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.

A clathrin mediated endocytosis scaffolding protein, Intersectin 1, changes in an isoform, brain region, and sex specific manner in Alzheimer’s disease

“…As such, disruption of CME function is associated with many diseases ( McMahon and Boucrot, 2011 ; Schreij et al, 2016 ). In humans with AD, genetic links have been made to Adaptor Related Protein Complex 2 ( AP2 ) and Phosphatidylinositol Binding Clathrin Assembly Protein ( PICALM ) ( Raj et al, 2018 ; Azarnia et al, 2019 ) and many proteins involved in CME have reported changes at the RNA and protein level over a wide variety of brain regions ( Yao et al, 1999 , 2000 , 2003 ; Cao et al, 2010 ; Jaye et al, 2024 ). There are many cellular functions disrupted in AD that are downstream of CME or use CME machinery.…”