Deciphering mechanisms of action of ACE inhibitors in neurodegeneration using Drosophila models of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disorder for which there is no cure. Recently, several studies have reported a significant reduction in the incidence and progression of dementia among some patients receiving antihypertensive medications such as angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs). Why these drugs are beneficial in some AD patients and not others is unclear although it has been shown to be independent of their role in regulating blood pressure. Given the enormous and immediate potential of ACE-Is and ARBs for AD therapeutics it is imperative that we understand how they function. Recently, studies have shown that ACE-Is and ARBs, which target the renin angiotensin system in mammals, are also effective in suppressing neuronal cell death and memory defects in Drosophila models of AD despite the fact that this pathway is not conserved in flies. This suggests that the beneficial effects of these drugs may be mediated by distinct and as yet, identified mechanisms. Here, we discuss how the short lifespan and ease of genetic manipulations available in Drosophila provide us with a unique and unparalleled opportunity to rapidly identify the targets of ACE-Is and ARBs and evaluate their therapeutic effectiveness in robust models of AD.

Keywords: Alzheimer’s disease; Drosophila; amyloid; angiotensin converting enzyme; neurodegeneration; renin angiotensin system.

Figure 1

RAS in mammals vs. Drosophila. (A) Mammalian brain RAS pathways and its inhibitors. ACE, angiotensin converting enzyme; ACE-I, angiotensin converting enzyme inhibitor; Ang, angiotensin; AP-A, aminopeptidase A; AP-N, aminopeptidase N; ARB, angiotensin receptor blocker; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; AT4R, angiotensin 4 receptor; LTP, long-term potentiation; MasR, Mas receptor. (B) ACE-I inhibit Acer and Ance, the Drosophila ACE homologs. Acer, angiotensin-converting-enzyme related; Ance, angiotensin converting enzyme. (Created with BioRender.com).

Figure 2

ACE family members in humans and Drosophila. Ance and Acer are homologous to ACE and share 61% (45% identity, 48% coverage) and 58% (41% identify, 45% coverage) amino acid similarity with ACE. Active site domains containing the conserved catalytic consensus zinc-binding motif (HEXXH) are indicated in red. sACE possess two active protein domains (N- and C- domain) whereas gACE, ACE2, Ance and Acer only have one. gACE is identical to that of the C domain of sACE except for its first 36 residues. Human ACE and ACE2 are integral-membrane proteins whereas Drosophila Ance and Acer lack a transmembrane domain. (Created with BioRender.com).