Clathrin mediated endocytosis in Alzheimer's disease: cell type specific involvement in amyloid beta pathology

Abstract

This review provides a comprehensive examination of the role of clathrin-mediated endocytosis (CME) in Alzheimer's disease (AD) pathogenesis, emphasizing its impact across various cellular contexts beyond neuronal dysfunction. In neurons, dysregulated CME contributes to synaptic dysfunction, amyloid beta (Aβ) processing, and Tau pathology, highlighting its involvement in early AD pathogenesis. Furthermore, CME alterations extend to non-neuronal cell types, including astrocytes and microglia, which play crucial roles in Aβ clearance and neuroinflammation. Dysregulated CME in these cells underscores its broader implications in AD pathophysiology. Despite significant progress, further research is needed to elucidate the precise mechanisms underlying CME dysregulation in AD and its therapeutic implications. Overall, understanding the complex interplay between CME and AD across diverse cell types holds promise for identifying novel therapeutic targets and interventions.

Keywords: Alzheimer’s disease; amyloid beta; clathrin mediated endocytosis; endolysosomal dysfunction; therapeutics.

Figure 1

CME step-by-step. (1) Nucleation: Initial invagination of the membrane surface and recruitment of support proteins to the pit. (2) Cargo selection: Budding vesicle couples with the intended cargo via receptors and adaptor proteins, which concurrently begin recruiting clathrin. (3) Coat assembly: Clathrin begins forming a lattice around the budding vesicle. (4) Scission: Dynamin assembles around the vesicle neck, and with support from accessory proteins the vesicle is removed from the extracellular membrane. (5) Uncoating: The clathrin lattice disassembles and the early endosome can be trafficked through several pathways including back to the cell surface or through the endolysosomal pathway.