Microglia-neuron crosstalk in Alzheimer's disease: an exploration of molecular mechanisms and pathological implications

Abstract

Microglia, the resident immune sentinels of the central nervous system (CNS), engage in dynamic crosstalk with neurons, the principal units of information transmission, to maintain CNS homeostasis. Emerging research has established that dysregulation of this intricate communication network critically contributes to Alzheimer's disease (AD) pathogenesis, offering novel insights for therapeutic development. In this review, we dissect molecular mechanisms underlying multifaceted microglia-neuron interactions in AD. Bidirectional communication occurs through neurotransmitter transmission, synaptic elimination, the secretion of signaling molecules and extracellular vesicles, and direct membrane contact. Disrupted crosstalk in AD triggers pathogenic cascades: cholinergic dysfunction induces microglial hyperactivation and oxidative stress; aberrant synaptic elimination accelerates memory loss; and neuron-derived pathological vesicles propagate neuroinflammation. Elucidating these interactions reveals promising therapeutic insights for AD. Targeting crosstalk pathways-such as activating TREM2, selectively inhibiting the complement cascade, or modulating inflammasome activity-may halt neurodegeneration while preserving essential immune surveillance. Moreover, integrating spatiotemporal omics with live imaging could dynamically track microglia-neuron crosstalk, revealing critical transition points from neuroprotection to neurodegeneration.

Keywords: Alzheimer’s disease; Central nervous system; Crosstalk; Microglia; Neuroinflammation; Neuron.