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

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.

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Effect of a centrally active angiotensin-converting enzyme inhibitor, perindopril, on cognitive performance in a mouse model of Alzheimer's disease

Brain Research ◽

10.1016/j.brainres.2010.07.006 ◽

2010 ◽

Vol 1352 ◽

pp. 176-186 ◽

Cited By ~ 48

Author(s):

Koji Yamada ◽

Shinichi Uchida ◽

Syusuke Takahashi ◽

Makoto Takayama ◽

Yoshinori Nagata ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Angiotensin Converting Enzyme ◽

Angiotensin Converting Enzyme Inhibitor ◽

Cognitive Performance ◽

Enzyme Inhibitor ◽

Converting Enzyme ◽

Converting Enzyme Inhibitor ◽

Model Of Alzheimer’S Disease

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A pilot crossover study of the angiotensin-converting enzyme inhibitor (ACEI) ceranapril in alzheimer's disease

Biological Psychiatry ◽

10.1016/0006-3223(92)90568-k ◽

1992 ◽

Vol 31 (5) ◽

pp. 153-154

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Angiotensin Converting Enzyme ◽

Crossover Study ◽

Angiotensin Converting Enzyme Inhibitor ◽

Enzyme Inhibitor ◽

Converting Enzyme ◽

Converting Enzyme Inhibitor

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Perindopril, a centrally active angiotensin‐converting enzyme inhibitor, prevents cognitive impairment in mouse models of Alzheimer's disease

The FASEB Journal ◽

10.1096/fj.11-182873 ◽

2011 ◽

Vol 25 (9) ◽

pp. 2911-2920 ◽

Cited By ~ 80

Author(s):

Yi‐Fei Dong ◽

Keiichiro Kataoka ◽

Yoshiko Tokutomi ◽

Hisato Nako ◽

Taishi Nakamura ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Angiotensin Converting Enzyme ◽

Angiotensin Converting Enzyme Inhibitor ◽

Mouse Models ◽

Enzyme Inhibitor ◽

Converting Enzyme ◽

Converting Enzyme Inhibitor

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Pharmacogenetics of Angiotensin-Converting Enzyme Inhibitors in Patients with Alzheimer's Disease Dementia

Current Alzheimer Research ◽

10.2174/1567205014666171016101816 ◽

2018 ◽

Vol 15 (4) ◽

pp. 386-398 ◽

Cited By ~ 22

Author(s):

Fabricio Ferreira de Oliveira ◽

Elizabeth Suchi Chen ◽

Marilia Cardoso Smith ◽

Paulo Henrique Ferreira Bertolucci

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Angiotensin Converting Enzyme ◽

Cognitive Decline ◽

Enzyme Inhibitors ◽

Late Onset ◽

Amyloid Β ◽

Converting Enzyme ◽

Converting Enzyme Inhibitors ◽

Alzheimer’S Disease Dementia

Background: While the angiotensin-converting enzyme degrades amyloid-β, angiotensinconverting enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer’s disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with AD, while also taking APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification. Methods: Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with ACEis. Results: For 193 patients, minor allele frequencies were 0.497 for rs1800764 – C (44.6% heterozygotes) and 0.345 for rs4291 – T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 – T and rs4291 – A, or for APOE4- carriers of rs1800764 – T or rs4291 – T, ACEis slowed cognitive decline independently of blood pressure variations. APOE4+ carriers were not responsive to treatment with ACEis. Conclusion: ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4- carriers of specific ACE genotypes.

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A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer's disease pathology in mice

Journal of Biological Chemistry ◽

10.1074/jbc.ra118.006420 ◽

2019 ◽

Vol 294 (25) ◽

pp. 9760-9770 ◽

Cited By ~ 5

Author(s):

Shuyu Liu ◽

Fujiko Ando ◽

Yu Fujita ◽

Junjun Liu ◽

Tomoji Maeda ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Angiotensin Converting Enzyme ◽

Amyloid Precursor Protein ◽

Ace Inhibitors ◽

Ace Inhibitor ◽

Precursor Protein ◽

Causative Role ◽

Converting Enzyme ◽

Clinical Dose

Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In addition to converting angiotensin I to angiotensin II, ACE also converts neurotoxic β-amyloid protein 42 (Aβ42) to Aβ40. Because of its neurotoxicity, Aβ42 is believed to play a causative role in the development of Alzheimer's disease (AD), whereas Aβ40 has neuroprotective effects against Aβ42 aggregation and also against metal-induced oxidative damage. Whether ACE inhibition enhances Aβ42 aggregation or impairs human cognitive ability are very important issues for preventing AD onset and for optimal hypertension management. In an 8-year longitudinal study, we found here that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in Aβ42-to-Aβ40–converting activity compared with sera from age-matched healthy individuals. Using human amyloid precursor protein transgenic mice, we found that a clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated human amyloid precursor protein/ACE+/− mice and found that a decrease in ACE levels promoted Aβ42 deposition and increased the number of apoptotic neurons. These results suggest that inhibition of ACE activity is a risk factor for impaired human cognition and for triggering AD onset.

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