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.

Hypertension and hyperhomocysteinemia as modifiable risk factors for Alzheimer's disease and dementia: New evidence, potential therapeutic strategies, and biomarkers

“…141 Another recent study also conducted in Drosophila that overexpressed APP and the human β-site APP-cleaving enzyme (BACE) in neurons, demonstrated that treatment of AD flies with the ACEI Isinopril improved learning and memory deficits on the aversive phototaxic suppression assay and reduced ROS levels. 142 Although ACEIs have been found to exhibit beneficial effects on AD pathology, some studies have demonstrated detrimental effects of ACEIs, with the main concern being that the ACE is capable of cleaving Aβ peptides into less aggregable species, thus its inhibition may actually lead to enhanced Aβ deposition. 143 This was demonstrated in APP Swedish transgenic mice treated with ACEI, captopril, resulting in increased cerebral Aβ deposition.…”

“…Treatment with captopril decreased cerebral cell death and demonstrated an ability to rescue memory deficits also in a Drosophila model expressing the Aβ42 transgene, but this trend was not seen in flies expressing human tau, suggesting that ACEIs may work through targeting Aβ pathology 141 . Another recent study also conducted in Drosophila that overexpressed APP and the human β‐site APP‐cleaving enzyme (BACE) in neurons, demonstrated that treatment of AD flies with the ACEI Isinopril improved learning and memory deficits on the aversive phototaxic suppression assay and reduced ROS levels 142 . Although ACEIs have been found to exhibit beneficial effects on AD pathology, some studies have demonstrated detrimental effects of ACEIs, with the main concern being that the ACE is capable of cleaving Aβ peptides into less aggregable species, thus its inhibition may actually lead to enhanced Aβ deposition 143 .…”

Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases

“…Drosophila is a powerful organism for modeling human disease, including neuromuscular disorders [ 107 , 108 , 109 , 110 , 111 , 112 , 113 ]. Such models have provided novel insights into disease mechanisms and identified potential drug targets and treatments [ 64 , 113 , 114 , 115 , 116 , 117 , 118 ]. In addition, Drosophila is one of a few selected model organisms used by the Undiagnosed Disease Network (UDN) to functionally test DNA sequence variants of uncertain significance in candidate disease genes ( ).…”

Angiotensin‐converting enzymes as druggable features of psychiatric and neurodegenerative disorders

“…The density of these neurofibrillary aggregates in the neocortex correlates with dementia (Wang et al, 2013). This could be potentially inhibited by employing a centrally acting ACEi, which has been demonstrated to mitigate memory deficits, as demonstrated in different experimental AD models, mainly by reducing inflammation and/ or reactive oxygen species levels (AbdAlla et al, 2013;Thomas et al, 2021;Torika et al, 2016), and is consistent with known dysregulation of redox in AD (Holubiec et al, 2022). This approach has also been investigated in patients, showing that a brainpenetrating ACEi can counteract the process of neurodegeneration and dementia (Quitterer & AbdAlla, 2020).…”