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

## TL;DR

This study shows that two Alzheimer's-linked ACE variants boost ACE1 activity and angiotensin II production, which may contribute to the disease.

## Contribution

The study identifies two new ACE variants linked to Alzheimer's and shows they increase ACE1 activity and Ang II production.

## Key findings

- ACE variants rs3730043 (T916M) and rs142947404 (N1036K) increase ACE1 catalytic activity.
- These variants lead to higher angiotensin II production, a known neurodegeneration mediator.
- ACE1 protein trafficking to the cell surface remains unaffected by the variants.

## Abstract

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.