Aβ-accelerated neurodegeneration caused by Alzheimer’s-associated <i>ACE</i> variant R1279Q is rescued by angiotensin system inhibition in mice
Leah K. Cuddy, Dmitry Prokopenko, Eric Cunningham, Ross Brimberry, Peter I. Song, Rory Kirchner, Brad Chapman, Oliver Hofmann, Winston Hide, Daniele Procissi, Taleen Hanania, Steven C. Leiser, Rudolph E. Tanzi, Robert Vassar
Abstract
variant-induced neurodegeneration did not depend on β-amyloid (Aβ) pathology, amyloidosis in 5XFAD mice crossed to KI mice accelerated neurodegeneration and neuroinflammation, whereas Aβ deposition was unchanged. KI mice had normal blood pressure and cerebrovascular functions. Our findings strongly suggest that increased ACE1/angII signaling causes aging-dependent, Aβ-accelerated selective hippocampal neuron vulnerability and female susceptibility, hallmarks of AD that have hitherto been enigmatic. We conclude that repurposed brain-penetrant ACE inhibitors and AT1R blockers may protect against AD.