The intricate interplay between microglia and adult neurogenesis in Alzheimer's disease

Abstract

Microglia, the resident immune cells of the central nervous system, play a crucial role in regulating adult neurogenesis and contribute significantly to the pathogenesis of Alzheimer's disease (AD). Under physiological conditions, microglia support and modulate neurogenesis through the secretion of neurotrophic factors, phagocytosis of apoptotic cells, and synaptic pruning, thereby promoting the proliferation, differentiation, and survival of neural progenitor cells (NPCs). However, in AD, microglial function becomes dysregulated, leading to chronic neuroinflammation and impaired neurogenesis. This review explores the intricate interplay between microglia and adult neurogenesis in health and AD, synthesizing recent findings to provide a comprehensive overview of the current understanding of microglia-mediated regulation of adult neurogenesis. Furthermore, it highlights the potential of microglia-targeted therapies to modulate neurogenesis and offers insights into potential avenues for developing novel therapeutic interventions.

Keywords: Alzheimer’s disease; adult neurogenesis; amyloid plaques; microglia; neurodegeneration.

Figure 1

Microglial modulation of hippocampal neurogenesis in health and disease. (A) During physiological conditions, neural stem cells (NSCs) in the hippocampal subgranular zone (SGZ) produce neural progenitor cells (NPCs), which differentiate into neuroblasts and migrate into the granule cell layer (GCL), where the cells mature and integrate into the hippocampal neural circuitry. Ramified microglia effectively eliminate excess apoptotic newborn cells by phagocytosis. Secretion of neurotrophic factors effects proliferation, differentiation, and survival of neurons. In addition, microglia prune synapses and induce spine formation to support adult neurogenesis. Furthermore, microglia communicate with neurons through CXCR1/CX3CL1 signaling, which contribute to the ability of microglia to maintain a ramified phenotype. (B) In Alzheimer’s disease neurogenesis is reduced. Proliferation and differentiation of neurons are inhibited due to amyloid-β (Aβ) aggregation and neurofibrillary tangles (NFTs). Activated microglia adapt a pro-inflammatory phenotype releasing neurotoxic cytokines that impair neurogenesis and synaptic integrity, such as interleukin (IL)-1β, IL-6, IL-17 and tumor necrosis factor (TNF)-α. These cytokines have profound detrimental effects on adult neurogenesis by reducing proliferation, differentiation, survival, and integration of newborn neurons. Microglia display an impaired phagocytic activity and CX3CR1-CX3CL1 signaling. BDNF, brain-derived neurotrophic factor; IGF-1, insulin-like growth factor 1; IL-(1β,4,6,10,17), Interleukin-(1β,4,6,10,17); TGFβ, transforming growth factor β; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor α. Created with BioRender.com.