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Higher Angiotensin II Type 1 Receptor Levels and Activity in the Postmortem Brains of Older Persons with Alzheimer’s Dementia

2021; Oxford University Press; Volume: 77; Issue: 4 Linguagem: Inglês

10.1093/gerona/glab376

1758-535X

Çağlar Coşarderelioğlu, Lolita S. Nidadavolu, Claudene J. George, Ruth Marx-Rattner, Laura Powell, Qian‐Li Xue, Jing Tian, Joy Salib, Esther S. Oh, Luigi Ferrucci, Pervin Dinçer, David A. Bennett, Jeremy Walston, Peter Abadir,

Receptor Mechanisms and Signaling

Abstract Aging is a key risk factor in Alzheimer’s dementia (AD) development and progression. The primary dementia-protective benefits of angiotensin II subtype 1 receptor (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, a brain-specific renin-angiotensin system (b-RAS) exists, which can be altered by AT1R blockers. Brain RAS acts mainly through 3 angiotensin receptors: AT1R, AT2R, and AT4R. Changes in these brain angiotensin receptors may accelerate the progression of AD. Using postmortem frontal cortex brain samples of age- and sex-matched cognitively normal individuals (n = 30) and AD patients (n = 30), we sought to dissect the b-RAS changes associated with AD and assess how these changes correlate with brain markers of oxidative stress, inflammation, and mitochondrial dysfunction as well as amyloid-β and paired helical filament tau pathologies. Our results show higher protein levels of the pro-inflammatory AT1R and phospho-ERK (pERK) in the brains of AD participants. Brain AT1R levels and pERK correlated with higher oxidative stress, lower cognitive performance, and higher tangle and amyloid-β scores. This study identifies molecular changes in b-RAS and offers insight into the role of b-RAS in AD-related brain pathology.