The Angiotensin-Converting Enzyme Inhibitor Lisinopril Mitigates Memory and Motor Deficits in a Drosophila Model of Alzheimer's Disease

Abstract

The use of angiotensin-converting enzyme inhibitors (ACEis) has been reported to reduce symptoms of cognitive decline in patients with Alzheimer’s disease (AD). Yet, the protective role of ACEis against AD symptoms is still controversial. Here, we aimed at determining whether oral treatment with the ACEi lisinopril has beneficial effects on cognitive and physical functions in a Drosophila melanogaster model of AD that overexpresses the human amyloid precursor protein and the human β-site APP-cleaving enzyme in neurons. We found a significant impairment in learning and memory as well as in climbing ability in young AD flies compared to control flies. After evaluation of the kynurenine pathway of tryptophan metabolism, we also found that AD flies displayed a >30-fold increase in the levels of the neurotoxic 3-hydroxykynurenine (3-HK) in their heads. Furthermore, compared to control flies, AD flies had significantly higher levels of the reactive oxygen species (ROS) hydrogen peroxide in their muscle-enriched thoraces. Lisinopril significantly improved deficits in learning and memory and climbing ability in AD flies. The positive impact of lisinopril on physical function might be, in part, explained by a significant reduction in ROS levels in the thoraces of the lisinopril-fed AD flies. However, lisinopril did not affect the levels of 3-HK. In conclusion, our findings provide novel and relevant insights into the therapeutic potential of ACEis in a preclinical AD model.

Keywords: Alzheimer’s disease; Drosophila; aging; angiotensin-converting enzyme inhibitors; kynurenine pathway of tryptophan metabolism.

Figure 1

Lisinopril treatment mitigates learning and memory impairments in AD flies. (A) Control elav-gal4/+ flies but not hAPP, hBACE/+; elav-gal4/+ AD flies prefer moving significantly more towards a dark chamber than a light chamber after training. (B) A higher proportion of lisinopril-fed flies chose a dark chamber after training, independent of genotype. p-values obtained from Tukey–Kramer post hoc tests for multiple comparisons.

Figure 2

Lisinopril treatment improves climbing ability in AD flies. On average, untreated hAPP, hBACE/+; elav-gal4/+ AD flies traveled significantly less than matched controls. However, while climbing is not affected by the ACEi treatment in controls, lisinopril-fed AD flies traveled significantly more than untreated AD flies. Error bars represent the S.E.M. p-values obtained from Tukey–Kramer post hoc tests for multiple comparisons.

Figure 3

Lisinopril reduces the abundance of reactive oxygen species in muscle-enriched thoraces of AD males. Untreated hAPP, hBACE/+; elav-gal4/+ AD flies displayed higher thoracic H₂O₂ levels than untreated and lisinopril-fed elav-gal4/+ controls. Lisinopril treatment significantly decreased the levels of H₂O₂ in AD flies compared to the untreated AD flies. Error bars represent the S.E.M. p-values obtained from Tukey–Kramer post hoc tests for multiple comparisons.

Figure 4

The kynurenine pathway metabolite 3-hydroxykinurenin (3-HK) is highly produced in AD flies. Concentrations of the neurotoxic 3-HK in the heads of hAPP, hBACE/+; elav-gal4/+ AD flies were dramatically higher than in control flies, independently of whether flies were fed lisinopril on not. p-value obtained from Tukey–Kramer post hoc tests for multiple comparisons. Tryptophan levels were used as a covariate in the analysis. Data points show unadjusted values.