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Recently, studies have reported that inhibitors of the mammalian renin angiotensin system (RAS) result in a significant reduction in the incidence and progression of AD by unknown mechanisms. Here, we used a genetic and pharmacological approach to evaluate the beneficial effects of angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) in<jats:italic>Drosophila<\/jats:italic>expressing AD-related transgenes. Importantly, while ACE orthologs have been identified in<jats:italic>Drosophila<\/jats:italic>, other RAS components are not conserved. We show that captopril, an ACE-I, and losartan, an ARB, can suppress a rough eye phenotype and brain cell death in flies expressing a mutant human<jats:italic>C99<\/jats:italic>transgene. Captopril also significantly rescues memory defects in these flies. Similarly, both drugs reduce cell death in<jats:italic>Drosophila<\/jats:italic>expressing human<jats:italic>A<\/jats:italic>\u03b2<jats:italic>42<\/jats:italic>and losartan significantly rescues memory deficits. However, neither drug affects production, accumulation or clearance of<jats:italic>A<\/jats:italic>\u03b2<jats:italic>42<\/jats:italic>. Importantly, neither drug rescued brain cell death in<jats:italic>Drosophila<\/jats:italic>expressing human Tau, suggesting that RAS inhibitors specifically target the amyloid pathway. Of note, we also observed reduced cell death and a complete rescue of memory deficits when we crossed a null mutation in<jats:italic>Drosophila Acer<\/jats:italic>into each transgenic line demonstrating that the target of captopril in<jats:italic>Drosophila<\/jats:italic>is Acer. Together, these studies demonstrate that captopril and losartan are able to modulate AD related phenotypes in the absence of the canonical RAS pathway and suggest that both drugs have additional targets that can be identified in<jats:italic>Drosophila<\/jats:italic>.<\/jats:p>","DOI":"10.1523\/eneuro.0235-20.2020","type":"journal-article","created":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T22:00:30Z","timestamp":1602799230000},"page":"ENEURO.0235-20.2020","source":"Crossref","is-referenced-by-count":28,"title":["Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Rescue Memory Defects in<i>Drosophila<\/i>-Expressing Alzheimer\u2019s Disease-Related Transgenes Independently of the Canonical Renin Angiotensin 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