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L. K. CUDDY, D. PROKOPENKO, R. BRIMBERRY, E. CUNNINGHAM, P. SONG, D. PROCISSI, T. HANANIA, S. C. LEISER, R. E. TANZI, R. J. VASSAR


The angiotensin I converting enzyme (ACE1) gene (ACE) has been recently established as a genome-wide significant Alzheimer’s disease (AD) risk gene. ACE1 is a zinc-dependent peptidase that is known for regulating blood pressure within the circulatory renin-angiotensin system (RAS). However, ACE1 has diverse physiological functions, including a role in in the peripheral immune response, and an intrinsic RAS has been found in the brain where ACE1 is expressed in neurons. ACE1 has been previously linked to AD by observations that midlife hypertension increases AD risk, ACE1 degrades Aβ42 and ACE1 protein level is upregulated in post-mortem AD brains. In this study, we identify rare functional ACE variants that could help identify new biologic insights. Here we gained access to a deep (>40x) whole genome sequencing family-based cohort from NIMH. The dataset consisted of 446 families with affected and unaffected siblings. We further focused on medium and high impact rare variants. Among rare variants with a potential functional impact we selected rs4980 (R1279Q). In this study, we investigate ACE1 R1279Q in knock-in (ACE1KI/KI) mice with the cognate mutation in the murine ACE gene (R1284Q). We find that ACE1 R1284Q increases ACE1 protein level and activity in neurons and plasma, and is a toxic, gain-of-function mutation. ACE1KI/KI mice exhibited age-related neurodegeneration, EEG disruption and memory deficits, but had normal blood pressure and cerebrovascular function. In the brain, ACE1 R1284Q increased angiotensin II levels and caused selective neuron loss in the hippocampus. ACE1 R1284Q also increased the levels of circulating pro-inflammatory mediators known to be involved in the pathogenesis of autoimmune neuroinflammatory disorders. In 5XFAD ACE1KI/KI crosses, neurodegeneration was accelerated while Aβ42 level was unchanged. Finally, both central and peripherally-acting RAS inhibitors prevented neurodegeneration in ACE1KI/KI mice, suggesting phenotypes in ACE1KI/KI mice are caused by a combined effect of central and peripheral, blood pressure-independent actions of ACE1 R1284Q. Our findings support of growing evidence that RAS-acting anti-hypertensive medications may have beneficial effects toward the treatment or prevention of AD, independently of their blood pressure lowering properties or effects on Aβ42 clearance. Our studies show for the first time a direct link between ACE1 function, neurodegeneration and AD.


1Dept. of Neurol., 2Northwestern Univ., Chicago, IL; 3Gen Hosp, Harvard Med. Sch., Charlestown, MA; 4Northwestern Radiology, Chicago, IL; 5Translational EEG, PsychoGenics, Paramus, NJ.