title: Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-β and tau pathology.
abstract: Hyperactivity of the classical axis of the renin-angiotensin system (RAS), mediated by angiotensin II (Ang II) activation of the angiotensin II type 1 receptor (AT1R), is implicated in the pathogenesis of Alzheimer's disease (AD). Angiotensin-converting enzyme-2 (ACE-2) degrades Ang II to angiotensin 1-7 (Ang ﻿﻿(1-7)) and counter-regulates the classical axis of RAS. We have investigated the expression and distribution of ACE-2 in post-mortem human brain tissue in relation to AD pathology and classical RAS axis activity.
  
  
  
  We measured ACE-2 activity by fluorogenic peptide substrate assay in mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59) for which we have previous data on ACE-1 activity, amyloid β (Aβ) level and tau pathology, as well as known ACE1 (rs1799752) indel polymorphism, apolipoprotein E (APOE) genotype, and cerebral amyloid angiopathy severity scores.
  
  
  
  ACE-2 activity was significantly reduced in AD compared with age-matched controls (P < 0.0001) and correlated inversely with levels of Aβ (r = -0.267, P < 0.001) and phosphorylated tau (p-tau) pathology (r = -0.327, P < 0.01). ACE-2 was reduced in individuals possessing an APOE ε4 allele (P < 0.05) and was associated with ACE1 indel polymorphism (P < 0.05), with lower ACE-2 activity in individuals homozygous for the ACE1 insertion AD risk allele. ACE-2 activity correlated inversely with ACE-1 activity (r = -0.453, P < 0.0001), and the ratio of ACE-1 to ACE-2 was significantly elevated in AD (P < 0.0001). Finally, we show that the ratio of Ang II to Ang (1-7) (a proxy measure of ACE-2 activity indicating  conversion of Ang II to Ang (1-7)) is reduced in AD.
  
  
  
  Together, our findings indicate that ACE-2 activity is reduced in AD and is an important regulator of the central classical ACE-1/Ang II/AT1R axis of RAS, and also that dysregulation of this pathway likely plays a significant role in the pathogenesis of AD.
authors.affiliation: Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK. Patrick.Kehoe@bristol.ac.uk.
authors.forename: Patrick Gavin
authors.initials: PG
authors.lastname: Kehoe
authors.affiliation: Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK.
authors.forename: Steffenny
authors.initials: S
authors.lastname: Wong
authors.affiliation: Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK.
authors.forename: Noura
authors.initials: N
authors.lastname: Al Mulhim
authors.affiliation: Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK.
authors.forename: Laura Elyse
authors.initials: LE
authors.lastname: Palmer
authors.affiliation: Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK. Scot.Miners@bristol.ac.uk.
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; D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics; D001344:Autopsy; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects; D013223:Statistics as Topic; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; D016875:tau Proteins; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C118790:angiotensin I (1-7)
keywords: Alzheimer’s disease; Angiotensin II; Angiotensin-converting enzyme-1; Angiotensin-converting enzyme-2; Renin-angiotensin system