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The classical renin\u2013angiotensin 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 A\u03b2 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 A\u03b2 and restored cognition in mid-aged (13\u201314-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 A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    and IL1-\u03b2 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\u00a0weeks) administration of DIZE to pre-symptomatic 9\u201310-month-old Tg2576 mice, and acute (10\u00a0days) treatment in cognitively impaired 12\u201313-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.\n                  <\/jats:p>","DOI":"10.1007\/s00401-019-02098-6","type":"journal-article","created":{"date-parts":[[2020,1,25]],"date-time":"2020-01-25T06:02:28Z","timestamp":1579932148000},"page":"485-502","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":131,"title":["ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer\u2019s disease"],"prefix":"10.1007","volume":"139","author":[{"given":"Charles E.","family":"Evans","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8594-1640","authenticated-orcid":false,"given":"James S.","family":"Miners","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Piva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3919-3642","authenticated-orcid":false,"given":"Christine L.","family":"Willis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3005-8222","authenticated-orcid":false,"given":"David M.","family":"Heard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5507-1170","authenticated-orcid":false,"given":"Emma J.","family":"Kidd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1824-1203","authenticated-orcid":false,"given":"Mark A.","family":"Good","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7542-1139","authenticated-orcid":false,"given":"Patrick G.","family":"Kehoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,25]]},"reference":[{"issue":"3","key":"2098_CR1","doi-asserted-by":"publisher","first-page":"1443","DOI":"10.3233\/JAD-171119","volume":"62","author":"PG Kehoe","year":"2018","unstructured":"Kehoe PG (2018) The coming of age of the angiotensin hypothesis in Alzheimer\u2019s disease: progress toward disease prevention and treatment? 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