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Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-β and tau pathology.
Alzheimers Res Ther 2016; 8(1):50AR

Abstract

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.

Authors+Show Affiliations

Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK. Patrick.Kehoe@bristol.ac.uk.Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK.Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK.Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK.Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK. Scot.Miners@bristol.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27884212

Citation

Kehoe, Patrick Gavin, et al. "Angiotensin-converting Enzyme 2 Is Reduced in Alzheimer's Disease in Association With Increasing Amyloid-β and Tau Pathology." Alzheimer's Research & Therapy, vol. 8, no. 1, 2016, p. 50.
Kehoe PG, Wong S, Al Mulhim N, et al. Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-β and tau pathology. Alzheimers Res Ther. 2016;8(1):50.
Kehoe, P. G., Wong, S., Al Mulhim, N., Palmer, L. E., & Miners, J. S. (2016). Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-β and tau pathology. Alzheimer's Research & Therapy, 8(1), p. 50.
Kehoe PG, et al. Angiotensin-converting Enzyme 2 Is Reduced in Alzheimer's Disease in Association With Increasing Amyloid-β and Tau Pathology. Alzheimers Res Ther. 2016 11 25;8(1):50. PubMed PMID: 27884212.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-β and tau pathology. AU - Kehoe,Patrick Gavin, AU - Wong,Steffenny, AU - Al Mulhim,Noura, AU - Palmer,Laura Elyse, AU - Miners,J Scott, Y1 - 2016/11/25/ PY - 2016/09/23/received PY - 2016/10/20/accepted PY - 2016/11/26/entrez PY - 2016/11/26/pubmed PY - 2017/10/14/medline KW - Alzheimer’s disease KW - Angiotensin II KW - Angiotensin-converting enzyme-1 KW - Angiotensin-converting enzyme-2 KW - Renin-angiotensin system SP - 50 EP - 50 JF - Alzheimer's research & therapy JO - Alzheimers Res Ther VL - 8 IS - 1 N2 - 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. SN - 1758-9193 UR - https://www.unboundmedicine.com/medline/citation/27884212/Angiotensin_converting_enzyme_2_is_reduced_in_Alzheimer's_disease_in_association_with_increasing_amyloid_β_and_tau_pathology_ L2 - https://alzres.biomedcentral.com/articles/10.1186/s13195-016-0217-7 DB - PRIME DP - Unbound Medicine ER -