{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:58:05Z","timestamp":1792688285819,"version":"4.5.0"},"reference-count":57,"publisher":"American Society for Clinical Investigation","issue":"4","funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","award":["MOP-142487"],"award-info":[{"award-number":["MOP-142487"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,2,27]]},"abstract":"<jats:p>\n                    Accumulation of amyloid \u03b2 protein (A\u03b2) due to increased generation and\/or impaired degradation plays an important role in Alzheimer\u2019s disease (AD) pathogenesis. In this report, we describe the identification of rare coding mutations in the endothelin-converting enzyme 2 (\n                    <jats:italic>ECE2<\/jats:italic>\n                    ) gene in 1 late-onset AD family, and additional case-control cohort analysis indicates\n                    <jats:italic>ECE2<\/jats:italic>\n                    variants associated with the risk of developing AD. The 2 mutations (R186C and F751S) located in the peptidase domain in the ECE2 protein were found to severely impair the enzymatic activity of ECE2 in A\u03b2 degradation. We further evaluated the effect of the R186C mutation in mutant\n                    <jats:italic>APP<\/jats:italic>\n                    \u2013knockin mice. Overexpression of wild-type ECE2 in the hippocampus reduced amyloid load and plaque formation, and improved learning and memory deficits in the AD model mice. However, the effect was abolished by the R186C mutation in\n                    <jats:italic>ECE2<\/jats:italic>\n                    . Taken together, the results demonstrated that ECE2 peptidase mutations contribute to AD pathogenesis by impairing A\u03b2 degradation, and overexpression of ECE2 alleviates AD phenotypes. This study indicates that\n                    <jats:italic>ECE2<\/jats:italic>\n                    is a risk gene for AD development and pharmacological activation of ECE2 could be a promising strategy for AD treatment.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.135119","type":"journal-article","created":{"date-parts":[[2020,2,26]],"date-time":"2020-02-26T11:01:31Z","timestamp":1582714891000},"source":"Crossref","is-referenced-by-count":24,"title":["Identification of Alzheimer\u2019s disease\u2013associated rare coding variants in the ECE2 gene"],"prefix":"10.1172","volume":"5","author":[{"given":"Xinxin","family":"Liao","sequence":"first","affiliation":[{"name":"Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China."},{"name":"Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, Canada."},{"name":"National Clinical Research Center for Geriatric 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