TY - JOUR T1 - Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers rescue memory defects in <em>Drosophila</em> expressing Alzheimer’s disease-related transgenes independently of the canonical Renin Angiotensin System JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0235-20.2020 SP - ENEURO.0235-20.2020 AU - Shin-Hann Lee AU - Sarah M. Gomes AU - Judy Ghalayini AU - Konstantin G. Iliadi AU - Gabrielle L. Boulianne Y1 - 2020/10/15 UR - http://www.eneuro.org/content/early/2020/10/15/ENEURO.0235-20.2020.abstract N2 - Alzheimer’s disease (AD) is a degenerative disorder that causes progressive memory and cognitive decline. 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 Drosophila expressing AD-related transgenes. Importantly, while ACE orthologs have been identified in Drosophila, 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 C99 transgene. Captopril also significantly rescues memory defects in these flies. Similarly, both drugs reduce cell death in Drosophila expressing human Aβ42 and losartan significantly rescues memory deficits. However, neither drug affects production, accumulation or clearance of Aβ42. Importantly, neither drug rescued brain cell death in Drosophila 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 Drosophila Acer into each transgenic line demonstrating that the target of captopril in Drosophila is Acer. Altogether, 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 Drosophila.Significance Statement AD is a devastating neurodegenerative disorder for which there is no cure. Recently, studies have reported a significant reduction in the incidence of AD and dementia among patients taking ACE-Is and ARBs. Given the enormous and immediate potential of ACE-Is and ARBs for AD therapeutics, it is imperative that we understand how they function and why they are beneficial in some patients but not others. Here we show that captopril, an ACE-I, and losartan, an ARB, can restore memory defects in flies expressing human AD transgenes in the absence of the canonical RAS pathway. These studies provide us with a unique opportunity to identify novel targets of ACE-Is and ARBs and evaluate their therapeutic effectiveness in robust models of AD. ER -