Research progress on functions of microglia in Alzheimer's disease
[Background]Alzheimer's disease(AD)is the most prevalent neurodegenerative disorder,characterized by progressive cognitive decline and memory loss.Despite decades of intensive research,the complex pathogenesis of AD remains incompletely understood.Recent advancements in human genetics have highlighted the central role of microglia,the brain's resident immune cells,in the development of AD.Notably,the majority of AD-associated genes exhibit enriched expression in microglia,with some being uniquely expressed in these cells.This genetic evidence has sparked renewed interest in understanding the multifaceted functions of microglia in AD progression and has led to a paradigm shift in our approach to studying the disease.The identification of rare variants in microglial-specific genes,such as triggering receptor expressed on myeloid cells 2(TREM2),has further underscored the importance of these cells in AD pathogenesis.[Progress]Current research has unveiled the dual role of microglia in AD pathology.On one hand,microglia demonstrate neuroprotective functions by mitigating Aβ-induced neurotoxicity.They achieve this through phagocytosing Aβ and forming physical barriers around amyloid plaques,which may limit the spread of toxic β-amyloid protein(Aβ)species to surrounding neural tissue.These actions are thought to be particularly important in the early stages of AD,potentially slowing disease progression.On the other hand,microglia can exacerbate neuronal damage through several pathways.They may contribute to the propagation of tau pathology by releasing extracellular vesicles containing pathological tau species,which can be taken up by neighboring neurons.This process could explain the observed spread of tau pathology throughout the brain as AD progresses.Aberrant synaptic pruning by microglia,possibly involving dysregulation of complement-mediated mechanisms,has been implicated in the excessive synaptic loss observed in AD.This excessive pruning may contribute significantly to cognitive decline,as synaptic loss correlates strongly with cognitive impairment in AD.Furthermore,chronic activation of microglia leads to sustained release of pro-inflammatory mediators,including cytokines,chemokines,and reactive oxygen species,which can damage neurons and exacerbate neuroinflammation.This persistent inflammatory state may create a neurotoxic environment that further accelerates disease progression.This review synthesizes the latest genetic and cellular biology studies,providing a comprehensive overview of recent discoveries about microglial involvement in the pathological process of AD.We offer a detailed analysis of the molecular mechanisms underlying both the protective and detrimental actions of microglia in AD,including their interactions with Aβ and tau pathologies,their role in synaptic homeostasis,and their contribution to neuroinflammation.Recent technological advances,particularly in single-cell transcriptomics,have revealed significant heterogeneity among microglial populations in the AD brain.These studies have identified distinct microglial subpopulations associated with different stages of AD progression,including homeostatic microglia,disease-associated microglia,and other specialized subtypes.This heterogeneity provides new perspectives for understanding the complex roles of microglia in AD and highlights the need for more nuanced approaches to targeting these cells therapeutically.[Perspective]The application of single-cell technologies has opened new avenues for exploring microglial biology in AD,offering unprecedented insights into their diverse phenotypes and functions.Future research needs to delve deeper into the molecular and functional heterogeneity of these microglial subpopulations throughout AD progression.Key areas of focus should include elucidating the temporal and spatial dynamics of microglial subpopulations during different stages of AD,investigating the functional significance of newly identified microglial subtypes in AD pathogenesis,exploring the potential for targeted modulation of specific microglial subpopulations as a therapeutic strategy,unraveling the complex interactions between microglia and other cell types in the AD brain,and developing novel models that better recapitulate the heterogeneity and complexity of human microglial responses in AD.These research directions aim to establish a solid scientific foundation for the development of precise therapeutic strategies,potentially leading to more effective treatments for AD.By targeting specific microglial subpopulations or modulating their functions at different disease stages,it may be possible to enhance their neuroprotective actions while mitigating their neurotoxic effects,offering new hope for AD patients.
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