Abstract
Hyperactivity of the renin-angiotensin system (RAS) is associated with the pathogenesis of Alzheimer’s disease (AD) believed to be mediated by angiotensin-II (Ang-II) activation of the angiotensin type 1 receptor (AT1R). We previously showed that angiotensin-converting enzyme-1 (ACE-1) activity, the rate-limiting enzyme in the production of Ang-II, is increased in human postmortem brain tissue in AD. Angiotensin-III (Ang-III) activates the AT1R and angiotensin type-2 receptor (AT2R), but its potential role in the pathophysiology of AD remains unexplored. We measured Ang-II and Ang-III levels by ELISA, and the levels and activities of aminopeptidase-A (AP-A) and aminopeptidase-N (AP-N) (responsible for the production and metabolism of Ang-III, respectively) in human postmortem brain tissue in the mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59), for which we had previous measurements of ACE-1 activity, Aβ level, and tau pathology (also in the mid-frontal cortex). We found that both Ang-II and Ang-III levels were significantly higher in AD compared to age-matched controls and that Ang-III, rather than Ang-II, was strongly associated with Aβ load and tau load. Levels of AP-A were significantly reduced in AD but AP-A enzyme activity was unchanged whereas AP-N activity was reduced in AD but AP-N protein level was unchanged. Together, these data indicate that the APA/Ang-III/APN/Ang-IV/AT4R pathway is dysregulated and that elevated Ang-III could contribute to the pathogenesis of AD.
Original language | English |
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Pages (from-to) | 203-214 |
Number of pages | 12 |
Journal | Journal of Alzheimer's Disease |
Volume | 58 |
Issue number | 1 |
Early online date | 3 May 2017 |
DOIs | |
Publication status | Published - 3 May 2017 |
Research Groups and Themes
- Cerebrovascular and Dementia Research Group
Keywords
- Alzheimer's disease
- aminopeptidase-A
- aminopeptidase-P
- angiotensin-II
- angiotensin-III
- renin-angiotensin system
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Professor Patrick Gavin Kehoe
- Bristol Medical School (THS) - Gestetner Professor of Translational Dementia Research
- Bristol Population Health Science Institute
- Bristol Neuroscience
Person: Academic , Member