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Although the amyloid cascade hypothesis underscores the centrality of A\u03b2 accumulation, the precise initiators of this process remain unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed cell-based assays, co-immunoprecipitation, in vivo experiments using APP\n                      <jats:sup>NL-G-F\/NL-G-F<\/jats:sup>\n                      knock-in mouse, and immunohistochemistry of human hippocampal sections.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>ECRG4(133\u2013148) associated with the amyloid precursor protein (APP) intracellular domain (AICD), leading to increased APP\/A\u03b2 accumulation. Furthermore, intracerebral injection of synthetic ECRG4(133\u2013148) into AD model mice significantly augmented APP\/A\u03b2 deposition. Notably, the co-localization of ECRG4(133\u2013148)-containing peptides with AICD-containing peptides increased with AD severity in human hippocampal tissue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877261462890","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T13:50:23Z","timestamp":1782827423000},"page":"1830-1842","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Carboxy terminal of ECRG4 is a potential initiator for amyloid pathology in Alzheimer's disease through interacting with APP intracellular 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