Angiotensin-converting enzyme 2 (ACE-2) is dysregulated in Alzheimer's disease but not Vascular dementia

Abstract

Introduction: The brain renin-angiotensin system (RAS) is dysregulated in dementia. We have previously shown that ACE-2, a central regulator of the protective counter-regulatory arm of RAS, is inversely associated with disease pathology in Alzheimer's disease (AD). We have investigated whether ACE-2 is similarly deficient in Vascular dementia (VaD) and mixed dementia (AD-VaD), in addition to AD. We also investigated whether ACE-2 is related to vascular pathology including CAA and SVD and explored whether ACE-2 varies according to gender, hypertension status, and ACE-2 genotype. Methods: We studied brain tissue (frontal cortex) from 147 dementia cases (AD (n=94), VaD (n=20) and AD-VaD (n=33)) and 104 age-matched non-demented controls from the South West Dementia Brain Bank, University of Bristol. Amyloid β (Aβ) and tau pathology and levels, had previously been measured by IHC and ELISA, respectively. ACE-2 protein levels were measured by ELISA, and ACE-2 enzyme activity was measured using a fluorometric sensolyte kit (Anaspec). ACE-1 activity was measured using a fluorogenic assay; Ang-II and Ang-(1-7) were measured by in-house direct ELISA. ACE-2 genotypes (rs2285666 and rs4240157) were obtained by PCR. Results: ACE-2 enzyme activity was significantly reduced in AD and AD-VaD cases (p<0.0001 and p=0.0039, respectively) but not VaD. ACE-2 protein levels were unchanged between dementia groups. ACE-2 activity correlated inversely with parenchymal Aβ (r=-0.223, p=0.0005) and tau load (r=-0.294, p<0.0001) and with insoluble Aβ40 and Aβ42 levels (r=-0.267 and r=-0.289, both p<0.0001). ACE-2 activity correlated inversely with ACE-1 activity (r=−0.227, p=0.0004), and the ratio of ACE-1 to ACE-2 was significantly increased in AD and AD-VaD cases (p<0.0001 and p=0.0029, respectively) but not in VaD. ACE-2 activity was lower in females with AD (p=0.0015). There is no relationship with CAA/SVD. ACE-2 activity was higher in people with late-stage hypertension (p=0.044), and females with hypertension have lower enzyme activity than males (p=0.041). ACE-2 levels and activity werenot associated with ACE-2 genotypes. Discussion: These findings indicate that, despite strong vascular properties, changes in ACE-2 function are AD-related and not altered in VaD. The reduction in ACE-2 in females in AD warrants further investigation. We did not find any association with ACE-2 genotypes.