Version 1
: Received: 7 June 2024 / Approved: 10 June 2024 / Online: 11 June 2024 (08:02:17 CEST)
How to cite:
Kryukova, O. V.; Islanov, I. O.; Zaklyazminskaya, E. V.; Korostin, D. O.; Belova, V. A.; Cheranev, V. V.; Repinskaia, Z. A.; Tonevitskaya, S. A.; Tonevitsky, A. G.; Petukhov, P. A.; Dudek, S. M.; Kost, O. A.; Rebrikov, D. V.; Danilov, S. M. Effects of ACE Mutations Associated with Alzheimer’s Disease on Blood ACE Phenotype. Preprints2024, 2024060599. https://doi.org/10.20944/preprints202406.0599.v1
Kryukova, O. V.; Islanov, I. O.; Zaklyazminskaya, E. V.; Korostin, D. O.; Belova, V. A.; Cheranev, V. V.; Repinskaia, Z. A.; Tonevitskaya, S. A.; Tonevitsky, A. G.; Petukhov, P. A.; Dudek, S. M.; Kost, O. A.; Rebrikov, D. V.; Danilov, S. M. Effects of ACE Mutations Associated with Alzheimer’s Disease on Blood ACE Phenotype. Preprints 2024, 2024060599. https://doi.org/10.20944/preprints202406.0599.v1
Kryukova, O. V.; Islanov, I. O.; Zaklyazminskaya, E. V.; Korostin, D. O.; Belova, V. A.; Cheranev, V. V.; Repinskaia, Z. A.; Tonevitskaya, S. A.; Tonevitsky, A. G.; Petukhov, P. A.; Dudek, S. M.; Kost, O. A.; Rebrikov, D. V.; Danilov, S. M. Effects of ACE Mutations Associated with Alzheimer’s Disease on Blood ACE Phenotype. Preprints2024, 2024060599. https://doi.org/10.20944/preprints202406.0599.v1
APA Style
Kryukova, O. V., Islanov, I. O., Zaklyazminskaya, E. V., Korostin, D. O., Belova, V. A., Cheranev, V. V., Repinskaia, Z. A., Tonevitskaya, S. A., Tonevitsky, A. G., Petukhov, P. A., Dudek, S. M., Kost, O. A., Rebrikov, D. V., & Danilov, S. M. (2024). Effects of ACE Mutations Associated with Alzheimer’s Disease on Blood ACE Phenotype. Preprints. https://doi.org/10.20944/preprints202406.0599.v1
Chicago/Turabian Style
Kryukova, O. V., Denis V. Rebrikov and Sergei M. Danilov. 2024 "Effects of ACE Mutations Associated with Alzheimer’s Disease on Blood ACE Phenotype" Preprints. https://doi.org/10.20944/preprints202406.0599.v1
Abstract
An analysis of 1300+ existing ACE mutations revealed that 400+ are damaging and led us to hy-pothesize 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) [Danilov, 2024]. Here we quantified blood ACE levels in EDTA-plasma from 41patients 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 ACE levels in plasma 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 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 a cell model of the transport-deficient ACE mutation, Q1069R [Danilov, 2010].
Medicine and Pharmacology, Neuroscience and Neurology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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