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Emerging Challenges in the Diagnosis and Treatment of Alzheimer’s Disease: The Role of Neuroinflammation and Microglia Biomarkers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (15 June 2023) | Viewed by 8501

Special Issue Editor

Dr. Giulia Bivona

E-Mail Website
Guest Editor
Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
Interests: laboratory medicine; vitamin D; biomarkers; neurodegeneration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Although the diagnosis and treatment of Alzheimer’s Disease (AD) is becoming even more challenging every day, new insights into the pathogenesis of the disease have been discovered. Understanding molecular mechanisms underlying the development of the disease is of great importance in order to discover novel, effective strategies to care for patients, and to ameliorate the quality of life for them and their care-givers. Amyloid β (Aβ) and intracellular neurofibrillary tangles (NFTs) of Tau protein represent the hallmarks of AD, and Aβ overproduction is known to lead to AD. This has paved the way for the amyloid cascade hypothesis of AD pathogenesis, which posits that the neuronal damage in AD is sustained by Aβ overproduction. However, it seems that the amyloid cascade hypothesis cannot fully disclose AD pathogenesis (3). Different processes could be involved in AD pathophysiology, and neuroinflammation is one of the most studied. This phenomenon relies on the activation of microglia and is mediated by some molecules, including CX3CL1, which is a neuronal chemokine that is received at the site of microglia. Many in vitro and in vivo studies have demonstrated a potential role of CX3CL1 as a biomarker for diagnosis in the early stage of AD and as a biochemical target for potential therapeutic strategies. Unfortunately, controversial findings have been achieved. Further, the signalling pathway of CX3CL1 in relation to the onset and progression of AD has been not investigated, and it still remains unknown whether some transcription factors and inflammatory molecules are over- or under-expressed in AD models and AD patients.

The current Special Issue aims to collect original articles and review articles exploring the mechanisms by which neuron-to-glia communication through CX3CL1 can be involved in the pathogenesis of AD. Additionally, this Special Issue aims to establish whether the chemokine, or some molecules within its signalling pathway, can be used for early identification and treatment of AD.

Dr. Giulia Bivona
Guest Editor

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Keywords

  • Alzheimer’s Disease
  • neurofibrillary tangles
  • CX3CL1
  • microglia
  • neuroinflammation
  • neuro-immune cross-talk
  • neurodegeneration

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Published Papers (3 papers)

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Review

22 pages, 2018 KiB  
Review
Emerging Roles of Cells and Molecules of Innate Immunity in Alzheimer’s Disease
by Bartolo Tamburini, Giusto Davide Badami, Marco Pio La Manna, Mojtaba Shekarkar Azgomi, Nadia Caccamo and Francesco Dieli
Int. J. Mol. Sci. 2023, 24(15), 11922; https://doi.org/10.3390/ijms241511922 - 25 Jul 2023
Cited by 14 | Viewed by 2726
Abstract
The inflammatory response that marks Alzheimer’s disease (neuroinflammation) is considered a double-edged sword. Microglia have been shown to play a protective role at the beginning of the disease. Still, persistent harmful stimuli further activate microglia, inducing an exacerbating inflammatory process which impairs β-amyloid [...] Read more.
The inflammatory response that marks Alzheimer’s disease (neuroinflammation) is considered a double-edged sword. Microglia have been shown to play a protective role at the beginning of the disease. Still, persistent harmful stimuli further activate microglia, inducing an exacerbating inflammatory process which impairs β-amyloid peptide clearance capability and leads to neurotoxicity and neurodegeneration. Moreover, microglia also appear to be closely involved in the spread of tau pathology. Soluble TREM2 also represents a crucial player in the neuroinflammatory processes. Elevated levels of TREM2 in cerebrospinal fluid have been associated with increased amyloid plaque burden, neurodegeneration, and cognitive decline in individuals with Alzheimer’s disease. Understanding the intricate relationship between innate immunity and Alzheimer’s disease will be a promising strategy for future advancements in diagnosis and new therapeutic interventions targeting innate immunity, by modulating its activity. Still, additional and more robust studies are needed to translate these findings into effective treatments. In this review, we focus on the role of cells (microglia, astrocytes, and oligodendrocytes) and molecules (TREM2, tau, and β-amyloid) of the innate immune system in the pathogenesis of Alzheimer’s disease and their possible exploitation as disease biomarkers and targets of therapeutical approaches. Full article
(This article belongs to the Special Issue Emerging Challenges in the Diagnosis and Treatment of Alzheimer’s Disease: The Role of Neuroinflammation and Microglia Biomarkers)
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11 pages, 293 KiB  
Review
CX3CL1 Pathway as a Molecular Target for Treatment Strategies in Alzheimer’s Disease
by Giulia Bivona, Matilda Iemmolo and Giulio Ghersi
Int. J. Mol. Sci. 2023, 24(9), 8230; https://doi.org/10.3390/ijms24098230 - 4 May 2023
Cited by 8 | Viewed by 2826
Abstract
Alzheimer’s disease (AD) is a scourge for patients, caregivers and healthcare professionals due to the progressive character of the disease and the lack of effective treatments. AD is considered a proteinopathy, which means that aetiological and clinical features of AD have been linked [...] Read more.
Alzheimer’s disease (AD) is a scourge for patients, caregivers and healthcare professionals due to the progressive character of the disease and the lack of effective treatments. AD is considered a proteinopathy, which means that aetiological and clinical features of AD have been linked to the deposition of amyloid β (Aβ) and hyperphosphorylated tau protein aggregates throughout the brain, with Aβ and hyperphosphorylated tau representing classical AD hallmarks. However, some other putative mechanisms underlying the pathogenesis of the disease have been proposed, including inflammation in the brain, microglia activation, impaired hippocampus neurogenesis and alterations in the production and release of neurotrophic factors. Among all, microglia activation and chronic inflammation in the brain gained some attention, with researchers worldwide wondering whether it is possible to prevent and stop, respectively, the onset and progression of the disease by modulating microglia phenotypes. The following key points have been established so far: (i) Aβ deposition in brain parenchyma represents repeated stimulus determining chronic activation of microglia; (ii) chronic activation and priming of microglia make these cells lose neuroprotective functions and favour damage and loss of neurons; (iii) quiescent status of microglia at baseline prevents chronic activation and priming, meaning that the more microglia are quiescent, the less they become neurotoxic. Many molecules are known to modulate the quiescent baseline state of microglia, attracting huge interest among scientists as to whether these molecules could be used as valuable targets in AD treatment. The downside of the coin came early with the observation that quiescent microglia do not display phagocytic ability, being unable to clear Aβ deposits since phagocytosis is crucial for Aβ clearance efficacy. A possible solution for this issue could be found in the modulation of microglia status at baseline, which could help maintain both neuroprotective features and phagocytic ability at the same time. Among the molecules known to influence the baseline status of microglia, C-X3-chemokine Ligand 1 (CX3CL1), also known as Fractalkine (FKN), is one of the most investigated. FKN and its microglial receptor CX3CR1 are crucial players in the interplay between neurons and microglia, modulating the operation of some neural circuits and the efficacy and persistence of immune response against injury. In addition, CX3CL1 regulates synaptic pruning and plasticity in the developmental age and in adulthood, when it strongly impacts the hippocampus neurogenesis of the adult. CX3CL1 has an effect on Aβ clearance and tau phosphorylation, as well as in microglia activation and priming. For all the above, CX3CL1/CX3CR1 signalling has been widely studied in relation to AD pathogenesis, and its biochemical pathway could hide molecular targets for novel treatment strategies in AD. This review summarizes the possible role of CX3CL1 in AD pathogenesis and its use as a potential target for AD treatment. Full article
(This article belongs to the Special Issue Emerging Challenges in the Diagnosis and Treatment of Alzheimer’s Disease: The Role of Neuroinflammation and Microglia Biomarkers)
19 pages, 1932 KiB  
Review
The Cytokine CX3CL1 and ADAMs/MMPs in Concerted Cross-Talk Influencing Neurodegenerative Diseases
by Matilda Iemmolo, Giulio Ghersi and Giulia Bivona
Int. J. Mol. Sci. 2023, 24(9), 8026; https://doi.org/10.3390/ijms24098026 - 28 Apr 2023
Cited by 10 | Viewed by 2297
Abstract
Neuroinflammation plays a fundamental role in the development and progression of neurodegenerative diseases. It could therefore be said that neuroinflammation in neurodegenerative pathologies is not a consequence but a cause of them and could represent a therapeutic target of neuronal degeneration. CX3CL1 and [...] Read more.
Neuroinflammation plays a fundamental role in the development and progression of neurodegenerative diseases. It could therefore be said that neuroinflammation in neurodegenerative pathologies is not a consequence but a cause of them and could represent a therapeutic target of neuronal degeneration. CX3CL1 and several proteases (ADAMs/MMPs) are strongly involved in the inflammatory pathways of these neurodegenerative pathologies with multiple effects. On the one hand, ADAMs have neuroprotective and anti-apoptotic effects; on the other hand, they target cytokines and chemokines, thus causing inflammatory processes and, consequently, neurodegeneration. CX3CL1 itself is a cytokine substrate for the ADAM, ADAM17, which cleaves and releases it in a soluble isoform (sCX3CL1). CX3CL1, as an adhesion molecule, on the one hand, plays an inhibiting role in the pro-inflammatory response in the central nervous system (CNS) and shows neuroprotective effects by binding its membrane receptor (CX3CR1) present into microglia cells and maintaining them in a quiescent state; on the other hand, the sCX3CL1 isoform seems to promote neurodegeneration. In this review, the dual roles of CX3CL1 and ADAMs/MMPs in different neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (MH), and multiple sclerosis (MS), are investigated. Full article
(This article belongs to the Special Issue Emerging Challenges in the Diagnosis and Treatment of Alzheimer’s Disease: The Role of Neuroinflammation and Microglia Biomarkers)
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