ACE is a metalloprotease that cleaves angiotensin 1, a major component of the renin angiotensin system (RAS) that regulates blood pressure in humans. Using a genetic approach in Drosophila, we previously identified Acer and Ance-5, two orthologs of human angiotensin converting enzyme (ACE), as modifiers of PS and C99 ( van de Hoef et al., 2009). Although extremely promising, only a few PS and γ-secretase modulators have been identified and their mechanism of action remains largely unknown. Similarly, proteins that modulate the interaction of γ-secretase with specific targets such as APP, or affect the production of Aβ peptides or their clearance, might allow for the development of new therapeutic targets for AD. Proteins that modulate γ-secretase assembly would provide valuable insight into the function of this important complex during development and disease. Recently, biochemical studies have shown that additional proteins can associate with PS and γ-secretase to modulate its assembly and/or interaction with specific targets ( Bursavich et al., 2016 Tan et al., 2016). Therefore, Aβ42 and plaques are often used as a diagnostic tool for AD prognosis and progression ( Hansson et al., 2007 Lewczuk et al., 2015). Generally, longer Aβ peptides (Aβ42) are prone to self-aggregation and are concentrated in amyloid plaques, which are associated with brain atrophy, regional hypometabolism, network dysfunction, inflammation, and oxidative stress ( Holtzman et al., 2011). PSs encode the catalytic component of γ-secretase ( Wolfe et al., 1999), which cleaves the C-terminal fragment of APP (APP-CTF, C99) to produce Aβ peptides. APP encodes a single-pass transmembrane protein that is cleaved by two proteases, β-secretase and γ-secretase, to generate amyloid peptides.
Mutations in three genes, APP, presenilin 1, and presenilin 2 ( PS1 and PS2), cause early-onset autosomal dominant AD, which accounts for <5% of AD cases ( Goate et al., 1991). 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 Drosophila.Īlzheimer’s disease (AD) is a degenerative disorder of the central nervous system that causes progressive memory and cognitive decline during mid to late adult life. 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.
Importantly, neither drug rescued brain cell death in Drosophila expressing human Tau, suggesting that RAS inhibitors specifically target the amyloid pathway. However, neither drug affects production, accumulation or clearance of Aβ 42.
Similarly, both drugs reduce cell death in Drosophila expressing human Aβ 42 and losartan significantly rescues memory deficits. Captopril also significantly rescues memory defects in these flies. 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. Importantly, while ACE orthologs have been identified in Drosophila, other RAS components are not conserved. 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.
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. Alzheimer’s disease (AD) is a degenerative disorder that causes progressive memory and cognitive decline.
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