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- Title
Aβ-accelerated neurodegeneration caused by Alzheimer's-associated ACE variant R1279Q is rescued by angiotensin system inhibition in mice.
- Authors
Cuddy, Leah K.; Prokopenko, Dmitry; Cunningham, Eric P.; Brimberry, Ross; Song, Peter; Kirchner, Rory; Chapman, Brad A.; Hofmann, Oliver; Hide, Winston; Procissi, Daniele; Hanania, Taleen; Leiser, Steven C.; Tanzi, Rudolph E; Vassar, Robert
- Abstract
A rACE to beat Alzheimer's disease: Alzheimer's disease (AD) has a strong genetic component and several genes have been associated with disease susceptibility, including the angiotensin-converting enzyme (ACE). Here, Cuddy et al. investigated the mechanistic link between ACE and AD using whole-genome sequencing databases and mouse models. The authors identified rare ACE variants associated with AD. They generated mice bearing a disease-associated mutation and showed increased neuronal ACE1 protein, neurodegeneration, and neuroinflammation with female animals developing a more severe phenotype. The variant accelerated disease development in a mouse model of AD and ACE inhibition rescued neuronal loss. The results suggest that ACE inhibitors might be effective in a subgroup of patients with AD. 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 cortex and cerebellum. Female KI mice exhibited greater hippocampal electroencephalograph disruption and memory impairment compared to males. ACE variant effects were more pronounced in female KI mice, suggesting a mechanism for higher AD risk in women. Hippocampal neurodegeneration was completely rescued by treatment with brain-penetrant drugs that inhibit ACE1 and AT1R. Although ACE 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.
- Subjects
ANGIOTENSIN converting enzyme; NEURODEGENERATION; ANGIOTENSIN II; ALZHEIMER'S disease; ACE inhibitors; MICE; CEREBRAL circulation
- Publication
Science Translational Medicine, 2020, Vol 12, Issue 563, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aaz2541