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

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 (AT(1)R) 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 AT(1)R blockers. Brain RAS acts mainly through 3 angiotensin receptors: AT(1)R, AT(2)R, and AT(4)R. 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-beta and paired helical filament tau pathologies. Our results show higher protein levels of the pro-inflammatory AT(1)R and phospho-ERK (pERK) in the brains of AD participants. Brain AT(1)R levels and pERK correlated with higher oxidative stress, lower cognitive performance, and higher tangle and amyloid-beta scores. This study identifies molecular changes in b-RAS and offers insight into the role of b-RAS in AD-related brain pathology.

Automated summary

Aging is a key risk factor in the development and progression of Alzheimer's dementia. This study identifies changes in AT(1)R in the brains of AD patients, which are associated with inflammation, oxidative stress, lower cognitive performance, and higher levels of amyloid-beta and tangle pathologies.