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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.    Electronic supplementary material  The online version of this article (doi:10.1186/s13195-016-0217-7) contains supplementary material, which is available to authorized users.

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