Revealing the Mechanism Underlying the Beneficial Effects of Angiotensin-Converting Enzyme Inhibitors in a Drosophila Alzheimer’s Disease Model

Alzheimer’s 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, although it is independent of their ability to regulate blood pressure. Given their therapeutic potential, our lab has been interested in evaluating the effects of ACE-Is and determining their mechanism of action using a Drosophila AD model that expresses human AD-related transgene, Aβ42. We have previously shown that captopril, an ACE-I, reduced levels of brain cell death and rescued memory deficits in these flies. Furthermore, we demonstrated that a null mutation in acer, a homolog of ace, is sufficient to recapitulate these effects suggesting that Acer is the target of captopril. Of note, while ACE homologs have been identified in Drosophila, other components of the RAS are not conserved, suggesting a potentially novel function of ACE linked to AD. My thesis aimed to reveal this novel function by characterizing the function of Acer in a Drosophila AD model. To this end, I showed that the benefits of captopril are independent of changes in amyloid levels but require inhibiting the catalytic activity of Acer and the potential processing of its downstream target. Furthermore, I identified CG2233 as a prospective target and demonstrated a functional interaction between the two proteins. Moreover, I showed that CG2233 is involved in pathways that contribute to AD-related phenotypes in Aβ42 expressing flies suggesting an ACER-CG2233 pathway underlying the captopril-driven beneficial effects. Altogether, these findings identified a pathway that can be dissected further in Drosophila to establish a potentially novel role for ACE and ACE- Is in AD.

Department dc:contributor.department

Molecular Genetics

Year dc:date.issued

2024

Author dc:creator

• Ghalayini, Judy

Advisor dc:contributor.advisor

• Boulianne, Gabrielle

Handle dc:identifier.uri

http://hdl.handle.net/1807/139634

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/139634