Aug 2026· International Journal of Developmental Neuroscience· Vol 86· 0 citations· 20 references
Medicine
TL;DR
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.
Abstract
Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide, affecting millions of individuals and imposing substantial socioeconomic burdens. While traditional research has focused on amyloid‐β (Aβ) plaques and neurofibrillary tangles as primary pathological hallmarks, mounting evidence implicates neuroinflammation as a critical third pillar in AD pathogenesis. This review critically evaluates current understanding of neuroinflammatory mechanisms in AD, examining the complex interplay between cellular mediators, molecular pathways and environmental triggers across a temporal disease‐stage framework. We explore the dual and stage‐dependent roles of microglia and astrocytes, expand discussion of blood–brain barrier (BBB) dysfunction and peripheral immune infiltration as underappreciated pathogenic contributors, and integrate emerging evidence linking neuroinflammation specifically to tau pathology and its stereotyped propagation through the brain. Diagnostic biomarkers, including translocator protein–positron emission tomography (TSPO‐PET) and plasma glial fibrillary acidic protein (GFAP), are evaluated with explicit attention to clinical utility, technical limitations, and their relationship to established AD biomarkers. Therapeutic strategies are critically assessed with careful distinction between preclinical proof‐of‐concept data and available clinical evidence, and key translational challenges are highlighted throughout. The review emphasizes the need for stage‐appropriate intervention windows, patient stratification by neuroinflammatory endotype, and biologically rational combination strategies. Understanding neuroinflammation's temporal and spatial dynamics offers promising but as yet insufficiently realized avenues for early intervention and disease modification in AD.
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.
Lian-Jing Xu, Ying Zhang, Li Jiang et al.· Frontiers in Cellular Neuros...· 0 citations
Overall, this review makes a case for integrative, pathway-based therapeutic models, and multiple approaches may facilitate for drug development, biomarker identification and patient management in Alzheimer's disease.
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
This review synthesises current understanding of neuroinflammatory pathogenesis in AD, with emphasis on Microglial polarisation (M1/M2), Disease-Associated Microglia (DAM), TREM2 signalling, and reactive astrocyte conversion.
Zizhen Ren· Journal of Clinical Technolo...· 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
Neuroinflammation is increasingly recognized as a key contributor and amplifier associated with the pathogenesis of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Neuroinflammation occurs throughout various stages of these diseases with expanding complexity. Currently, no effective therapies exist that specifically target neuroinflammatory processes in these disorders. In this review, we synthesize current understanding of central and peripheral inflammatory mechanisms implicated in both diseases. We illustrate how endogenous pathological triggers, such as amyloid-β (Aβ) peptide, hyperphosphorylated tau, and α-synuclein, activate glial cells, contributing to chronic neuroinflammation that exacerbates neurodegeneration. Additionally, peripheral factors, including systemic inflammation, environmental exposures, and gut-brain axis interactions, are discussed for their roles in modulating neuroinflammatory responses. Notably, the underappreciated roles of oligodendrocyte precursor cells and oligodendrocytes in neuroimmune crosstalk are also highlighted. Advanced methodologies, including glial cell imaging, single-cell transcriptomics, and human induced pluripotent stem cell-derived organoid models, are providing unprecedented insights into the molecular and cellular mechanisms underlying neuroinflammation. Finally, we evaluate emerging therapeutic strategies and ongoing clinical trials targeting neuroinflammatory pathways and analyze the potential of immunomodulatory approaches to slow disease progression. This comprehensive review emphasizes that precise targeting of neuroinflammation represents a tractable strategy for developing effective disease‑modifying treatments for AD and PD.