ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

Evans, Charles E., Miners, James S., Piva, Giulia, Willis, Christine L., Heard, David M., Kidd, Emma J. ORCID: https://orcid.org/0000-0001-5507-1170, Good, Mark A. ORCID: https://orcid.org/0000-0002-1824-1203 and Kehoe, Patrick G. 2020. ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease. Acta Neuropathologica 139 , pp. 485-502. 10.1007/s00401-019-02098-6

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Abstract

Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer’s disease (AD). The classical renin–angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of Aβ and tau in both animal models and human pathological studies. cRAS activity is moderated by a downstream regulatory RAS pathway (rRAS), which is underactive in AD and is strongly associated with pathological hallmarks in human AD, and cognitive decline in animal models of CNS disease. We now show that enhancement of brain ACE2 activity, a major effector of rRAS, by intraperitoneal administration of diminazene aceturate (DIZE), an established activator of ACE2, lowered hippocampal Aβ and restored cognition in mid-aged (13–14-month-old) symptomatic Tg2576 mice. We confirmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble Aβ42 and IL1-β levels. DIZE restored hippocampal MasR levels in conjunction with increased NMDA NR2B and downstream ERK signalling expression in hippocampal synaptosomes from Tg2576 mice. Chronic (10 weeks) administration of DIZE to pre-symptomatic 9–10-month-old Tg2576 mice, and acute (10 days) treatment in cognitively impaired 12–13-month-old mice, prevented the development of cognitive impairment. Together these data demonstrate that ACE2 enhancement protects against and reverses amyloid-related hippocampal pathology and cognitive impairment in a preclinical model of AD.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Psychology
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher:	Springer Verlag
ISSN:	0001-6322
Date of First Compliant Deposit:	14 November 2019
Date of Acceptance:	8 November 2019
Last Modified:	06 Nov 2024 16:45
URI:	https://orca.cardiff.ac.uk/id/eprint/126824

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