The role of angiotensin-converting enzyme-1 (ACE-1) in Alzheimer's disease, and its association with ACE1 genotype.

Overactivation of the classical renin-angiotensin system (cRAS) correlates with cognitive impairment and disease pathology in humans and mouse models of Alzheimer`s disease (AD) (Miners et al., 2008, Kehoe et al., 2018). ACE1, a gene identified by GWAS as a genetic risk factor for AD, encodes ACE-1, a rate-limiting enzyme in the cRAS pathway which generates disease-associated angiotensin II (Ang II) but also degrades and facilitates the clearance of Aβ. ACE-2 counter-balances the actions of cRAS and converts Ang-II to Ang(1-7) (Jiang et al., 2012). The relationship between ACE1, cRAS activation and disease pathology remains unclear. We investigated the relationship between the ACE1 variant (rs4343) (a proxy marker for the more commonly studied indel polymorphism) and disease pathology (Aβ and Tau), ACE-1 protein level and enzyme activity, in a large (n=434) post-mortem study. We studied 318 dementia cases comprising AD, mixed AD and vascular dementia and 116 age-matched controls from the South West Dementia Brain Bank, University of Bristol. ACE1 polymorphism was genotyped by PCR and gene expression determined by qPCR. ACE-1 protein level was measured by sandwich ELISA and enzyme activity by using a fluorogenic peptide activity assay in frontal and parietal lobes in samples for which we have previously obtained data on Aβ and tau pathology by computer-assisted field fraction analysis. ACE-1 protein level was lower in homozygous (I/I) at-risk individuals compared to homozygous (D/D) in AD and mixed dementia cases (p=0.0051). Individuals with I/I genotype had significantly higher (p=0.008) parenchymal Aβ load in the frontal cortex compared with I/D and D/D genotypes, but there is no evidence for an association with tau load in AD. Our study indicates that individuals that are homozygous I/I for ACE1 i.e. at risk have lower ACE-1 protein and enzyme activity and corresponding higher levels of Aβ consistent with a predicted protective role of ACE-1 in AD that acts beyond its central deleterious role in cRAS activation. We will further explore ACE-2 protein and activity levels as well as ACE2 genotype. © 2021 the Alzheimer's Association.

Citation

Ozge Guzel, Hannah Mary Tayler, Scott Miners, Olivia Anna Skrobot, Patrick G Kehoe. The role of angiotensin-converting enzyme-1 (ACE-1) in Alzheimer's disease, and its association with ACE1 genotype. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2021 Dec;17 Suppl 3:e053569

PMID: 35109048

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