Effect of ACE mutations on blood ACE phenotype parameters

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• Investigating Angiotensin-I-Converting Enzyme (ACE) mutations suggests a link between carriers of damaging mutations and low ACE levels.
• This observation leads to a hypothesis that these individuals may be at higher risk for developing late-onset Alzheimer's disease (AD).

Purpose of the Study:

• To analyze blood ACE levels in patients with various ACE mutations.
• To identify specific ACE mutations associated with decreased ACE levels and potential risk factors for late-onset AD.

Main Methods:

• Quantified blood ACE levels in plasma from 15 patients with 11 heterozygous ACE mutations.
• Utilized a set of monoclonal antibodies (mAbs) to ACE and two ACE substrates to estimate mutation effects on ACE phenotypes.

Main Results:

• Confirmed Y215C mutation is associated with AD and reduced ACE levels, likely due to impaired transport.
• Identified four additional mutations (M118T, C734Y, V992M, V997M) linked to decreased blood ACE levels, posing potential risks for AD.
• Discovered mutation C734Y is likely transport-deficient, while others affect ACE catalytic properties. Identified I989T mutation associated with increased ACE levels.

Conclusions:

• Systematic analysis of blood ACE levels in patients with ACE mutations can identify individuals at risk for late-onset AD.
• Patients with transport-deficient ACE mutations might benefit from chaperone and proteasome inhibitor therapies, as shown in prior cell models.