3
NPINeuropsychiatric Inventory
NSAIDsNon-steroidal anti-inflammatory drugs
p70S6Kp70 ribosomal S6 kinase
PALPaired associate learning scale
PAMPsPathogen-associated molecular patterns
PEAPalmitoylethanolamide
PGProstaglandin
PPAR-αPeroxisome proliferator-activated receptor alpha
PRRsPattern recognition receptors
PUFAsPolyunsaturated fatty acids
RANTESRegulated on Activation, Normal T cell Expressed and Secreted
RBANSRepeatable Battery for the Assessment of Neuropsychological Status
RVResveratrol
SMMSEStandardized mini-mental state examination
T2DMType 2 diabetes mellitus
TGF-βTransforming growth factor beta
THCTetrahidrocannabinol
TLRsToll-like receptors
TNF-αTumor necrosis factor alpha
WAIS-RWechsler Adults Intelligence Scale
WMS-RWechsler Memory Scale
WTWild-type

References

  1. Alzheimer’s Association. 2018 Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2018, 14, 367–429. [Google Scholar] [CrossRef]
  2. Rubio-Perez, J.M.; Morillas-Ruiz, J.M. A Review: Inflammatory process in Alzheimer’s disease, role of cytokines. Sci. World J. 2012, 2012, 1–15. [Google Scholar] [CrossRef] [PubMed]
  3. Calsolaro, V.; Edison, P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimer’s Dement. 2016, 12, 719–732. [Google Scholar] [CrossRef] [PubMed]
  4. Szabo, L.; Eckert, A.; Grimm, A. Insights into disease-associated tau impact on mitochondria. Int. J. Mol. Sci. 2020, 21, 6344. [Google Scholar] [CrossRef] [PubMed]
  5. Vogel, J.W.; Initiative, A.D.N.; Iturria-Medina, Y.; Strandberg, O.T.; Smith, R.; Levitis, E.; Evans, A.C.; Hansson, O.; The Swedish BioFINDER Study. Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease. Nat. Commun. 2020, 11, 1–15. [Google Scholar] [CrossRef]
  6. Kayed, R.; Lasagna-Reeves, C.A. Molecular mechanisms of amyloid oligomers toxicity. J. Alzheimer’s Dis. 2012, 33, S67–S78. [Google Scholar] [CrossRef] [Green Version]
  7. Haass, C.; Kaether, C.; Thinakaran, G.; Sisodia, S.S. Trafficking and proteolytic processing of APP. Cold Spring Harb. Perspect. Med. 2012, 2, a006270. [Google Scholar] [CrossRef]
  8. Lee, C.Y.D.; Landreth, G.E. The role of microglia in amyloid clearance from the AD brain. J. Neural Transm. 2010, 117, 949–960. [Google Scholar] [CrossRef] [Green Version]
  9. Birla, H.; Minocha, T.; Kumar, G.; Misra, A.; Singh, S.K. Role of oxidative stress and metal toxicity in the progression of Alzheimer’s disease. Curr. Neuropharmacol. 2020, 18, 552–562. [Google Scholar] [CrossRef]
  10. Zhao, Y.; Zhao, B. Oxidative stress and the pathogenesis of Alzheimer’s disease. PubMed. Oxid. Med. Cell. Longev. 2013, 2013, 1–10. [Google Scholar] [CrossRef] [Green Version]
  11. Skaper, S.D. Alzheimer’s disease and amyloid: Culprit or coincidence? Int. Rev. Neurobiol. 2012, 102, 277–316. [Google Scholar] [CrossRef] [PubMed]
  12. Lee, K.S.; Chung, J.H.; Choi, T.K.; Suh, S.Y.; Oh, B.H.; Hong, C.H. Peripheral cytokines and chemokines in Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 2009, 28, 281–287. [Google Scholar] [CrossRef] [PubMed]
  13. DaRocha-Souto, B.; Scotton, T.C.; Coma, M.; Serrano-Pozo, A.; Hashimoto, T.; Serenó, L.; Rodríguez, M.; Sánchez, B.; Hyman, B.T.; Gómez-Isla, T. Brain oligomeric β-amyloid but not total amyloid plaque burden correlates with neuronal loss and astrocyte inflammatory response in amyloid precursor protein/tau transgenic mice. J. Neuropathol. Exp. Neurol. 2011, 70, 360–376. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Pereira, C.F.; Santos, A.E.; Moreira, P.I.; Pereira, A.C.; Sousa, F.J.; Cardoso, S.M.; Cruz, M.T. Is Alzheimer’s disease an inflammasomopathy? Ageing Res. Rev. 2019, 56, 100966. [Google Scholar] [CrossRef]
  15. Tarkowski, E.; Andreasen, N.; Blennow, K. Intrathecal inflammation precedes development of Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 2003, 74, 1200–1205. [Google Scholar] [CrossRef]
  16. Ransohoff, R.M.; Brown, M.A. Innate immunity in the central nervous system. J. Clin. Investig. 2012, 122, 1164–1171. [Google Scholar] [CrossRef]
  17. Nimmerjahn, A.; Kirchhoff, F.; Helmchen, F. Neuroscience: Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005, 308, 1314–1318. [Google Scholar] [CrossRef] [Green Version]
  18. Sharma, D.; Kanneganti, T.-D. The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation. J. Cell Biol. 2016, 213, 617–629. [Google Scholar] [CrossRef] [Green Version]
  19. Anwar, M.A.; Shah, M.; Kim, J.; Choi, S. Recent clinical trends in Toll-like receptor targeting therapeutics. Med. Res. Rev. 2019, 39, 1053–1090. [Google Scholar] [CrossRef] [Green Version]
  20. Albornoz, E.A.; Woodruff, T.M.; Gordon, R. Inflammasomes in CNS Diseases. Experientia Supplementum 2018, 108, 41–60. [Google Scholar] [CrossRef]
  21. Bagyinszky, E.; Van Giau, V.; Shim, K.; Suk, K.; An, S.S.A.; Kim, S. Role of inflammatory molecules in the Alzheimer’s disease progression and diagnosis. J. Neurol. Sci. 2017, 376, 242–254. [Google Scholar] [CrossRef] [PubMed]
  22. Obulesu, M.; Lakshmi, M.J. Neuroinflammation in Alzheimer’s disease: An understanding of physiology and pathology. Int. J. Neurosci. 2013, 124, 227–235. [Google Scholar] [CrossRef] [PubMed]
  23. Tournier, B.B.; Tsartsalis, S.; Ceyzériat, K.; Valentina, G.; Millet, P. In vivo TSPO signal and neuroinflammation in Alzheimer’s disease. Cells 2020, 9, 1941. [Google Scholar] [CrossRef] [PubMed]
  24. Meda, L.; Cassatella, M.A.; Szendrei, G.I.; Otvos, L.; Baron, P.; Villalba, M.; Ferrari, D.; Rossi, F. Activation of microglial cells by β-amyloid protein and interferon-γ. Nat. Cell Biol. 1995, 374, 647–650. [Google Scholar] [CrossRef] [PubMed]
  25. Perea, J.R.; Bolós, M.; Avila, J. Microglia in Alzheimer’s disease in the context of Tau pathology. Biomolecules 2020, 10, 1439. [Google Scholar] [CrossRef]
  26. François, A.; Bilan, A.R.; Quellard, N.; Fernandez, B.; Janet, T.; Chassaing, D.; Paccalin, M.; Terro, F.; Page, G. Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice. J. Neuroinflamm. 2014, 11, 1–14. [Google Scholar] [CrossRef] [Green Version]
  27. Heneka, M.T.; Kummer, M.P.; Stutz, A.; Delekate, A.; Schwartz, S.; Vieira-Saecker, A.; Griep, A.; Axt, D.; Remus, A.; Tzeng, T.-C.; et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nat. Cell Biol. 2013, 493, 674–678. [Google Scholar] [CrossRef]
  28. Hanslik, K.L.; Ulland, T.K. The Role of microglia and the Nlrp3 inflammasome in Alzheimer’s disease. Front. Neurol. 2020, 11, 11. [Google Scholar] [CrossRef]
  29. Feng, Y.-S.; Tan, Z.-X.; Wu, L.-Y.; Dong, F.; Zhang, F. The involvement of NLRP3 inflammasome in the treatment of Alzheimer’s disease. Ageing Res. Rev. 2020, 101192. [Google Scholar] [CrossRef]
  30. Clement, A.; Wiborg, O.; Asuni, A.A. Steps towards developing effective treatments for neuropsychiatric disturbances in Alzheimer’s disease: Insights from preclinical models, clinical data, and future directions. Front. Aging Neurosci. 2020, 12, 56. [Google Scholar] [CrossRef]
  31. McGeer, P.L.; Rogers, J.; McGeer, E.G. Inflammation, antiinflammatory agents, and Alzheimer’s disease: The last 22 years. J. Alzheimer’s Dis. 2016, 54, 853–857. [Google Scholar] [CrossRef] [PubMed]
  32. Pasinetti, G.M. From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer’s disease: The role of NSAIDs and cyclooxygenase in β-amyloidosis and clinical dementia1. J. Alzheimer’s Dis. 2002, 4, 435–445. [Google Scholar] [CrossRef] [PubMed]
  33. Ricciotti, E.; Fitzgerald, G.A. Prostaglandins and inflammation. Arterioscler. Thromb. Vasc. Biol. 2011, 31, 986–1000. [Google Scholar] [CrossRef] [PubMed]
  34. Breitner, J.; Meyer, P.-F. Author response: INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease. Neurology 2020, 94, 594. [Google Scholar] [CrossRef] [PubMed]
  35. Breitner, J.; Baker, L.; Drye, L.; Evans, D.; Lyketsos, C.G.; Ryan, L.; Zandi, P.; Saucedo, H.H.; Anau, J.; Cholerton, B. Follow-up evaluation of cognitive function in the randomized Alzheimer’s disease anti-inflammatory prevention trial and its follow-up study. Alzheimer’s Dement. 2015, 11, 216–225. [Google Scholar]
  36. Butchart, J.; Brook, L.; Hopkins, V.; Teeling, J.L.; Püntener, U.; Culliford, D.; Sharples, R.; Sharif, S.; McFarlane, B.; Raybould, R.; et al. Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. Neurology 2015, 84, 2161–2168. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Najem, D.; Bamji-Mirza, M.; Chang, N.; Liu, Q.Y.; Zhang, W. Insulin resistance, neuroinflammation, and Alzheimer’s disease. Rev. Neurosci. 2014, 25, 509–525. [Google Scholar] [CrossRef]
  38. Kandimalla, R.; Thirumala, V.; Reddy, P.H. Is Alzheimer’s disease a type 3 diabetes? A critical appraisal. Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 2017, 1863, 1078–1089. [Google Scholar] [CrossRef]
  39. Chen, L.; Chen, R.; Wang, H.; Liang, F. Mechanisms linking inflammation to insulin resistance. Int. J. Endocrinol. 2015, 2015, 1–9. [Google Scholar] [CrossRef]
  40. De La Monte, S.M. Brain insulin resistance and deficiency as therapeutic targets in Alzheimers disease. Curr. Alzheimer Res. 2012, 9, 35–66. [Google Scholar] [CrossRef]
  41. Cukierman, T.; Gerstein, H.C.; Williamson, J.D. Cognitive decline and dementia in diabetes-systematic overview of prospective observational studies. Diabetologia 2005, 48, 2460–2469. [Google Scholar] [CrossRef] [PubMed]
  42. Avgerinos, K.I.; Kalaitzidis, G.; Malli, A.; Kalaitzoglou, D.; Myserlis, P.G.; Lioutas, V.-A. Intranasal insulin in Alzheimer’s dementia or mild cognitive impairment: A systematic review. J. Neurol. 2018, 265, 1497–1510. [Google Scholar] [CrossRef] [PubMed]
  43. Salminen, A.; Kaarniranta, K.; Haapasalo, A.; Soininen, H.; Hiltunen, M. AMP-activated protein kinase: A potential player in Alzheimer’s disease. J. Neurochem. 2011, 118, 460–474. [Google Scholar] [CrossRef] [PubMed]
  44. Hartley, D.; Cooper, G.M. Role of mTOR in the degradation of IRS-1: Regulation of PP2A activity. J. Cell. Biochem. 2002, 85, 304–314. [Google Scholar] [CrossRef] [PubMed]
  45. Yoneyama, Y.; Inamitsu, T.; Chida, K.; Iemura, S.-I.; Natsume, T.; Maeda, T.; Hakuno, F.; Takahashi, S.-I. Serine phosphorylation by mTORC1 promotes IRS-1 degradation through SCFβ-TRCP E3 ubiquitin ligase. iScience 2018, 5, 1–18. [Google Scholar] [CrossRef] [PubMed]
  46. Koenig, A.M.; Mechanic-Hamilton, D.; Xie, S.X.; Combs, M.F.; Cappola, A.R.; Xie, L.; Detre, J.A.; Wolk, D.A.; Arnold, S.E. Effects of the insulin sensitizer metformin in Alzheimer disease. Alzheimer Dis. Assoc. Disord. 2017, 31, 107–113. [Google Scholar] [CrossRef]
  47. Fernández-Real, J.M.; García-Fuentes, E.; Moreno-Navarrete, J.M.; Murri-Pierri, M.; Garrido-Sánchez, L.; Ricart, W.; Tinahones, F. Fat overload induces changes in circulating lactoferrin that are associated with postprandial lipemia and oxidative stress in severely obese subjects. Obesity 2010, 18, 482–488. [Google Scholar] [CrossRef]
  48. Artym, J. A remedy against obesity? The role of lactoferrin in the metabolism of glucose and lipids. Postęp. Higien. Med. Dośw. 2012, 66, 937–953. [Google Scholar] [CrossRef]
  49. Brizzio, E.; Castro, M.; Narbaitz, M.; Borda, N.; Carbia, C.D.; Correa, L.; Mengarelli, R.; Merelli, A.; Brizzio, V.; Sosa, M.; et al. Ulcerated hemosiderinic dyschromia and iron deposits within lower limbs treated with a topical application of biological chelator. Veins Lymphat. 2012, 1, e6. [Google Scholar] [CrossRef]
  50. Mohamed, W.A.; Salama, R.M.; Schaalan, M.F. A pilot study on the effect of lactoferrin on Alzheimer’s disease pathological sequelae: Impact of the p-Akt/PTEN pathway. Biomed. Pharmacother. 2019, 111, 714–723. [Google Scholar] [CrossRef]
  51. Manzanares, W.; Hardy, G. Vitamin B12: The forgotten micronutrient for critical care. Curr. Opin. Clin. Nutr. Metab. Care 2010, 13, 662–668. [Google Scholar] [CrossRef] [PubMed]
  52. Kouroglou, E.; Anagnostis, P.; Daponte, A.; Bargiota, A. Vitamin B12 insufficiency is associated with increased risk of gestational diabetes mellitus: A systematic review and meta-analysis. Endocrine 2019, 66, 149–156. [Google Scholar] [CrossRef] [PubMed]
  53. Li, Z.; Gueant-Rodriguez, R.-M.; Quilliot, D.; Sirveaux, M.-A.; Meyre, D.; Gueant, J.-L.; Brunaud, L. Folate and vitamin B12 status is associated with insulin resistance and metabolic syndrome in morbid obesity. Clin. Nutr. 2018, 37, 1700–1706. [Google Scholar] [CrossRef] [PubMed]
  54. Ma, F.; Zhou, X.; Li, Q.; Zhao, J.; Song, A.; An, P.; Du, Y.; Xu, W.; Huang, G. Effects of folic acid and vitamin B12, alone and in combination on cognitive function and inflammatory factors in the elderly with mild cognitive impairment: A single-blind experimental design. Curr. Alzheimer Res. 2019, 16, 622–632. [Google Scholar] [CrossRef]
  55. Vakilian, A.; Razavi-Nasab, S.M.; Ravari, A.; Mirzaei, T.; Moghadam-Ahmadi, A.; Jalali, N.; Bahramabadi, R.; Rezayati, M.; Yazdanpanah-Ravari, A.; Bahmaniar, F.; et al. Vitamin B12 in association with antipsychotic drugs can modulate the expression of pro-/anti-inflammatory cytokines in Alzheimer disease patients. Neuroimmunomodulation 2018, 24, 310–319. [Google Scholar] [CrossRef]
  56. Bahramabadi, R.; Samadi, M.; Vakilian, A.; Jafari, E.; Fathollahi, M.S.; Arababadi, M.K. Evaluation of the effects of anti-psychotic drugs on the expression of CD68 on the peripheral blood monocytes of Alzheimer patients with psychotic symptoms. Life Sci. 2017, 179, 73–79. [Google Scholar] [CrossRef]
  57. Ramprasad, M.P.; Terpstra, V.; Kondratenko, N.; Quehenberger, O.; Steinberg, D. Cell surface expression of mouse macrosialin and human CD68 and their role as macrophage receptors for oxidized low density lipoprotein. Proc. Natl. Acad. Sci. USA 1996, 93, 14833–14838. [Google Scholar] [CrossRef] [Green Version]
  58. Farah, R.R.; Khamisy-Farah, R.S.-S. Calcium channel blocker effect on insulin resistance and inflammatory markers in essential hypertension patients. PubMed. Int. Angiol. 2013, 32, 85–93. [Google Scholar]
  59. Cabezas-Cerrato, J.; García-Estévez, D.A.; Araújo, D.; Iglesias, M. Insulin sensitivity, glucose effectiveness, and β-cell function in obese males with essential hypertension: Investigation of the effects of treatment with a calcium channel blocker (diltiazem) or an angiotensin-converting enzyme inhibitor (quinapril). Metabolism 1997, 46, 173–178. [Google Scholar] [CrossRef]
  60. Weitz-Schmidt, G. Statins as anti-inflammatory agents. Trends Pharmacol. Sci. 2002, 23, 482–487. [Google Scholar] [CrossRef]
  61. Wang, Q.; Yan, J.; Chen, X.; Li, J.; Yang, Y.; Weng, J.; Deng, C.; Yenari, M.A. Statins: Multiple neuroprotective mechanisms in neurodegenerative diseases. Exp. Neurol. 2011, 230, 27–34. [Google Scholar] [CrossRef] [PubMed]
  62. Lawlor, B.A.; Segurado, R.; Kennelly, S.; Rikkert, M.G.M.O.; Howard, R.; Pasquier, F.; Börjesson-Hanson, A.; Tsolaki, M.; Lucca, U.; Molloy, D.W.; et al. Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. PLoS Med. 2018, 15, e1002660. [Google Scholar] [CrossRef] [PubMed]
  63. Huang, W.; Li, Z.; Zhao, L.; Zhao, W. Simvastatin ameliorate memory deficits and inflammation in clinical and mouse model of Alzheimer’s disease via modulating the expression of miR-106b. Biomed. Pharmacother. 2017, 92, 46–57. [Google Scholar] [CrossRef] [PubMed]
  64. Sano, M.; Bell, K.L.; Galasko, D.; Galvin, J.E.; Thomas, R.G.; Van Dyck, C.H.; Aisen, P.S. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology 2011, 77, 556–563. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Zhao, L.; Zhao, Q.; Zhou, Y.; Zhao, Y.; Wan, Q. Atorvastatin may correct dyslipidemia in adult patients at risk for Alzheimer’s disease through an anti-inflammatory pathway. CNS Neurol. Disord. Drug Targets 2016, 15, 80–85. [Google Scholar] [CrossRef] [PubMed]
  66. Feldman, H.; Doody, R.S.; Kivipelto, M.; Sparks, D.L.; Waters, D.D.; Jones, R.W.; Schwam, E.; Schindler, R.; Hey-Hadavi, J.; Demicco, D.A.; et al. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 2010, 74, 956–964. [Google Scholar] [CrossRef]
  67. Elsen, G.V.D.; Ahmed, A.I.; Verkes, R.-J.; Kramers, C.; Feuth, T.; Rosenberg, P.B.; Van Der Marck, M.A.; Rikkert, M.G.O. Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: A randomized controlled trial. Neurology 2015, 84, 2338–2346. [Google Scholar] [CrossRef] [Green Version]
  68. Gera, M.; Sharma, N.; Ghosh, M.; Huynh, D.L.; Lee, S.J.; Min, T.; Kwon, T.; Jeong, D.K. Nanoformulations of curcumin: An emerging paradigm for improved remedial application. Oncotarget 2017, 8, 66680–66698. [Google Scholar] [CrossRef] [Green Version]
  69. Fidelis, E.M.; Savall, A.S.P.; Abreu, E.D.L.; Carvalho, F.; Teixeira, F.E.G.; Haas, S.E.; Sampaio, T.B.; Pinton, S. Curcumin-loaded nanocapsules reverses the depressant-like behavior and oxidative stress induced by β-amyloid in mice. Neuroscience 2019, 423, 122–130. [Google Scholar] [CrossRef]
  70. Teter, B.; Morihara, T.; Lim, G.; Chu, T.; Jones, M.; Zuo, X.; Paul, R.; Frautschy, S.A.; Cole, G.M. Curcumin restores innate immune Alzheimer’s disease risk gene expression to ameliorate Alzheimer pathogenesis. Neurobiol. Dis. 2019, 127, 432–448. [Google Scholar] [CrossRef]
  71. Panahi, Y.; Hosseini, M.S.; Khalili, N.; Naimi, E.; Simental-Mendía, L.E.; Majeed, M.; Sahebkar, A. Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: A post-hoc analysis of a randomized controlled trial. Biomed. Pharmacother. 2016, 82, 578–582. [Google Scholar] [CrossRef] [PubMed]
  72. Rainey-Smith, S.R.; Brown, B.M.; Sohrabi, H.R.; Shah, T.; Goozee, K.G.; Gupta, V.B.; Martins, R.N. Curcumin and cognition: A randomised, placebo-controlled, double-blind study of community-dwelling older adults. Br. J. Nutr. 2016, 115, 2106–2113. [Google Scholar] [CrossRef] [PubMed]
  73. Baum, L.; Lam, C.W.K.; Cheung, S.K.-K.; Kwok, T.; Lui, V.; Tsoh, J.; Lam, L.; Leung, V.; Hui, E.; Ng, C.; et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J. Clin. Psychopharmacol. 2008, 28, 110–113. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Bastianetto, S.; Ménard, C.; Quirion, R. Neuroprotective action of resveratrol. Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 2015, 1852, 1195–1201. [Google Scholar] [CrossRef] [Green Version]
  75. Baur, J.A.; Sinclair, D.A. Therapeutic potential of resveratrol: The in vivo evidence. Nat. Rev. Drug Discov. 2006, 5, 493–506. [Google Scholar] [CrossRef]
  76. Moussa, C.; Hebron, M.; Huang, X.; Ahn, J.; Rissman, R.A.; Aisen, P.S.; Turner, R.S. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. J. Neuroinflamm. 2017, 14, 1–10. [Google Scholar] [CrossRef] [Green Version]
  77. Turner, R.S.; Thomas, R.G.; Craft, S.; Van Dyck, C.H.; Mintzer, J.; Reynolds, B.A.; Brewer, J.B.; Rissman, R.A.; Raman, R.; Aisen, P.S.; et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology 2015, 85, 1383–1391. [Google Scholar] [CrossRef]
  78. Lee, J.W.; Lee, Y.K.; Ban, J.O.; Ha, T.Y.; Yun, Y.P.; Han, S.-B.; Oh, K.W.; Hong, J.T. Green tea (-)-epigallocatechin-3-gallate inhibits β-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-κB pathways in mice. J. Nutr. 2009, 139, 1987–1993. [Google Scholar] [CrossRef]
  79. Cascella, M.; Bimonte, S.; Muzio, M.R.; Schiavone, V.; Cuomo, A. The efficacy of Epigallocatechin-3-gallate (green tea) in the treatment of Alzheimer’s disease: An overview of pre-clinical studies and translational perspectives in clinical practice. Infect. Agents Cancer 2017, 12, 1–7. [Google Scholar] [CrossRef]
  80. Mori, T.; Koyama, N.; Guillot-Sestier, M.-V.; Tan, J.; Town, T. Ferulic Acid Is a Nutraceutical β-secretase modulator that improves behavioral impairment and Alzheimer-like pathology in transgenic mice. PLoS ONE 2013, 8, e55774. [Google Scholar] [CrossRef] [Green Version]
  81. Mori, T.; Koyama, N.; Tan, J.; Segawa, T.; Maeda, M.; Town, T. Combined treatment with the phenolics (−)-epigallocatechin-3-gallate and ferulic acid improves cognition and reduces Alzheimer-like pathology in mice. J. Biol. Chem. 2018, 294, 2714–2731. [Google Scholar] [CrossRef] [Green Version]
  82. Jin, G.; Bai, D.; Yin, S.; Yang, Z.; Zou, D.; Zhang, Z.; Li, X.; Sun, Y.; Zhu, Q. Silibinin rescues learning and memory deficits by attenuating microglia activation and preventing neuroinflammatory reactions in SAMP8 mice. Neurosci. Lett. 2016, 629, 256–261. [Google Scholar] [CrossRef]
  83. Hostetler, G.L.; Ralston, R.A.; Schwartz, S.J. Flavones: Food sources, bioavailability, metabolism, and bioactivity. Adv. Nutr. 2017, 8, 423–435. [Google Scholar] [CrossRef] [Green Version]
  84. Zhao, L.; Wang, J.-L.; Liu, R.; Li, X.-X.; Li, J.-F.; Zhang, L. Neuroprotective, anti-amyloidogenic and neurotrophic effects of Apigenin in an Alzheimer’s disease mouse model. Molecules 2013, 18, 9949–9965. [Google Scholar] [CrossRef] [PubMed]
  85. Wu, L.; Tong, T.; Wan, S.; Yan, T.; Ren, F.; Bi, K.; Jia, Y. Protective effects of Puerarin against A β 1-42-induced learning and memory impairments in mice. Planta Med. 2017, 83, 224–231. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Huang, H.-J.; Huang, C.-Y.; Lee, M.; Lin, J.-Y.; Hsieh-Li, H.M. Puerariae radix prevents anxiety and cognitive deficits in mice under oligomeric Aβ-induced stress. Am. J. Chin. Med. 2019, 47, 1459–1481. [Google Scholar] [CrossRef] [PubMed]
  87. Pandareesh, M.D.; Chauhan, V.; Chauhan, A. Walnut supplementation in the diet reduces oxidative damage and improves antioxidant status in transgenic mouse model of Alzheimer’s disease. J. Alzheimer’s Dis. 2018, 64, 1295–1305. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Chauhan, N.; Wang, K.C.; Wegiel, J.; Malik, M.N. Walnut extract inhibits the fibrillization of amyloid beta-protein, and also defibrillizes its preformed fibrils. Curr. Alzheimer Res. 2004, 1, 183–188. [Google Scholar] [CrossRef] [PubMed]
  89. Verme, J.L.; Fu, J.; Astarita, G.; La Rana, G.; Russo, R.; Calignano, A.; Piomelli, D. The nuclear receptor peroxisome proliferator-activated receptor-α mediates the anti-inflammatory actions of palmitoylethanolamide. Mol. Pharmacol. 2005, 67, 15–19. [Google Scholar] [CrossRef] [PubMed]
  90. Beggiato, S.; Tomasini, M.C.; Ferraro, L. Palmitoylethanolamide (PEA) as a potential therapeutic agent in Alzheimer’s disease. Front. Pharmacol. 2019, 10, 10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  91. Andrieu, S.; Guyonnet, S.; Coley, N.; Cantet, C.; Bonnefoy, M.; Bordes, S.; Bories, L.; Noëlle-Cuffi, M.; Dantoine, T.; Dartigues, J.-F.; et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): A randomised, placebo-controlled trial. Lancet Neurol. 2017, 16, 377–389. [Google Scholar] [CrossRef]
  92. Im, D.-S. Pro-Resolving Effect of ginsenosides as an anti-inflammatory mechanism of Panax ginseng. Biomololecules 2020, 10, 444. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Leung, K.; Wong, A.S.T. Pharmacology of ginsenosides: A literature review. Chin. Med. 2010, 5, 20. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Heo, J.-H.; Lee, S.-T.; Chu, K.; Oh, M.J.; Park, H.J.; Shim, J.-Y.; Kim, M. Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer’s disease. Nutr. Neurosci. 2012, 15, 278–282. [Google Scholar] [CrossRef]
  95. Sachdeva, A.K.; Chopra, K. Lycopene abrogates Aβ (1–42)-mediated neuroinflammatory cascade in an experimental model of Alzheimer’s disease. J. Nutr. Biochem. 2015, 26, 736–744. [Google Scholar] [CrossRef]
  96. Von Arnim, C.A.F.; Herbolsheimer, F.; Nikolaus, T.; Peter, R.; Biesalski, H.K.; Ludolph, A.C.; Riepe, M.; Nagel, G.; The ActiFE Ulm Study Group. Dietary antioxidants and dementia in a population-based case-control study among older people in South Germany. J. Alzheimer’s Dis. 2012, 31, 717–724. [Google Scholar] [CrossRef] [Green Version]
  97. Atkinson, F.S.; Villar, A.; Mulà, A.; Zangara, A.; Risco, E.; Smidt, C.R.; Hontecillas, R.; Leber, A.; Bassaganya-Riera, J. Abscisic acid standardized fig (Ficus carica) extracts ameliorate postprandial glycemic and insulinemic responses in healthy adults. Nutrients 2019, 11, 1757. [Google Scholar] [CrossRef] [Green Version]
  98. Bassaganya-Riera, J.; Skoneczka, J.; Kingston, D.G.I.; Krishnan, A.; Misyak, S.; Guri, A.; Pereira, A.; Carter, A.; Minorsky, P.; Tumarkin, R.; et al. Mechanisms of action and medicinal applications of abscisic acid. Curr. Med. Chem. 2010, 17, 467–478. [Google Scholar] [CrossRef]
  99. Bi, B.; Tang, J.; Han, S.; Guo, J.; Miao, Y. Sinapic acid or its derivatives interfere with abscisic acid homeostasis during Arabidopsis thaliana seed germination. BMC Plant Biol. 2017, 17, 1–12. [Google Scholar] [CrossRef] [Green Version]
  100. Li, H.-H.; Hao, R.-L.; Wu, S.-S.; Guo, P.-C.; Chen, C.-J.; Pan, L.-P.; Ni, H. Occurrence, function and potential medicinal applications of the phytohormone abscisic acid in animals and humans. Biochem. Pharmacol. 2011, 82, 701–712. [Google Scholar] [CrossRef]
  101. Sánchez-Sarasúa, S.; Moustafa, S.; García-Avilés, Á.; López-Climent, M.F.; Gómez-Cadenas, A.; Olucha-Bordonau, F.E.; Sánchez-Pérez, A.M. The effect of abscisic acid chronic treatment on neuroinflammatory markers and memory in a rat model of high-fat diet induced neuroinflammation. Nutr. Metab. 2016, 13, 73. [Google Scholar] [CrossRef] [Green Version]
  102. Ribes-Navarro, A.; Atef, M.; Sánchez-Sarasúa, S.; Beltrán-Bretones, M.T.; Olucha-Bordonau, F.; Sánchez-Pérez, A.M. Abscisic acid supplementation rescues high fat diet-induced alterations in hippocampal inflammation and IRSs expression. Mol. Neurobiol. 2019, 56, 454–464. [Google Scholar] [CrossRef] [PubMed]
  103. Espinosa-Fernández, V.; Mañas-Ojeda, A.; Pacheco-Herrero, M.; Castro-Salazar, E.; Ros-Bernal, F.; Sánchez-Pérez, A.M. Early intervention with ABA prevents neuroinflammation and memory impairment in a triple transgenic mice model of Alzheimer’s disease. Behav. Brain Res. 2019, 374, 112106. [Google Scholar] [CrossRef] [PubMed]
  104. Zou, S.; Kumar, U. Cannabinoid receptors and the endocannabinoid system: Signaling and function in the central nervous system. Int. J. Mol. Sci. 2018, 19, 833. [Google Scholar] [CrossRef] [Green Version]
  105. Watt, G.; Karl, T. In vivo evidence for therapeutic properties of cannabidiol (CBD) for Alzheimer’s disease. Front. Pharmacol. 2017, 8, 20. [Google Scholar] [CrossRef] [Green Version]
  106. Murataeva, N.; Straiker, A.; Mackie, K. Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS. Br. J. Pharmacol. 2014, 171, 1379–1391. [Google Scholar] [CrossRef] [Green Version]
  107. Pertwee, R.G. Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr. Med. Chem. 2010, 17, 1360–1381. [Google Scholar] [CrossRef] [Green Version]
  108. Lu, Y.; Anderson, H.D. Cannabinoid signaling in health and disease. Can. J. Physiol. Pharmacol. 2017, 95, 311–327. [Google Scholar] [CrossRef]
  109. Ahmed, A.I.A.; Elsen, G.A.H.V.D.; Colbers, A.; Kramers, C.; Burger, D.M.; Van Der Marck, M.A.; Rikkert, M.G.M.O. Safety, pharmacodynamics, and pharmacokinetics of multiple oral doses of delta-9-tetrahydrocannabinol in older persons with dementia. Psychopharmacology 2015, 232, 2587–2595. [Google Scholar] [CrossRef] [Green Version]
  110. Cassano, T.; Calcagnini, S.; Pace, L.; De Marco, F.; Romano, A.; Gaetani, S. Cannabinoid receptor 2 signaling in neurodegenerative disorders: From pathogenesis to a promising therapeutic target. Front. Neurosci. 2017, 11, 30. [Google Scholar] [CrossRef] [Green Version]
  111. Kendall, D.A.; Yudowski, G. Cannabinoid receptors in the central nervous system: Their signaling and roles in disease. Front. Cell. Neurosci. 2017, 10, 294. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Mulder, J.; Zilberter, M.; Pasquaré, S.J.; Alpár, A.; Schulte, G.; Ferreira, S.G.; Köfalvi, A.; Martín-Moreno, A.M.; Keimpema, E.; Tanila, H.; et al. Molecular reorganization of endocannabinoid signalling in Alzheimer’s disease. Brain 2011, 134, 1041–1060. [Google Scholar] [CrossRef] [PubMed]
  113. Solas, M.; Francis, P.T.; Franco, R.; Ramirez, M.J. CB2 receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients. Neurobiol. Aging 2013, 34, 805–808. [Google Scholar] [CrossRef] [PubMed]
  114. Tolón, R.M.; Núñez, E.; Pazos, M.R.; Benito, C.; Castillo, A.I.; Martínez-Orgado, J.A.; Romero, J. The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages. Brain Res. 2009, 1283, 148–154. [Google Scholar] [CrossRef] [PubMed]
  115. Bonnet, A.E.; Marchalant, Y. Potential therapeutical contributions of the endocannabinoid system towards aging and Alzheimer’s disease. Aging Dis. 2015, 6, 400–405. [Google Scholar] [CrossRef] [Green Version]
  116. Aso, E.; Juvés, S.; Maldonado, R.; Ferrer, I. CB2 Cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AβPP/PS1 mice. J. Alzheimer’s Dis. 2013, 35, 847–858. [Google Scholar] [CrossRef] [Green Version]
  117. Pihlaja, R.; Takkinen, J.; Eskola, O.; Vasara, J.; López-Picón, F.R.; Haaparanta-Solin, M.; Rinne, J.O. Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells. J. Neuroinflamm. 2015, 12, 1–6. [Google Scholar] [CrossRef] [Green Version]
  118. Janefjord, E.; Mååg, J.L.V.; Harvey, B.S.; Smid, S.D. Cannabinoid effects on β amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro. Cell. Mol. Neurobiol. 2013, 34, 31–42. [Google Scholar] [CrossRef]
  119. Scuderi, C.; Steardo, L.; Esposito, G. Cannabidiol promotes amyloid precursor protein ubiquitination and reduction of beta amyloid expression in SHSY5Y APP + cells through PPARγ involvement. Phytother. Res. 2014, 28, 1007–1013. [Google Scholar] [CrossRef]
  120. Cassano, T.; Villani, R.; Pace, L.; Carbone, A.; Bukke, V.N.; Orkisz, S.; Avolio, C.; Serviddio, G. From cannabis sativa to cannabidiol: Promising therapeutic candidate for the treatment of neurodegenerative diseases. Front. Pharmacol. 2020, 11, 124. [Google Scholar] [CrossRef] [Green Version]
  121. Cheng, D.; Spiro, A.S.; Jenner, A.M.; Garner, B.; Karl, T. Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer’s disease transgenic mice. J. Alzheimer’s Dis. 2014, 42, 1383–1396. [Google Scholar] [CrossRef] [PubMed]
  122. Thompson, K.J.; Tobin, A.B. Crosstalk between the M1 muscarinic acetylcholine receptor and the endocannabinoid system: A relevance for Alzheimer’s disease? Cell. Signal. 2020, 70, 109545. [Google Scholar] [CrossRef] [PubMed]
  123. Arumugam, M.; Raes, J.; Pelletier, E.; Le Paslier, D.; Yamada, T.; Mende, D.R.; Fernandes, G.R.; Tap, J.; Bruls, T.; Batto, J.M.; et al. Enterotypes of the human gut microbiome. Nature 2011, 473, 174–180. [Google Scholar] [CrossRef] [PubMed]
  124. Jandhyala, S.M. Role of the normal gut microbiota. World J. Gastroenterol. 2015, 21, 8787–8803. [Google Scholar] [CrossRef]
  125. Rinninella, E.; Raoul, P.; Cintoni, M.; Franceschi, F.; Miggiano, G.A.; Gasbarrini, A.; Mele, M.C. What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms 2019, 7, 14. [Google Scholar] [CrossRef] [Green Version]
  126. Dinan, T.G.; Cryan, J.F. The microbiome-gut-brain axis in health and disease. Gastroenterol. Clin. N. Am. 2017, 46, 77–89. [Google Scholar] [CrossRef] [Green Version]
  127. Wang, H.-X.; Wang, Y.-P. Gut Microbiota-brain Axis. Chin. Med. J. 2016, 129, 2373–2380. [Google Scholar] [CrossRef]
  128. Mayer, E.A.; Tillisch, K.; Gupta, A. Gut/brain axis and the microbiota. J. Clin. Investig. 2015, 125, 926–938. [Google Scholar] [CrossRef]
  129. Carabotti, M.; Scirocco, A.; Maselli, M.A.; Severi, C. The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems. Ann. Gastroenterol. 2015, 28, 203–209. [Google Scholar]
  130. Strandwitz, P. Neurotransmitter modulation by the gut microbiota. Brain Res. 2018, 1693, 128–133. [Google Scholar] [CrossRef]
  131. Liu, S.; Gao, J.; Zhu, M.; Liu, K.; Zhang, H.-L. Gut microbiota and dysbiosis in Alzheimer’s disease: Implications for pathogenesis and treatment. Mol. Neurobiol. 2020, 57, 5026–5043. [Google Scholar] [CrossRef] [PubMed]
  132. Collins, S.M.; Surette, M.G.; Bercik, P. The interplay between the intestinal microbiota and the brain. Nat. Rev. Genet. 2012, 10, 735–742. [Google Scholar] [CrossRef] [PubMed]
  133. Sampson, T.R.; Mazmanian, S.K. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe 2015, 17, 565–576. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Kowalski, K.; Mulak, A. Brain-gut-microbiota axis in Alzheimer’s disease. J. Neurogastroenterol. Motil. 2019, 25, 48–60. [Google Scholar] [CrossRef] [Green Version]
  135. Goyal, D.; Ali, S.A.; Singh, R.K. Emerging role of gut microbiota in modulation of neuroinflammation and neurodegeneration with emphasis on Alzheimer’s disease. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2020, 110112. [Google Scholar] [CrossRef]
  136. Angelucci, F.; Cechova, K.; Amlerova, J.; Hort, J. Antibiotics, gut microbiota, and Alzheimer’s disease. J. Neuroinflamm. 2019, 16, 1–10. [Google Scholar] [CrossRef]
  137. Vogt, N.M.; Kerby, R.L.; Dill-McFarland, K.A.; Harding, S.J.; Merluzzi, A.P.; Johnson, S.C.; Carlsson, C.M.; Asthana, S.; Zetterberg, H.; Blennow, K.; et al. Gut microbiome alterations in Alzheimer’s disease. Sci. Rep. 2017, 7, 1–11. [Google Scholar] [CrossRef]
  138. Schwartz, K.; Boles, B.R. Microbial amyloids-functions and interactions within the host. Curr. Opin. Microbiol. 2013, 16, 93–99. [Google Scholar] [CrossRef] [Green Version]
  139. Sochocka, M.; Donskow-Łysoniewska, K.; Diniz, B.S.; Kurpas, D.; Brzozowska, E.; Leszek, J. The gut microbiome alterations and inflammation-driven pathogenesis of Alzheimer’s disease-A critical review. Mol. Neurobiol. 2019, 56, 1841–1851. [Google Scholar] [CrossRef] [Green Version]
  140. Lin, C.; Zhao, S.; Zhu, Y.; Fan, Z.; Wang, J.; Zhang, B.; Chen, Y. Microbiota-gut-brain axis and toll-like receptors in Alzheimer’s disease. Comput. Struct. Biotechnol. J. 2019, 17, 1309–1317. [Google Scholar] [CrossRef]
  141. Gąsiorowski, K.; Brokos, B.; Echeverria, V.; Barreto, G.E.; Leszek, J. RAGE-TLR crosstalk sustains chronic inflammation in neurodegeneration. Mol. Neurobiol. 2018, 55, 1463–1476. [Google Scholar] [CrossRef] [PubMed]
  142. Cerovic, M.; Forloni, G.; Balducci, C. Neuroinflammation and the gut microbiota: Possible alternative therapeutic targets to counteract Alzheimer’s disease? Front. Aging Neurosci. 2019, 11, 284. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Zhan, X.; Stamova, B.; Jin, L.-W.; DeCarli, C.; Phinney, B.; Sharp, F.R. Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology 2016, 87, 2324–2332. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Shi, H.; Wang, Q.; Zheng, M.; Hao, S.; Lum, J.S.; Chen, X.; Huang, X.-F.; Yu, Y.; Zheng, K. Supplement of microbiota-accessible carbohydrates prevents neuroinflammation and cognitive decline by improving the gut microbiota-brain axis in diet-induced obese mice. J. Neuroinflamm. 2020, 17, 1–21. [Google Scholar] [CrossRef] [PubMed]
  145. De Filippis, F.; Pellegrini, N.; Vannini, L.; Jeffery, I.B.; La Storia, A.; Laghi, L.; Serrazanetti, D.I.; Di Cagno, R.; Ferrocino, I.; Lazzi, C.; et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut 2015, 65, 1812–1821. [Google Scholar] [CrossRef] [PubMed]
  146. Nagpal, R.; Neth, B.J.; Wang, S.; Craft, S.; Yadav, H. Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer’s disease markers in subjects with mild cognitive impairment. EBioMedicine 2019, 47, 529–542. [Google Scholar] [CrossRef] [Green Version]
  147. Martínez-Lapiscina, E.H.; Clavero, P.; Toledo, E.; Estruch, R.; Salas-Salvadó, J.; Julián, B.S.; Sanchez-Tainta, A.; Ros, E.; Valls-Pedret, C.; Martinez-Gonzalez, M. Á Mediterranean diet improves cognition: The PREDIMED-NAVARRA randomised trial. J. Neurol. Neurosurg. Psychiatry 2013, 84, 1318–1325. [Google Scholar] [CrossRef] [Green Version]
  148. Probiotics: What You Need To Know. National Center for Complementary and Integrative Health (NIH). 2019 August. Available online: https://www.nccih.nih.gov/health/probiotics-what-you-need-to-know#:~%20:%20text=Probiotics%20are%20live%20microorganisms%20that,dietary%20supplements%2C%20and%20beauty%20products (accessed on 17 November 2020).
  149. Bonfili, L.; Cecarini, V.; Berardi, S.; Scarpona, S.; Suchodolski, J.S.; Nasuti, C.; Fiorini, D.; Boarelli, M.C.; Rossi, G.; Eleuteri, A.M. Microbiota modulation counteracts Alzheimer’s disease progression influencing neuronal proteolysis and gut hormones plasma levels. Sci. Rep. 2017, 7, 1–21. [Google Scholar] [CrossRef]
  150. Kobayashi, Y.; Sugahara, H.; Shimada, K.; Mitsuyama, E.; Kuhara, T.; Yasuoka, A.; Kondo, T.; Abe, K.; Xiao, J.-Z. Therapeutic potential of Bifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer’s disease. Sci. Rep. 2017, 7, 1–10. [Google Scholar] [CrossRef]
  151. Kobayashi, Y.; Kuhara, T.; Oki, M.; Xiao, J.-Z. Effects of Bifidobacterium breve A1 on the cognitive function of older adults with memory complaints: A randomised, double-blind, placebo-controlled trial. Benef. Microbes 2019, 10, 511–520. [Google Scholar] [CrossRef]
  152. Chen, D.-L.; Yang, X.; Yang, J.; Lai, G.; Yong, T.; Tang, X.; Shuai, O.; Zhou, G.; Xie, Y.; Wu, Q. Prebiotic effect of Fructooligosaccharides from Morinda officinalis on Alzheimer’s disease in rodent models by targeting the microbiota-gut-brain axis. Front. Aging Neurosci. 2017, 9, 403. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Sun, J.; Liu, S.; Ling, Z.; Wang, F.; Ling, Y.; Gong, T.; Fang, N.; Ye, S.; Si, J.; Liu, J. Fructooligosaccharides ameliorating cognitive deficits and neurodegeneration in APP/PS1 transgenic mice through modulating gut microbiota. J. Agric. Food Chem. 2019, 67, 3006–3017. [Google Scholar] [CrossRef]
  154. Hoffman, J.D.; Yanckello, L.M.; Chlipala, G.; Hammond, T.C.; McCulloch, S.D.; Parikh, I.; Sun, S.; Morganti, J.M.; Green, S.; Lin, A.-L. Dietary inulin alters the gut microbiome, enhances systemic metabolism and reduces neuroinflammation in an APOE4 mouse model. PLoS ONE 2019, 14, e0221828. [Google Scholar] [CrossRef] [PubMed]
  155. Sun, J.; Xu, J.; Ling, Y.; Wang, F.; Gong, T.; Yang, C.; Ye, S.; Ye, K.; Wei, D.; Song, Z.; et al. Fecal microbiota transplantation alleviated Alzheimer’s disease-like pathogenesis in APP/PS1 transgenic mice. Transl. Psychiatry 2019, 9, 1–13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Kim, M.-S.; Kim, Y.; Choi, H.; Kim, W.; Park, S.; Lee, D.; Kim, D.K.; Kim, H.J.; Choi, H.; Hyun, D.-W.; et al. Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model. Gut 2020, 69, 283–294. [Google Scholar] [CrossRef] [PubMed]
  157. Moreira, S.C.; Jansen, A.K.; Silva, F.M. Dietary interventions and cognition of Alzheimer’s disease patients: A systematic review of randomized controlled trial. Dement. Neuropsychol. 2020, 14, 258–282. [Google Scholar] [CrossRef]
  158. Ngandu, T.; Lehtisalo, J.; Solomon, A.; Levälahti, E.; Ahtiluoto, S.; Antikainen, R.; Bäckman, L.; Hänninen, T.; Jula, A.; Laatikainen, T.; et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): A randomised controlled trial. Lancet 2015, 385, 2255–2263. [Google Scholar] [CrossRef]
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Figure 1. Amyloid precursor protein (APP) processing. The α and γ secretases are involved in the non-amyloidogenic pathway, whereas the β and the γ secretases are involved in the amyloidogenic pathway, generating the Aβ toxic oligomer.
Figure 1. Amyloid precursor protein (APP) processing. The α and γ secretases are involved in the non-amyloidogenic pathway, whereas the β and the γ secretases are involved in the amyloidogenic pathway, generating the Aβ toxic oligomer.
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Figure 2. Insulin signaling cascade. The scheme shows the negative feedback mechanism that mTORC1 exerts over IRS1/2. Activation of AMPK inhibits mTORC1, thus improving insulin signaling. In pathological situations, insulin resistance reduces Akt activity, leading to higher GSK-3β activity and subsequent Tau hyperphosphorylation, an important hallmark of AD.
Figure 2. Insulin signaling cascade. The scheme shows the negative feedback mechanism that mTORC1 exerts over IRS1/2. Activation of AMPK inhibits mTORC1, thus improving insulin signaling. In pathological situations, insulin resistance reduces Akt activity, leading to higher GSK-3β activity and subsequent Tau hyperphosphorylation, an important hallmark of AD.
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Figure 3. Working hypothesis, namely, the role of the ECS, on neuroinflammation in AD. Inflammatory cytokines activate CB2 signaling in microglia, which, in turn, initiates a feedback mechanism to finish this process. Due to the chronic inflammatory process in the AD brain, the CB2 pathway remain active; however, it fails to reduce inflammation.
Figure 3. Working hypothesis, namely, the role of the ECS, on neuroinflammation in AD. Inflammatory cytokines activate CB2 signaling in microglia, which, in turn, initiates a feedback mechanism to finish this process. Due to the chronic inflammatory process in the AD brain, the CB2 pathway remain active; however, it fails to reduce inflammation.
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Table
Table 1. Clinical studies testing antioxidant molecules with potential therapeutic value for Alzheimer’s disease treatment. Other: other symptoms or biomarkers evaluated; NT: not tested; U: unspecified; ADAS-Cog: Alzheimer disease assessment scale–cognitive; APS: Alzheimer Progression Score; BADLS: Bristol Activities of Daily Living Scale; CGI-I: Clinical Global Impression-improvement; MMSE: Mini Mental Status Evaluation Test; NPI: Neuropsychiatry Inventory.
Table 1. Clinical studies testing antioxidant molecules with potential therapeutic value for Alzheimer’s disease treatment. Other: other symptoms or biomarkers evaluated; NT: not tested; U: unspecified; ADAS-Cog: Alzheimer disease assessment scale–cognitive; APS: Alzheimer Progression Score; BADLS: Bristol Activities of Daily Living Scale; CGI-I: Clinical Global Impression-improvement; MMSE: Mini Mental Status Evaluation Test; NPI: Neuropsychiatry Inventory.
Compound (Dose).SourcePatients
(Years Old)		Study DesignInflammatory/AD BiomarkersCognitive EffectOther Citation
Year
Naproxen
(220 mg/twice daily)		Derived from propionic acid195
(>55)		2 yearsNT= APS progression -[34]
2020
Celecoxib
(200 mg/twice daily)		Derived from propionic acid2356
(70–85)		3 yearsNT= ADAPT score-[35]
2015
Etanercept
(50 mg/once weekly subcutaneous)		U41
(70–74)		24 weeks= TNF-α levels
= IL-6 levels
= IL-10 levels
= IL-12p70 levels
= CRP levels		= ADAS-cog score
= BADLS score
= CGI-I
= Cornell Scale score
= MMSE score
= NPI score		-[36]
2015
Table
Table 2. Clinical studies testing anti-inflammatory molecules with potential therapeutic value for Alzheimer disease treatment. Other: other symptoms or biomarkers evaluated. NT (not tested); U (unspecified). Acetate, propionate and butyrate are short-chain fatty acids. ADAS-Cog: Alzheimer disease assessment scale–cognitive; ADFACS: Alzheimer’s Disease Functional Assessment and Change Scale; ADCS-ADL: ADCS Activity of Daily Living; CDR: Clinical Dementia Rating; MMSE: Mini Mental Status Evaluation Test; NPI: Neuropsychiatric Inventory; PAL-WMS-R: Paired-Associate Learning Wechsler Memory Scale.
Table 2. Clinical studies testing anti-inflammatory molecules with potential therapeutic value for Alzheimer disease treatment. Other: other symptoms or biomarkers evaluated. NT (not tested); U (unspecified). Acetate, propionate and butyrate are short-chain fatty acids. ADAS-Cog: Alzheimer disease assessment scale–cognitive; ADFACS: Alzheimer’s Disease Functional Assessment and Change Scale; ADCS-ADL: ADCS Activity of Daily Living; CDR: Clinical Dementia Rating; MMSE: Mini Mental Status Evaluation Test; NPI: Neuropsychiatric Inventory; PAL-WMS-R: Paired-Associate Learning Wechsler Memory Scale.
Compound (Dose)SourcePatients (Years Old)Study DesignInflammatory/AD BiomarkersCognitive EffectOther Citation
Year
Metformin (200 mg/day)Galega officinalis plant20 (55–80)8 weeks= Aβ42 levels↑ Learning and memory (CANTAB PAL scale)Crosses the BBB[46]
2017
= phospho-TAU levels↑ Attention (DMS Percent Correct Simultaneous)
= total TAU levels
Lactoferrin (250 mg/day)Milk50 (>65)3 months↑ IL-10 levels [50]
2019
↑ GSH levels ↑ Ach levels
↓ IL-6 levels ↑ 5-HT levels
↓ Aβ42 levels ↑ AKT levels
↓ Caspase-3 levels↑ MMSE score↑ phospho- AKT(S473) levels
↓ Cholesterol levels↑ ADAS-Cog11 score↑ PI3K levels
↓ HSP90 levels
↓ TAU pTAU(181) ↓ PTEN levels
↓ NO levels ↓ MAPK1 levels
↓ MDA levels
Vitamin B12 (25 μg/day) + Folic acid (800 μg/day)Vitamin B12: animal products
Folic acid: broccoli, peas, chickpeas, leafy green vegetables		240 (>65)6 months↓ IL-6 levels -[54]
2019
↓ TNF-α levels↑ Full Scale IQ (FSIQ) score
↓ MCP-1 levels↑ Verbal intelligence quotient (VIQ) score
↓ Homocysteine levels↑ Information and Digit Span
Vitamin B12 + Risperidone and Quetiapine (atypical antipsychotic drugs)Risperidone: and
Quetiapine are synthetic		102 (>65)U↑ TGF-β score
↓ IL-8 levels
↓ TNF-α levels
↓ CD68 levels		NT↓ Pain (VAS scale)[55,56]
2018
Nilvadipine (8 mg/day)Pyridine (crude coal tar)511 (>50)18 monthsNT= ADAS-Cog 12
= CDR-sb
= DAD		-[62]
2018
Simvastatin 80 mg/dayStatins (Fungus Aspergillus terreus)80 (>50)18 months↓ IL-6 levels -[63]
2017
↓ IL-1β levels↑ ADAS-Cog score
↓ ACT levels↑ MMSE score
↓ TNF-α levels↑ Dependence Scale score
↓ APP levels↑ ADCS-ADL score
↓ BACE1 levels↑ NPI score
↓ Aβ levels
Simvastatin 40 mg/day 406 (>50)18 months↓ CRP levels= ADAS-Cog score↑ HDL levels[64]
2011
= MMSE score
= Dependence Scale score↓ Total cholesterol levels
= ADCS-ADL score
= NPI score↓ LDL levels
Atorvastatin 40 mg/dayStatins178 (45–60)18 months↓ IL-1β levels
↓ IL-6 levels
↓ TNF-α levels
↓ CRP levels
↓ MCP-1 levels		NT↓ Lipid levels[65]
2016
Atorvastatin 80 mg/day640 (50–90)18 monthsNT= ADAS-Cog score [66]
2010
= ADCS-CGIC score↓ Total cholesterol levels
= MMSE score
= CDR-SB score↓ LDL-C levels
= ADFACS score↓ Triglycerides levels
= NPI score
Tetrahydrocannabinol
(4.5 mg/day)		Cannabis plant50 (78–79)3 weeksNT= NPI score
= Cohen-Mansfield Agitation Inventory
= Quality of Life-Alzheimer’s Disease
= Barthel Index score
= PAL WMS-R score		 [67]
2015
Table
Table 3. Clinical studies testing nutraceuticals with a potential therapeutic value for Alzheimer’s disease treatment. Other: other symptoms or biomarkers evaluated; NT: not tested; U: unspecified; ADAS-Cog: Alzheimer disease assessment scale–cognitive; ADCS-ADL: ADCS Activity of Daily Living; AVL: Auditory Verbal Learning Test; CCR: Cambridge Contextual Reading Test; CN: Category naming test; COWA: Controlled Oral Word Association Test; DSS: Digit Symbol Substitution Test; MMSE: Mini Mental Status Evaluation Test; MoCA: Montreal Cognitive Assessment; WAIS-R: Wechsler Adults Intelligence Scale.
Table 3. Clinical studies testing nutraceuticals with a potential therapeutic value for Alzheimer’s disease treatment. Other: other symptoms or biomarkers evaluated; NT: not tested; U: unspecified; ADAS-Cog: Alzheimer disease assessment scale–cognitive; ADCS-ADL: ADCS Activity of Daily Living; AVL: Auditory Verbal Learning Test; CCR: Cambridge Contextual Reading Test; CN: Category naming test; COWA: Controlled Oral Word Association Test; DSS: Digit Symbol Substitution Test; MMSE: Mini Mental Status Evaluation Test; MoCA: Montreal Cognitive Assessment; WAIS-R: Wechsler Adults Intelligence Scale.
Compound (Dose)Source/StudyPatients
(Years Old)		Study DesignInflammatory/AD BiomarkersCognitive EffectOther Citation
Curcumin(1.5–4 g/day)Turmeric34
(>50)		6
months 		↓ Aβ aggregation= MMSE score-[72]
2008
(1500 mg/day)160
(40–90)		12 monthsNT↑ MoCA score
= CCR Test score
= DASS score
= AVL Test score
= COWA Test score
= WAIS-R score
= CogState score		-[73]
2016
Resveratrol
(500 mg/day)		Red grapes, peanuts and other plant species119
(>49)		52
weeks 		↑ MDC levels
↑ IL-4 levels
↑ FGF-2 levels
↑ MMP10 levels
↓ MMP9 levels
↓ IL-12 levels
↓ RANTES levels		↑ ADCS-ADL score-[76,77]
2015
PUFA
800 mg docosahexaenoic acid 225 mg eicosapentaenoic acid/day.		Multimodal
The MAPT study 		1680 Non demented
(>70)		3
years		NT= MMSE score
= DSS Test score
= CN Test		Safe[91]
2017
Heat processed Ginseng
(4.5 g/day)		 40
(U)		6
months		NT↑ ADAS-Cog score
↑ MMSE score		-[94]
2012
Abscisic acid
(40/80 µg) 		Fig fruit extract10 Non-demented
(18–45)		4 non-consecutive sessionsNTNTSafe
↓Postprandial glycemic responses.		[97]
2019
Table
Table 4. Clinical studies focused on the regulation of the activity of the gut microbiota as a potential treatment against Alzheimer’s disease. Other: other symptoms or biomarkers evaluated; NT: not tested; CDT: clock Drawing test; MMSE: Mini-Mental Status; RBANS: Repeatable Battery for the Assessment of Neuropsychological Status.
Table 4. Clinical studies focused on the regulation of the activity of the gut microbiota as a potential treatment against Alzheimer’s disease. Other: other symptoms or biomarkers evaluated; NT: not tested; CDT: clock Drawing test; MMSE: Mini-Mental Status; RBANS: Repeatable Battery for the Assessment of Neuropsychological Status.
Compound (Dose)Patients
(Years Old)		Study DesignInflammatory/AD BiomarkersCognitive EffectOther Citation
Year
Mediterranean-Ketogenic diet
(MMKD)
(<10% carbohydrate, 60–65% fat, and 30–35% protein)
American Heart Association diet (AHAD)
(55–65% carbohydrate, 15–20% fat, and 20–30% protein)		17
(64.6 ± 6.4)		6
weeks		↓ Aß42
↓ Tau-p181		NT↑ Enterobacteriaceae, Akkermansia, Slackia, Christensenellaceae and Erysipelotriaceae
↑ Propionate and butyrate
↓ Bifidobacterium and Lachnobacterium
↓ Fecal acetate and lactate		[146]
2019
= Aß-42
= Tau-p181		NT↑ Mollicutes
↑ Acetate and propionate
↓ Butyrate
Mediterranean diet (extra-virgin olive oil 1 l/week) or 30 g/day nuts522
(55–80)		6.5
years		NT↑ MMSE score
↑ CDT score		-[147]
2013
Bifidobacterium breve A1
(daily)		117
(50–80)		12
weeks		NT↑ RBANS score
↑ MMSE score		Safe[151]
2019
Table
Table 5. Clinical studies testing a multidomain intervention as a treatment against Alzheimer’s disease. Other: other symptoms or biomarkers evaluated; NT: not tested; NTB; Neuropsychological Test Battery.
Table 5. Clinical studies testing a multidomain intervention as a treatment against Alzheimer’s disease. Other: other symptoms or biomarkers evaluated; NT: not tested; NTB; Neuropsychological Test Battery.
Compound (Dose)
and Treatment 		SourcePatients
(Years Old)		Study DesignInflammatory/AD BiomarkersCognitive EffectOther Citation
Nutritional intervention (10–20% of daily energy (E%) from proteins, 25–35E% from fat, 45–55 E% from carbohydrates, 25–35 g/day dietary fiber)
+
Physical exercise training
+
Cognitive training
(executive processes, working memory, episodic
memory and mental speed)
+
Social activities		Multimodal
The FINGER
study		1260
(60–77)		2 yearsNT↑ NTB score
↑ NTB Executive functioning domain score
↑ NTB Processing speed domain score
= NTB Memory domain score		-[158]
2015
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Sánchez-Sarasúa, S.; Fernández-Pérez, I.; Espinosa-Fernández, V.; Sánchez-Pérez, A.M.; Ledesma, J.C. Can We Treat Neuroinflammation in Alzheimer’s Disease? Int. J. Mol. Sci. 2020, 21, 8751. https://doi.org/10.3390/ijms21228751

AMA Style

Sánchez-Sarasúa S, Fernández-Pérez I, Espinosa-Fernández V, Sánchez-Pérez AM, Ledesma JC. Can We Treat Neuroinflammation in Alzheimer’s Disease? International Journal of Molecular Sciences. 2020; 21(22):8751. https://doi.org/10.3390/ijms21228751

Chicago/Turabian Style

Sánchez-Sarasúa, Sandra, Iván Fernández-Pérez, Verónica Espinosa-Fernández, Ana María Sánchez-Pérez, and Juan Carlos Ledesma. 2020. "Can We Treat Neuroinflammation in Alzheimer’s Disease?" International Journal of Molecular Sciences 21, no. 22: 8751. https://doi.org/10.3390/ijms21228751

APA Style

Sánchez-Sarasúa, S., Fernández-Pérez, I., Espinosa-Fernández, V., Sánchez-Pérez, A. M., & Ledesma, J. C. (2020). Can We Treat Neuroinflammation in Alzheimer’s Disease? International Journal of Molecular Sciences, 21(22), 8751. https://doi.org/10.3390/ijms21228751

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