International Journal of Molecular Sciences

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29 pages, 5833 KiB

Open AccessArticle

iTRAQ-Based Proteomic Analysis of APP Transgenic Mouse Urine Exosomes

by Xiaojing Zhou, Abdullah Md. Sheikh, Ken-ichi Matsumoto, Shingo Mitaki, Abu Zaffar Shibly, Yuchi Zhang, Garu A, Shozo Yano and Atsushi Nagai

Int. J. Mol. Sci. 2023, 24(1), 672; https://doi.org/10.3390/ijms24010672 - 30 Dec 2022

Cited by 2 | Viewed by 2592

Abstract

Alzheimer’s disease (AD) is a common dementia disease in the elderly. To get a better understanding of the pathophysiology, we performed a proteomic analysis of the urine exosomes (U-exo) in AD model mice (J20). The polymer precipitation method was used to isolate U-exo [...] Read more.

Alzheimer’s disease (AD) is a common dementia disease in the elderly. To get a better understanding of the pathophysiology, we performed a proteomic analysis of the urine exosomes (U-exo) in AD model mice (J20). The polymer precipitation method was used to isolate U-exo from the urine of 3-month-old J20 and wild-type (WT) mice. Neuron-derived exosome (N-exo) was isolated from U-exo by immunoprecipitation. iTRAQ-based MALDI TOF MS/MS was used for proteomic analysis. The results showed that compared to WT, the levels of 61 and 92 proteins were increased in the J20 U-exo and N-exo, respectively. Gene ontology enrichment analysis demonstrated that the sphingolipid catabolic process, ceramide catabolic process, membrane lipid catabolic process, Aβ clearance, and Aβ metabolic process were highly enriched in U-exo and N-exo. Among these, Asah1 was shown to be the key protein in lipid metabolism, and clusterin, ApoE, neprilysin, and ACE were related to Aβ metabolism and clearance. Furthermore, protein–protein interaction analysis identified four protein complexes where clusterin and ApoE participated as partner proteins. Thus, J20 U-exo and N-exo contain proteins related to lipid- and Aβ-metabolism in the early stages of AD, providing a new insight into the underlying pathological mechanism of early AD. Full article

(This article belongs to the Special Issue Diabetes and Dementia)

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17 pages, 1459 KiB

Open AccessArticle

The Cognitive Improvement and Alleviation of Brain Hypermetabolism Caused by FFAR3 Ablation in Tg2576 Mice Is Persistent under Diet-Induced Obesity

by Maite Solas, Marta Zamarbide, Carlos G. Ardanaz, María J. Ramírez and Alberto Pérez-Mediavilla

Int. J. Mol. Sci. 2022, 23(21), 13591; https://doi.org/10.3390/ijms232113591 - 5 Nov 2022

Cited by 5 | Viewed by 2211

Abstract

Obesity and aging are becoming increasingly prevalent across the globe. It has been established that aging is the major risk factor for Alzheimer’s disease (AD), and it is becoming increasingly evident that obesity and the associated insulin resistance are also notably relevant risk [...] Read more.

Obesity and aging are becoming increasingly prevalent across the globe. It has been established that aging is the major risk factor for Alzheimer’s disease (AD), and it is becoming increasingly evident that obesity and the associated insulin resistance are also notably relevant risk factors. The biological plausibility of the link between high adiposity, insulin resistance, and dementia is central for understanding AD etiology, and to form bases for prevention efforts to decrease the disease burden. Several studies have demonstrated a strong association between short chain fatty acid receptor FFAR3 and insulin sensitivity. Interestingly, it has been recently established that FFAR3 mRNA levels are increased in early stages of the AD pathology, indicating that FFAR3 could play a key role in AD onset and progression. Indeed, in the present study we demonstrate that the ablation of the Ffar3 gene in Tg2576 mice prevents the development of cognitive deficiencies in advanced stages of the disease. Notably, this cognitive improvement is also maintained upon a severe metabolic challenge such as the exposure to high-fat diet (HFD) feeding. Moreover, FFAR3 deletion restores the brain hypermetabolism displayed by Tg2576 mice. Collectively, these data postulate FFAR3 as a potential novel target for AD. Full article

(This article belongs to the Special Issue Diabetes and Dementia)

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23 pages, 3582 KiB

Open AccessArticle

Alteration in the Synaptic and Extrasynaptic Organization of AMPA Receptors in the Hippocampus of P301S Tau Transgenic Mice

by Rocio Alfaro-Ruiz, Carolina Aguado, Alejandro Martín-Belmonte, Ana Esther Moreno-Martínez, Jesús Merchán-Rubira, Félix Hernández, Jesús Ávila, Yugo Fukazawa and Rafael Luján

Int. J. Mol. Sci. 2022, 23(21), 13527; https://doi.org/10.3390/ijms232113527 - 4 Nov 2022

Cited by 6 | Viewed by 2314

Abstract

Tau pathology is a hallmark of Alzheimer’s disease (AD) and other tauopathies, but how pathological tau accumulation alters the glutamate receptor dynamics driving synaptic dysfunction is unclear. Here, we determined the impact of tau pathology on AMPAR expression, density, and subcellular distribution in [...] Read more.

Tau pathology is a hallmark of Alzheimer’s disease (AD) and other tauopathies, but how pathological tau accumulation alters the glutamate receptor dynamics driving synaptic dysfunction is unclear. Here, we determined the impact of tau pathology on AMPAR expression, density, and subcellular distribution in the hippocampus of P301S mice using immunoblot, histoblot, and quantitative SDS-digested freeze-fracture replica labeling (SDS-FRL). Histoblot and immunoblot showed differential regulation of GluA1 and GluA2 in the hippocampus of P301S mice. The GluA2 subunit was downregulated in the hippocampus at 3 months while both GluA1 and GluA2 subunits were downregulated at 10 months. However, the total amount of GluA1-4 was similar in P301S mice and in age-matched wild-type mice. Using quantitative SDS-FRL, we unraveled the molecular organization of GluA1-4 in various synaptic connections at a high spatial resolution on pyramidal cell spines and interneuron dendrites in the CA1 field of the hippocampus in 10-month-old P301S mice. The labeling density for GluA1-4 in the excitatory synapses established on spines was significantly reduced in P301S mice, compared to age-matched wild-type mice, in the strata radiatum and lacunosum-moleculare but unaltered in the stratum oriens. The density of synaptic GluA1-4 established on interneuron dendrites was significantly reduced in P301S mice in the three strata. The labeling density for GluA1-4 at extrasynaptic sites was significantly reduced in several postsynaptic compartments of CA1 pyramidal cells and interneurons in the three dendritic layers in P301S mice. Our data demonstrate that the progressive accumulation of phospho-tau is associated with alteration of AMPARs on the surface of different neuron types, including synaptic and extrasynaptic membranes, leading to a decline in the trafficking and synaptic transmission, thereby likely contributing to the pathological events taking place in AD. Full article

(This article belongs to the Special Issue Diabetes and Dementia)

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Review

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31 pages, 3643 KiB

Open AccessReview

Imaging Methods Applicable in the Diagnostics of Alzheimer’s Disease, Considering the Involvement of Insulin Resistance

by Petra Hnilicova, Ema Kantorova, Stanislav Sutovsky, Milan Grofik, Kamil Zelenak, Egon Kurca, Norbert Zilka, Petra Parvanovova and Martin Kolisek

Int. J. Mol. Sci. 2023, 24(4), 3325; https://doi.org/10.3390/ijms24043325 - 7 Feb 2023

Cited by 6 | Viewed by 3429

Abstract

Alzheimer’s disease (AD) is an incurable neurodegenerative disease and the most frequently diagnosed type of dementia, characterized by (1) perturbed cerebral perfusion, vasculature, and cortical metabolism; (2) induced proinflammatory processes; and (3) the aggregation of amyloid beta and hyperphosphorylated Tau proteins. Subclinical AD [...] Read more.

Alzheimer’s disease (AD) is an incurable neurodegenerative disease and the most frequently diagnosed type of dementia, characterized by (1) perturbed cerebral perfusion, vasculature, and cortical metabolism; (2) induced proinflammatory processes; and (3) the aggregation of amyloid beta and hyperphosphorylated Tau proteins. Subclinical AD changes are commonly detectable by using radiological and nuclear neuroimaging methods such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). Furthermore, other valuable modalities exist (in particular, structural volumetric, diffusion, perfusion, functional, and metabolic magnetic resonance methods) that can advance the diagnostic algorithm of AD and our understanding of its pathogenesis. Recently, new insights into AD pathoetiology revealed that deranged insulin homeostasis in the brain may play a role in the onset and progression of the disease. AD-related brain insulin resistance is closely linked to systemic insulin homeostasis disorders caused by pancreas and/or liver dysfunction. Indeed, in recent studies, linkages between the development and onset of AD and the liver and/or pancreas have been established. Aside from standard radiological and nuclear neuroimaging methods and clinically fewer common methods of magnetic resonance, this article also discusses the use of new suggestive non-neuronal imaging modalities to assess AD-associated structural changes in the liver and pancreas. Studying these changes might be of great clinical importance because of their possible involvement in AD pathogenesis during the prodromal phase of the disease. Full article

(This article belongs to the Special Issue Diabetes and Dementia)

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13 pages, 677 KiB

Open AccessReview

The Effectiveness of Antidiabetic Drugs in Treating Dementia: A Peek into Pharmacological and Pharmacokinetic Properties

by Jiro Ogura and Hiroaki Yamaguchi

Int. J. Mol. Sci. 2022, 23(12), 6542; https://doi.org/10.3390/ijms23126542 - 11 Jun 2022

Cited by 7 | Viewed by 3345

Abstract

Dementia dramatically affects the activities of daily living and quality of life; thus, many therapeutic approaches for overcoming dementia have been developed. However, an effective treatment regimen is yet to be developed. As diabetes is a well-known risk factor for dementia, drug repositioning [...] Read more.

Dementia dramatically affects the activities of daily living and quality of life; thus, many therapeutic approaches for overcoming dementia have been developed. However, an effective treatment regimen is yet to be developed. As diabetes is a well-known risk factor for dementia, drug repositioning and repurposing of antidiabetic drugs are expected to be effective dementia treatments. Several observational studies have been useful for understanding the effectiveness of antidiabetic drugs in treating dementia, but it is difficult to conclusively analyze the association between antidiabetic drug treatment and the risk of developing dementia after correcting for potential confounding factors. Mechanism-based approaches may provide a better understanding of the effectiveness of antidiabetic drugs for treating dementia. Since the peripheral circulation and the central nerve system are separated by the blood–brain barrier, it is important to understand the regulation of the central glucose metabolism. In this review, we discuss the pharmacological and pharmacokinetic properties of antidiabetic drugs in relation to treating dementia. Full article

(This article belongs to the Special Issue Diabetes and Dementia)

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17 pages, 3097 KiB

Open AccessReview

Antidiabetic Drugs in the Treatment of Alzheimer’s Disease

by Michalis Michailidis, Despina A. Tata, Despina Moraitou, Dimitrios Kavvadas, Sofia Karachrysafi, Theodora Papamitsou, Patroklos Vareltzis and Vasileios Papaliagkas

Int. J. Mol. Sci. 2022, 23(9), 4641; https://doi.org/10.3390/ijms23094641 - 22 Apr 2022

Cited by 36 | Viewed by 5671

Abstract

The public health burden of type 2 diabetes mellitus and Alzheimer’s disease is steadily increasing worldwide, especially in the population of older adults. Epidemiological and clinical studies suggest a possible shared pathophysiology between the two diseases and an increased risk of AD in [...] Read more.

The public health burden of type 2 diabetes mellitus and Alzheimer’s disease is steadily increasing worldwide, especially in the population of older adults. Epidemiological and clinical studies suggest a possible shared pathophysiology between the two diseases and an increased risk of AD in patients with type 2 diabetes mellitus. Therefore, in recent years, there has been a substantial interest in identifying the mechanisms of action of antidiabetic drugs and their potential use in Alzheimer’s disease. Human studies in patients with mild cognitive impairment and Alzheimer’s disease have shown that administration of some antidiabetic medications, such as intranasal insulin, metformin, incretins, and thiazolidinediones, can improve cognition and memory. This review aims to examine the latest evidence on antidiabetic medications as a potential candidate for the treatment of Alzheimer’s disease. Full article

(This article belongs to the Special Issue Diabetes and Dementia)

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14 pages, 952 KiB

Open AccessReview

Alzheimer’s Disease as Type 3 Diabetes: Common Pathophysiological Mechanisms between Alzheimer’s Disease and Type 2 Diabetes

by Michalis Michailidis, Despina Moraitou, Despina A. Tata, Kallirhoe Kalinderi, Theodora Papamitsou and Vasileios Papaliagkas

Int. J. Mol. Sci. 2022, 23(5), 2687; https://doi.org/10.3390/ijms23052687 - 28 Feb 2022

Cited by 103 | Viewed by 13223

Abstract

Globally, the incidence of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) epidemics is increasing rapidly and has huge financial and emotional costs. The purpose of the current review article is to discuss the shared pathophysiological connections between AD and T2DM. Research [...] Read more.

Globally, the incidence of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) epidemics is increasing rapidly and has huge financial and emotional costs. The purpose of the current review article is to discuss the shared pathophysiological connections between AD and T2DM. Research findings are presented to underline the vital role that insulin plays in the brain’s neurotransmitters, homeostasis of energy, as well as memory capacity. The findings of this review indicate the existence of a mechanistic interplay between AD pathogenesis with T2DM and, especially, disrupted insulin signaling. AD and T2DM are interlinked with insulin resistance, neuroinflammation, oxidative stress, advanced glycosylation end products (AGEs), mitochondrial dysfunction and metabolic syndrome. Beta-amyloid, tau protein and amylin can accumulate in T2DM and AD brains. Given that the T2DM patients are not routinely evaluated in terms of their cognitive status, they are rarely treated for cognitive impairment. Similarly, AD patients are not routinely evaluated for high levels of insulin or for T2DM. Studies suggesting AD as a metabolic disease caused by insulin resistance in the brain also offer strong support for the hypothesis that AD is a type 3 diabetes. Full article

(This article belongs to the Special Issue Diabetes and Dementia)

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10 pages, 478 KiB

Open AccessReview

Alzheimer’s Disease and Type 2 Diabetes Mellitus: The Use of MCT Oil and a Ketogenic Diet

by Junpei Takeishi, Yasuko Tatewaki, Taizen Nakase, Yumi Takano, Naoki Tomita, Shuzo Yamamoto, Tatsushi Mutoh and Yasuyuki Taki

Int. J. Mol. Sci. 2021, 22(22), 12310; https://doi.org/10.3390/ijms222212310 - 15 Nov 2021

Cited by 22 | Viewed by 14245

Abstract

Recently, type 2 diabetes mellitus (T2DM) has been reported to be strongly associated with Alzheimer’s disease (AD). This is partly due to insulin resistance in the brain. Insulin signaling and the number of insulin receptors may decline in the brain of T2DM patients, [...] Read more.

Recently, type 2 diabetes mellitus (T2DM) has been reported to be strongly associated with Alzheimer’s disease (AD). This is partly due to insulin resistance in the brain. Insulin signaling and the number of insulin receptors may decline in the brain of T2DM patients, resulting in impaired synaptic formation, neuronal plasticity, and mitochondrial metabolism. In AD patients, hypometabolism of glucose in the brain is observed before the onset of symptoms. Amyloid-β accumulation, a main pathology of AD, also relates to impaired insulin action and glucose metabolism, although ketone metabolism is not affected. Therefore, the shift from glucose metabolism to ketone metabolism may be a reasonable pathway for neuronal protection. To promote ketone metabolism, medium-chain triglyceride (MCT) oil and a ketogenic diet could be introduced as an alternative source of energy in the brain of AD patients. Full article

(This article belongs to the Special Issue Diabetes and Dementia)

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