Journal article

A beta-accelerated neurodegeneration caused by Alzheimer's-associated ACE variant R1279Q is rescued by angiotensin system inhibition in mice

Leah K Cuddy, Dmitry Prokopenko, Eric P Cunningham, Ross Brimberry, Peter Song, Rory Kirchner, Brad A Chapman, Oliver Hofmann, Winston Hide, Daniele Procissi, Taleen Hanania, Steven C Leiser, Rudolph E Tanzi, Robert Vassar

Science Translational Medicine | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2020

Abstract

Recent genome-wide association studies identified the angiotensin-converting enzyme gene (ACE) as an Alzheimer's disease (AD) risk locus. However, the pathogenic mechanism by which ACE causes AD is unknown. Using whole-genome sequencing, we identified rare ACE coding variants in AD families and investigated one, ACE1 R1279Q, in knockin (KI) mice. Similar to AD, ACE1 was increased in neurons, but not microglia or astrocytes, of KI brains, which became elevated further with age. Angiotensin II (angII) and angII receptor AT1R signaling were also increased in KI brains. Autosomal dominant neurodegeneration and neuroinflammation occurred with aging in KI hippocampus, which were absent in the cort..

View full abstract

University of Melbourne Researchers

Grants

Awarded by Northwestern Alzheimer's Disease Center


Funding Acknowledgements

We thank the Cure Alzheimer's Fund for generously supporting this study to R. V. and R.E.T. We also thank the American Federation for Aging Research (AFAR) for a postdoctoral fellowship award to L.K.C. We thank E. Bigio and the Northwestern Alzheimer's Disease Center (P30 AG013854 to R.V.) for fixed AD brain tissue. Frozen human frontal cortex was obtained from D. Bennett at Rush University (R01AG17917). R.K., B.A.C., O.H., and W.H. at the Harvard Chan Bioinformatics Core were supported, in part, by the Harvard NeuroDiscovery Center.