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JCI Insight. 2020 Feb 27;5(4). pii: 135119. doi: 10.1172/jci.insight.135119.

Identification of Alzheimer's disease-associated rare coding variants in the ECE2 gene.

Liao X1,2,3, Cai F2, Sun Z1,3, Zhang Y2, Wang J2, Jiao B1,3, Guo J1,3,4, Li J3, Liu X1,3, Guo L1,3, Zhou Y3, Wang J1,3, Yan X1,3, Jiang H1,3,4, Xia K5, Li J5, Tang B1,3,4, Shen L1,3,4, Song W2.

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Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, Canada.
National Clinical Research Center for Geriatric Disorders.
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, China.
School of Life Sciences, and.


Accumulation of amyloid β protein (Aβ) due to increased generation and/or impaired degradation plays an important role in Alzheimer's disease (AD) pathogenesis. In this report, we describe the identification of rare coding mutations in the endothelin-converting enzyme 2 (ECE2) gene in 1 late-onset AD family, and additional case-control cohort analysis indicates ECE2 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 Aβ degradation. We further evaluated the effect of the R186C mutation in mutant APP-knockin 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 ECE2. Taken together, the results demonstrated that ECE2 peptidase mutations contribute to AD pathogenesis by impairing Aβ degradation, and overexpression of ECE2 alleviates AD phenotypes. This study indicates that ECE2 is a risk gene for AD development and pharmacological activation of ECE2 could be a promising strategy for AD treatment.


Alzheimer’s disease; Genetic variation; Neuroscience

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