Alzheimer's disease was associated with significantly higher levels of Ang-II and Ang-III in the mid-frontal cortex compared to controls, with Ang-III strongly associated with Aβ and tau load.
Case-Control (n=149)
Elevated Ang-III levels in the brain are associated with Alzheimer's disease pathology, suggesting dysregulation of the APA/Ang-III/APN/Ang-IV/AT4R pathway.
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.
Kehoe et al. (Fri,) conducted a case-control in Alzheimer's disease (n=149). Alzheimer's disease vs. Age-matched non-demented controls was evaluated on Ang-II and Ang-III levels. Alzheimer's disease was associated with significantly higher levels of Ang-II and Ang-III in the mid-frontal cortex compared to controls, with Ang-III strongly associated with Aβ and tau load.