Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-β and tau pathology

Alzheimers Res Ther. 2016 Nov 25;8(1):50. doi: 10.1186/s13195-016-0217-7.


Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Alzheimer’s disease; Angiotensin II; Angiotensin-converting enzyme-1; Angiotensin-converting enzyme-2; Renin-angiotensin system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Analysis of Variance
  • Angiotensin I / metabolism
  • Angiotensin II / genetics
  • Angiotensin II / metabolism*
  • Apolipoproteins E / genetics
  • Autopsy
  • Brain / metabolism*
  • Case-Control Studies
  • Cohort Studies
  • Female
  • Humans
  • Male
  • Peptide Fragments / metabolism
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism
  • Polymorphism, Single Nucleotide / drug effects
  • Statistics as Topic*
  • tau Proteins / metabolism*


  • Amyloid beta-Peptides
  • Apolipoproteins E
  • Peptide Fragments
  • tau Proteins
  • Angiotensin II
  • Angiotensin I
  • Peptidyl-Dipeptidase A
  • angiotensin I (1-7)