A Novel Pathway Implicated in Regulating Cognitive disfunction in a DrosophilaAlzheimer's Disease Model through Acer Inhibition and CG2233 Modulation

Alzheimers disease (AD) is a progressive neurodegenerative disorder, accounting for most dementia cases worldwide. Current therapies for AD have limited effectiveness in slowing disease progression or delivering a cure. As such, there is an immediate need for ongoing research and innovative strategies to tackle this multifaceted disease. Recently, several studies have implicated the renin-angiotensin system (RAS), known to regulate blood pressure, as a possible therapeutic target for AD. RAS-inhibiting drugs, including angiotensin-converting enzyme inhibitors (ACE-Is), have been shown to reduce the incidence and progression of AD. However, the literature describing their beneficial effects is inconsistent, with contradictory findings reporting no effects. How these drugs may function in AD remains poorly understood. Our previous work in Drosophila models expressing AD-related transgenes investigated the benefits of captopril, an ACE-I, and found it effectively rescued AD-related phenotypes including cognitive performance independent of A{beta}42 changes. Importantly, our study implicated Acer, a homolog of mammalian ACE, as a key player. In our current study, we demonstrate that the beneficial outcomes of Acer inhibition depend on preventing its catalytic activity and downstream target processing. We identify CG2233 as a prospective target and reveal its functional interaction with Acer. Furthermore, we show CG2233 is implicated in AD-related pathways in A{beta}42 expressing flies. Together, these findings provide a new avenue to study the role of ACE in AD. Significance StatementAD is a devastating neurodegenerative disorder with limited therapeutic success. Emerging research highlights the potential of inhibiting the renin-angiotensin system (RAS) in AD. Epidemiological findings and experimental studies have shown promising outcomes with RAS-targeting drugs including angiotensin-converting enzyme inhibitors (ACE-Is). Our previous work in Drosophila AD models revealed the efficacy of captopril, an ACE-I, in improving AD-related phenotypes. Moreover, we identified Acer as a key player in these mechanisms. Our current study further elucidates the role of Acer, identifies CG2233 as a potential target, and uncovers their functional interaction, shedding light on pathways relevant to AD phenotypes. This research underscores the significance of investigating ACE and ACE-I mechanisms in AD, offering potential innovative means for AD therapy.