Biochimica et biophysica acta. Molecular basis of disease · 2025
ACE-dependent Alzheimer's disease: Further assessment of the impact of ACE mutations on blood ACE levels.
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Korf Ekaterina A, Belinskaia Daria A, Glotov Andrei S, Glotov Oleg S, Novokovich Yulia S, Korostin Dmitry O, Rebrikov Denis V, Dudek Steven M, Goncharov Nikolay V, Danilov Sergei M
Аннотация
BACKGROUND: Carriers of damaging mutations in the angiotensin-I-converting enzyme (ACE) that result in low ACE levels may be at increased risk for late-onset Alzheimer's disease (AD).
METHODOLOGY/PRINCIPAL FINDINGS: We measured blood ACE levels in EDTA-plasma from 74 subjects with 12 different heterozygous ACE mutations. Using a panel of monoclonal antibodies to ACE and two ACE substrates, we assessed the impact of these mutations on ACE phenotypes. We identified several mutations spanning both ACE domains, including the most frequent mutation, Y215C, that significantly reduce blood ACE levels. Therefore, these mutations may serve as potential risk factors for late-onset AD. Additionally, two mutations tested, G325R and E738K, altered ACE catalytic properties. We also found that the binding of certain mAbs to mutant ACEs could serve as markers for these and other ACE mutations. This would enable monitoring the fate of mutant ACEs in the blood during potential future therapies, particularly in the case of transport-deficient ACE mutations. The interaction between ACE and amyloid beta 1-42 (Aβ42) was studied using molecular modeling, which predicts which ACE mutations may influence Aβ42 hydrolysis, and consequently increase the risk of AD development.
CONCLUSIONS/SIGNIFICANCE: Systematic analysis of blood ACE levels in patients with ACE mutations holds promise for identifying individuals at increased risk of late-onset AD. Patients with ACE mutations affecting transport efficiency may potentially benefit from therapeutic strategies combining chemical and pharmacological chaperones with proteasome inhibitors, as demonstrated previously in a cellular model of the transport-deficient ACE mutation Q1069R.
METHODOLOGY/PRINCIPAL FINDINGS: We measured blood ACE levels in EDTA-plasma from 74 subjects with 12 different heterozygous ACE mutations. Using a panel of monoclonal antibodies to ACE and two ACE substrates, we assessed the impact of these mutations on ACE phenotypes. We identified several mutations spanning both ACE domains, including the most frequent mutation, Y215C, that significantly reduce blood ACE levels. Therefore, these mutations may serve as potential risk factors for late-onset AD. Additionally, two mutations tested, G325R and E738K, altered ACE catalytic properties. We also found that the binding of certain mAbs to mutant ACEs could serve as markers for these and other ACE mutations. This would enable monitoring the fate of mutant ACEs in the blood during potential future therapies, particularly in the case of transport-deficient ACE mutations. The interaction between ACE and amyloid beta 1-42 (Aβ42) was studied using molecular modeling, which predicts which ACE mutations may influence Aβ42 hydrolysis, and consequently increase the risk of AD development.
CONCLUSIONS/SIGNIFICANCE: Systematic analysis of blood ACE levels in patients with ACE mutations holds promise for identifying individuals at increased risk of late-onset AD. Patients with ACE mutations affecting transport efficiency may potentially benefit from therapeutic strategies combining chemical and pharmacological chaperones with proteasome inhibitors, as demonstrated previously in a cellular model of the transport-deficient ACE mutation Q1069R.