Aug 2026· Frontiers in Cellular Neuroscience· 0 citations· 188 references
TL;DR
A “cellular state–pathological network–therapeutic window” framework is proposed and the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA–cGAS–STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia–tau feedback are systematically discussed.
Abstract
Alzheimer’s disease is a complex neurodegenerative disorder characterized pathologically by amyloid-β deposition and pathological tau aggregation. Amyloid-β deposition typically occurs during the preclinical stage; however, amyloid burden does not exhibit a simple linear relationship with neurodegeneration or cognitive decline. In contrast, the spatial distribution of tau pathology is more closely associated with clinical progression. As the resident innate immune cells of the central nervous system, microglia participate in the recognition, uptake, and containment of amyloid-β and tau. Nevertheless, persistent exposure to damage-associated signals can lead to lysosomal dysfunction, dysregulated lipid metabolism, and mitochondrial impairment in microglia, thereby amplifying neuroinflammation, aberrant synaptic elimination, and neuronal injury. The traditional binary M1/M2 classification is inadequate to capture the continuous, overlapping, and context-dependent functional states of microglia, which vary across brain regions, genetic backgrounds, and disease stages. This review integrates recent evidence from genetic, single-cell/single-nucleus, and spatial transcriptomic studies and proposes a “cellular state–pathological network–therapeutic window” framework. We systematically discuss the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA–cGAS–STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia–tau feedback. On this basis, we critically evaluate the mechanistic rationale, stage dependence, and translational limitations of therapeutic axes involving TREM2/CD33, P2X7–NLRP3 and cGAS–STING, CSF1R/complement, and TNF–TNFR1–RIPK1. Current evidence suggests that the key to microglia-targeted therapy is not the broad activation or suppression of immune responses, but rather the biomarker-guided and disease-stage-specific modulation of pathogenic signaling while preserving homeostatic functions such as plaque containment, debris clearance, synaptic maintenance, and tissue repair.
Alzheimer’s disease (AD) is the most common cause of dementia and major public-health challenge in aging societies worldwide. Accumulating evidence suggests that olfactory and visual deficits can precede overt cognitive symptoms and are closely associated with amyloid-β deposition, pathological tau phosphorylation, and disease progression. Early sensory abnormalities in AD likely arise from converging pathological processes. Among these, chronic neuroinflammation marked by microglial and astrocytic reactivity, inflammasome activation and increased pro-inflammatory mediators might play a pivotal role linking sensory-circuit injury to neurodegeneration. A coherent synthesis of the inflammatory mechanisms underlying early olfactory and visual impairment in AD remains limited, and putative molecular pathways and interventions have not been fully integrated. We aimed to identify AD-related olfactory and visual or retinal abnormalities, combine core inflammatory pathways and their interactions with amyloid-β and tau pathology, and summarize actionable targets and candidate interventions along a “receptor–intracellular signaling-inflammasome-effector” axis, to inform earlier-stage detection and mechanism-guided intervention in AD.
Yanjiao Xu, Guimei Zhang, Xinran Cui et al.· Frontiers in Aging Neuroscie...· 0 citations
New knowledge about the protective and detrimental aspects of neuroinflammation in AD and PD is summarized, providing an analysis on these developing prospects for targeted interventions toward slowing or stopping neurodegeneration.
R. Kumar, Kamaljeet, Sourabh Kosey· InflammoPharmacology· 0 citations
The dual and stage‐dependent roles of microglia and astrocytes are explored, discussion of blood–brain barrier dysfunction and peripheral immune infiltration as underappreciated pathogenic contributors are expanded, and emerging evidence linking neuroinflammation specifically to tau pathology is integrated.
S. Papelian· International Journal of Dev...· 0 citations
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder traditionally characterized by the extracellular accumulation of amyloid-beta (Abeta) plaques and the formation of intracellular neurofibrillary tau tangles; however, the prevailing scientific paradigm has shifted toward an integrative model of pathogenesis that recognizes neuroinflammation as a critical, self-perpetuating driver of cognitive attrition. This multifaceted interplay is mediated by the brain–body axis, wherein chronic systemic inflammation—stemming from metabolic dysfunction, cardiovascular disease, or environmental stressors such as fine particulate matter PM2.5—compromises the structural integrity of the blood–brain barrier. Such environmental insults serve as priming agents for the innate immune system, shifting peripheral immune populations toward a pro-inflammatory phenotype that is further exacerbated by the stabilization of hypoxia-inducible factors (HIFs) through oxidative stress-induced pseudohypoxia, even under normoxic conditions. The subsequent activation of microglia and astrocytes transitions the cerebral microenvironment from a homeostatic, neurosupportive state into a neurotoxic milieu that actively promotes synaptic loss and neuronal death. Consequently, contemporary research has pivoted from broad-spectrum anti-inflammatory interventions toward targeted immune modulation, emphasizing that a comprehensive understanding of how systemic dysfunction perpetuates neuroinflammatory cascades is essential for developing efficacious therapies capable of attenuating AD progression and mitigating its global health burden.
Alejandro García-Núñez· Journal of Dementia and Alzh...· 0 citations
Alzheimer's disease (AD) is one of the most common types of neurodegenerative diseases. Its pathogenesis involves the interaction of multiple factors, including β-amyloid deposition, excessive tau protein phosphorylation, neuroinflammation, and synaptic dysfunction. Among these, neuroinflammation is widely recognized as a key factor driving the onset and progression of AD. As the two main types of glial cells in the central nervous system, microglia and astrocytes play central roles in the regulation of neuroinflammation. This paper systematically reviews the structural characteristics and functional states of microglia and astrocytes in AD-related neuroinflammation, as well as their interactions with Aβ and tau pathologies. Both types of glial cells exhibit a bidirectional transition from a protective to a damaging phenotype. In the early stage, they exert neuroprotective effects by phagocytosing and clearing abnormal proteins and releasing neurotrophic factors. Under sustained inflammatory stimulation, both gradually shift to a pro-inflammatory activated state, releasing large amounts of inflammatory factors, disrupting the blood-brain barrier and glymphatic system, and abnormally phagocytosing synaptic structures, forming a vicious cycle in which pathological protein deposition and excessive glial cell activation mutually exacerbate each other. More importantly, the two types of glial cells interact through various pathways such as cytokines, complement pathways, and signaling molecules, jointly amplifying the inflammatory cascade. This paper also summarizes therapeutic strategies for drugs targeting these two glial cells, including cholinesterase inhibitors, NMDA receptor antagonists, non-steroidal anti-inflammatory drugs, and biological agents targeting Aβ and tau proteins. In conclusion, functional abnormalities and interactive disorders of microglia and astrocytes are the core driving factors of AD neuroinflammation. An in-depth understanding of the molecular mechanisms underlying their interaction will provide a new breakthrough for shifting AD treatment from symptomatic management to etiological eradication.
Ruoyu Liu· Theoretical and Natural Scie...· 0 citations
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by β-amyloid plaques, tau tangles, synaptic dysfunction, and large-scale network failure. While the amyloid cascade hypothesis has dominated, emerging evidence suggests distinct yet interacting amyloid and tau trajectories influenced by genetic, vascular, metabolic, and inflammatory factors. Understanding this multimodal convergence is key to redefining AD pathogenesis. Following PRISMA 2020 guidelines, mechanistic studies published from January 2016 to August 2025 were reviewed from pubmed and the cochrane library. Eligible studies provided original data on molecular, cellular, or systems-level mechanisms of AD. Findings were synthesized across seven domains: amyloid, tau, neuroinflammation, synaptic dysfunction, mitochondrial stress, metabolic dysregulation, and genetics. Across 22 studies, evidence supports a shift from a linear amyloid model to a multidimensional framework. Amyloid and tau initiate independently but later interact to accelerate degeneration. APOE ε4 carriers show amyloid-driven disease, while non-carriers exhibit tau-dominant progression, with females showing higher vulnerability. fMRI and DTI reveal early Default Mode Network and white matter disruption. Biomarkers (Aβ42, tau, NfL, neurogranin, SNAP25) detect early changes, while mitochondrial and glial dysfunction and vascular-metabolic stress further modulate progression. AD emerges from converging genetic, molecular, and network-level abnormalities. A multimodal approach integrating imaging, fluid biomarkers, and genetics offers promise for early detection, risk stratification, and personalized multi-target therapies.
Cavan D. Souza, Shiva Murthy Nanjundappa, N. Murali· International Journal of Bas...· 0 citations
