title: Angiotensin-III is Increased in Alzheimer's Disease in Association with Amyloid-β and Tau Pathology.
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.
authors.forename: Patrick Gavin
authors.initials: PG
authors.lastname: Kehoe
authors.forename: Elliott
authors.initials: E
authors.lastname: Hibbs
authors.forename: Laura E
authors.initials: LE
authors.lastname: Palmer
authors.forename: J Scott
authors.initials: JS
authors.lastname: Miners
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000704:Analysis of Variance; D000805:Angiotensin III / Q000378:metabolism*; D018826:CD13 Antigens / Q000378:metabolism; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D043384:Glutamyl Aminopeptidase / Q000378:metabolism; D006801:Humans; D008297:Male; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins; D000805:Angiotensin III; D018826:CD13 Antigens; D043384:Glutamyl Aminopeptidase
keywords: Alzheimer’s disease; aminopeptidase-A; aminopeptidase-P; angiotensin-II; angiotensin-III; renin-angiotensin system