Title : ACE-dependent alzheimer’s disease
Abstract:
An analysis of 1200+ existing missense ACE mutations revealed that >400 are predicted to be damaging and led us to hypothesize that heterozygous carriers of these loss-of-function (LoF) ACE mutations (which result in low ACE levels) may be at risk for the development of late-onset Alzheimer’s disease (AD) [Danilov, 2024].
The 1st stage of this ACE-dependent AD project is characterization of blood ACE levels, catalytic properties, and conformations (ACE phenotyping) using a wide set of mAbs to ACE that were developed in our lab. We already have performed ACE phenotyping in >200 carriers of 80+ different ACE mutations and 200+ controls [Kryukova, Biomedicines, 2024, PloS One, 2024, unpublished]. We found that several of the relatively frequent AD-associated ACE mutations (present in at least 2% of the population) are truly damaging and, likely transport-deficient, resulting in plasma ACE levels only ~50% of controls. Some other AD-associated ACE mutations were not associated with a decrease in blood ACE levels, and likely do not affect ACE surface expression. Thus, their mechanism of association with AD is likely different, such as via catalytic changes. However, both these types of ACE mutations may result in reduced degradation of amyloid beta peptide Aβ42, an important component for amyloid deposition, and may pose a risk factor for the development of AD. Therefore, a systematic analysis of blood ACE levels in patients with ACE mutations has the potential to identify individuals at increased risk of late-onset AD.
The 2nd stage of this project will include 1) Cell-based in vitro model (HEK cells transfected with cDNA of different ACE mutations) in order to find transport-deficient ACE mutations, which may be amenable to rescue of impaired trafficking of mutant ACE to the cell surface; 2) medico-genetic analysis of 50-100 families of carriers with the most damaging and transport-deficient ACE mutations. This stage will identify prospective candidates for a future limited clinical trial of preventive or therapeutic interventions to delay the development of ACE-dependent AD.
The 3rd stage of the project could be a limited clinical trial in individuals with several transport-deficient ACE mutations (starting with the most frequent damaging ACE mutation, Y215C) aiming to enhance mutant ACE protein traffic, as we previously demonstrated for the transport-deficient ACE mutation, Q1069R, using a combination of chemical and pharmacological chaperones and proteosome inhibitors [Danilov, PloS One, 2010].
