Alzheimer's disease (AD), the most prevalent form of dementia, is pathologically defined by amyloid-β (Aβ) plaques, neurofibrillary tangles, synaptic loss, and progressive neuronal degeneration. Increasing evidence highlights neuroinflammation as a central and modifiable factor in AD pathogenesis. This review critically explores the roles of microglia and astrocytes in mediating neuroinflammatory cascades, emphasizing their dual protective and detrimental functions. Microglial activation and astrocytic polarization into A1 (neurotoxic) and A2 (neuroprotective) subtypes are discussed alongside their contributions to Aβ clearance, tau pathology propagation, and synaptic dysfunction. The disruption of the blood-brain barrier, activation of inflammasome pathways such as NLRP3, and release of cytokines and chemokines exacerbate chronic inflammation and neurodegeneration. Advances in single-cell transcriptomics and lipidomics have revealed glial heterogeneity and novel molecular targets, including disease-associated microglia. Genetic risk factors like apolipoprotein E (APOE) and TREM2 variants further modulate inflammatory responses. Emerging therapeutic strategies, including non-steroidal anti-inflammatory drugs, monoclonal antibodies, and targeted immunomodulators, hold promise for modifying disease progression. Overall, precise targeting of neuroinflammatory pathways offers a compelling avenue for future AD therapies.
Kakkar et al. (Fri,) studied this question.