Microglial Responses in Alzheimer’s Disease Pathophysiology

Microglia, the brain’s resident immune cells, occupy a central role in Alzheimer’s disease by sensing, responding to and potentially clearing pathogenic hallmarks such as amyloid-β plaques and tau tangles. In early stages, microglia adopt a protective profile, engaging phagocytosis to remove debris and secreting trophic factors to support neuronal health. As disease progresses, sustained stimulation drives a shift to a pro-inflammatory, disease-associated microglial state characterised by release of cytokines, impaired clearance capacity and altered metabolic programmes. Genetic risk factors, notably variants in TREM2 and APOE, modulate these transitions and influence the balance between neuroprotection and neurotoxicity. Advanced transcriptomic and proteomic studies have delineated distinct microglial subpopulations that correlate with cognitive decline, offering mechanistic insight and guiding therapeutic approaches aimed at recalibrating microglial activation to restore homeostasis and slow neurodegeneration.

Research from Nature Portfolio

Single-cell transcriptomic analyses of human stem cell-derived microglia xenotransplanted into amyloid-laden mouse models have revealed multiple discrete activation states. These states range from antigen-presenting profiles enriched in human leukocyte antigen genes to pro-inflammatory chemokine-driven responses specific to oligomeric amyloid-β. Loss- and gain-of-function experiments targeting TREM2 and APOE variants demonstrated that these risk genes differentially regulate each transcriptomic state. Complementary work disrupting INPP5D (SHIP1) in human induced-pluripotent-stem-cell-derived microglia uncovered direct links between reduced SHIP1 activity, autophagy impairment and assembly of the NLRP3 inflammasome, leading to caspase-1 activation and interleukin-1β secretion. These findings underscore complex, multifaceted microglial programmes in Alzheimer’s pathology and highlight precise molecular nodes for potential intervention.

Microglial Responses in Alzheimer’s Disease Pathophysiology publication trend

The graph below shows the total number of articles in microglial responses in alzheimer’s disease pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Microglia: resident macrophage-like cells in the central nervous system responsible for immune surveillance and response.

Disease-associated microglia (DAM): a specialised activation state characterised by a unique gene expression profile in neurodegenerative contexts.

NLRP3 inflammasome: a multiprotein complex that activates inflammatory cytokines such as interleukin-1β in response to cellular stress signals.

Transcriptomics: the comprehensive analysis of RNA transcripts to profile gene expression patterns across cell populations.

Phagocytosis: the cellular process of engulfing and degrading extracellular debris, including protein aggregates.

Cytokine: soluble signalling proteins secreted by immune cells to modulate inflammatory and immune responses.

TREM2: a microglial surface receptor involved in lipid sensing and phagocytosis regulation.

APOE: apolipoprotein E, a lipid-binding protein influencing microglial function and genetic risk of Alzheimer’s disease.

References

1. Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related amyloid-β pathology. Nature Neuroscience (2024).
2. Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease. Molecular Neurodegeneration (2023).
3. INPP5D regulates inflammasome activation in human microglia. Nature Communications (2023).
4. Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation. Cell Reports (2020).
5. Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology. EMBO Molecular Medicine (2020).