Effects of Angiotensin-I-Converting Enzyme (ACE) Mutations Associated with Alzheimer's Disease on Blood ACE Phenotype

Our recent analysis of 1200+ existing missense ACE mutations revealed that 400+ mutations are damaging and led us to hypothesize that carriers of heterozygous loss-of-function (LoF) ACE mutations (which result in low ACE levels) could be at risk for the development of late-onset Alzheimer's dis...

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Published in:	Biomedicines Vol. 12; no. 10; p. 2410
Main Authors:	Kryukova, Olga V, Islanov, Igor O, Zaklyazminskaya, Elena V, Korostin, Dmitry O, Belova, Vera A, Cheranev, Valery V, Repinskaia, Zhanna A, Tonevitskaya, Svetlana A, Petukhov, Pavel A, Dudek, Steven M, Kost, Olga A, Rebrikov, Denis V, Danilov, Sergei M
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 21-10-2024 MDPI
Subjects:	ACE inhibitors ACE protein Alzheimer's disease Analysis Angiotensin angiotensin-I-converting enzyme blood ACE Blood levels Care and treatment conformational changes Diagnosis Dosage and administration Enzymes Gene mutations Genetic aspects Genotype & phenotype Health aspects Health risk assessment Mutation mutations Neurodegenerative diseases Peptides Phenotype Phenotypes Plasma Proteasome inhibitors Proteasomes Protein transport Proteins Quality control Risk factors screening Therapeutic applications β-Amyloid Russia St Louis Missouri United States > US blood ACE screening angiotensin-I-converting enzyme conformational changes mutations Alzheimer’s disease
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Summary:	Our recent analysis of 1200+ existing missense ACE mutations revealed that 400+ mutations are damaging and led us to hypothesize that carriers of heterozygous loss-of-function (LoF) ACE mutations (which result in low ACE levels) could be at risk for the development of late-onset Alzheimer's disease (AD). Here, we quantified blood ACE levels in EDTA plasma from 41 subjects with 10 different heterozygous ACE mutations, as well as 33 controls, and estimated the effect of these mutations on ACE phenotype using a set of mAbs to ACE and two ACE substrates. We found that relatively frequent (~1%) AD-associated ACE mutations in the N domain of ACE, Y215C, and G325R are truly damaging and likely transport-deficient, with the ACE levels in plasma at only ~50% of controls. Another AD-associated ACE mutation, R1250Q, in the cytoplasmic tail, did not cause a decrease in ACE and likely did not affect surface ACE expression. We have also developed a method to identify patients with anti-catalytic mutations in the N domain. These mutations may result in reduced degradation of amyloid beta peptide Aβ42, an important component for amyloid deposition. Consequently, these could pose a risk factor for the development of AD. Therefore, a systematic analysis of blood ACE levels in patients with all ACE mutations has the potential to identify individuals at an increased risk of late-onset AD. These individuals may benefit from future preventive or therapeutic interventions involving a combination of chemical and pharmacological chaperones, as well as proteasome inhibitors, aiming to enhance ACE protein traffic. This approach has been previously demonstrated in our cell model of the transport-deficient ACE mutation Q1069R.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2227-9059 2227-9059
DOI:	10.3390/biomedicines12102410