Mechanisms of a novel angiotensin converting enzyme 1 mutation in Alzheimer’s disease pathogenesis

Project: Research project

Project Details


Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, and age is the primary risk factor for AD. Yet, little is known about the mechanisms of aging that predispose to AD. Our collaborator, Dr. Rudolph Tanzi (MGH Harvard) identified by whole-genome sequencing a novel, highly penetrant missense mutation in the angiotensin converting enzyme 1 (ACE1) gene that is associated with increased risk for late-onset AD. ACE1 is best known for converting angiotensin I (angI) to the vasoconstrictor angiotensin II (angII), thus raising blood pressure. This AD-associated ACE1 mutation could promote pathogenesis by increasing angII production, since midlife hypertension has been identified as a risk factor for AD. However, ACE1 is expressed in all tissues including CNS neurons and has been implicated in diverse physiological functions. Therefore, any of the myriad ACE1 functions in the brain or periphery could have a role in AD pathogenesis. The goal of this study is to determine the mechanism by which the ACE1 mutation increases the risk of AD. To do so, we used CRISPR-Cas9 gene editing to introduce the AD-associated ACE1 mutation into the murine genome to make cognate mutant knock-in (KI) mice. I am investigating the role of mutant ACE1 in AD pathogenesis in vitro in primary neurons from wild-type (WT) and KI mice and in human neuronal SH-SY5Y cells stably expressing either WT ACE1 or mutant ACE1 and in vivo in aged cohorts of WT and KI mice. Unexpectedly, my preliminary data show that expression of mutant ACE1 reduces cell survival in both cultured mouse primary neurons and in stably overexpressing human SH-SY5Y cells. Additionally, 4 month old homozygous ACE1 KI mice have slightly reduced brain weight, suggesting neurodegeneration that may increase with age. Based on my findings so far I hypothesize that the mutation alters the function of neuronal ACE1, and cellular stress induced by a loss of function or gain of function of mutant ACE1 itself, or by aging or amyloid, eventually leads to neuronal cell death. I anticipate that my studies will provide information about the physiological function of neuronal ACE1, currently unknown, and how altered ACE1 function may promote AD.
Effective start/end date12/31/1712/30/18


  • American Federation for Aging Research (Agmt 1/17/18)


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