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Alzheimer-s Research and Therapy

, 8:50

First Online: 25 November 2016Received: 23 September 2016Accepted: 20 October 2016

Abstract

BackgroundHyperactivity 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.

MethodsWe 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.

ResultsACE-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.

ConclusionsTogether, 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.

KeywordsAngiotensin-converting enzyme-2 Renin-angiotensin system Angiotensin-converting enzyme-1 Angiotensin II Alzheimer’s disease AbbreviationsACEAngiotensin-converting enzyme

ACEIAngiotensin-converting enzyme inhibitors

ADAlzheimer’s disease

Ang 1–7Angiotensin 1–7 peptide

Ang 1–9Angiotensin 1–9 peptide

Ang IIAngiotensin II peptide

ANOVAAnalysis of variance

APOEApolipoprotein E

APPAmyloid precursor protein

ARBAngiotensin II type 1 receptor blocker

AT1RAngiotensin II type 1 receptor

AβAmyloid-β

CAACerebral amyloid angiopathy

D-D ACE-1 rs1799752Deletion-deletion polymorphism

ELISAEnzyme-linked immunosorbent assay

FRETFluorescence resonance energy transfer

I-D ACE-1 rs1799752Insertion-deletion polymorphism

I-I ACE-1 rs1799752Insertion-insertion polymorphism

Mca7-Methoxycoumarin-4-yl-acetyl

MRCMedical Research Council

MRC UK-BBNMedical Research Council UK Brain Banks Network

p-tauPhosphorylated tau

PMPost-mortem

RASRenin-angiotensin system

rfuRelative fluorescence units

TMB3,3′,5,5′-Tetramethylbenzidine

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

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Autor: Patrick Gavin Kehoe - Steffenny Wong - Noura AL Mulhim - Laura Elyse Palmer - J. Scott Miners

Fuente: https://link.springer.com/



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