Carboxy terminal of ECRG4 is a potential initiator for amyloid pathology in Alzheimer's disease through interacting with APP intracellular domain

Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) and the formation of neurofibrillary tangles. Although the amyloid cascade hypothesis underscores the centrality of Aβ accumulation, the precise initiators of this process remain unknown. Objective In this study, we investigate the potential role of Esophageal Cancer-Related Gene 4 (ECRG4) in AD. We hypothesized that ECRG4, which is associated with cognitive impairment and upregulated in AD, directly contributes to amyloid pathology. Methods We performed cell-based assays, co-immunoprecipitation, in vivo experiments using APP NL-G-F/NL-G-F knock-in mouse, and immunohistochemistry of human hippocampal sections. Results ECRG4(133–148) associated with the amyloid precursor protein (APP) intracellular domain (AICD), leading to increased APP/Aβ accumulation. Furthermore, intracerebral injection of synthetic ECRG4(133–148) into AD model mice significantly augmented APP/Aβ deposition. Notably, the co-localization of ECRG4(133–148)-containing peptides with AICD-containing peptides increased with AD severity in human hippocampal tissue. Conclusions Our findings establish that the carboxy-terminal fragment of ECRG4 acts as a potential initiator of amyloid pathology in AD through its interaction with AICD.