How brain ‘cleaners’ fail: Mechanisms and therapeutic value of microglial phagocytosis in Alzheimer's disease

Abstract

Microglia are the resident phagocytes of the brain, where they primarily function in the clearance of dead cells and the removal of un‐ or misfolded proteins. The impaired activity of receptors or proteins involved in phagocytosis can result in enhanced inflammation and neurodegeneration. RNA‐seq and genome‐wide association studies have linked multiple phagocytosis‐related genes to neurodegenerative diseases, while the knockout of such genes has been demonstrated to exert protective effects against neurodegeneration in animal models. The failure of microglial phagocytosis influences AD‐linked pathologies, including amyloid β accumulation, tau propagation, neuroinflammation, and infection. However, a precise understanding of microglia‐mediated phagocytosis in Alzheimer's disease (AD) is still lacking. In this review, we summarize current knowledge of the molecular mechanisms involved in microglial phagocytosis in AD across a wide range of pre‐clinical, post‐mortem, ex vivo, and clinical studies and review the current limitations regarding the detection of microglia phagocytosis in AD. Finally, we discuss the rationale of targeting microglial phagocytosis as a therapeutic strategy for preventing AD or slowing its progression.

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“…Endocytic clearance of Aβ 1-42 by microglia can occur through several mechanisms, the most commonly studied being micropinocytosis and phagocytosis ( Ni et al, 2024 ). However, recent studies have begun to implicate CME in this process.…”

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“…Additionally, microglial activation exacerbates inflammation and tau seeding in AD mice, selectively increasing NF-κB signaling in microglia, which induces inflammation and tau-mediated synaptic loss. In vivo, it has been observed that microglia support the spread of tau by taking up and breaking down the seed-component form of tau [173]. Inhibition of microglial proliferation has been shown to attenuate tau-induced neurodegeneration and cognitive deficits [174].…”

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