Alzheimer's disease-linked ACE variants increase ACE1 catalytic activity and production of angiotensin II

Angiotensin-converting enzyme (ACE) is a validated risk locus for developing late-onset Alzheimer's disease (AD). Although ACE1 expression and enzyme activity correlate with AD diagnosis, the mechanism by which this occurs is unclear. As a cell membrane-bound and shed peptidase, ACE1 is most commonly known to produce angiotensin II (Ang II), which has been linked to AD pathogenesis but also has been shown to cleave toxic Aβ₄₂ to Aβ₄₀, further complicating its role in AD. Previous work from our group characterized a rare ACE coding variant discovered through whole-genome and whole-exome sequencing of late-onset AD families: ACE rs4980 (R1279Q mutation) increases neuronal ACE1 and subsequent signaling through the central renin-angiotensin system (RAS), inducing age-associated hippocampal neurodegeneration. In this work, we report on two additional ACE variants associated with increased risk for developing AD: rs3730043 (T916M) and rs142947404 (N1036K). These variants were selected to investigate their effect on ACE1 protein processing and function in SH-SY5Y stable cell lines. In these cell lines, ACE1 protein trafficking to the cell surface was unaltered. Interestingly, however, both T916M and N1036K mutant cell lines resulted in increased ACE1 catalytic activity. Consequently, both mutant cell lines produced elevated levels of Ang II, a known mediator of neurodegeneration. This study provides further evidence for the role of ACE1 in AD and warrants continued research on this topic.