ADAM10 and its role in Alzheimer disease

The amyloidogenic pathway of amyloid precursor protein (APP) processing is well known in the pathogenesis and therapeutics of Alzheimer disease (AD), whereas the non-amyloidogenic pathway has been less studied. ADAM10 is the main α-secretase responsible for this pathway in the human brain.

ADAM10 belongs to a family of transmembrane proteins with catalytic activity. It acts as an α-secretase on APP and many other substrates, some of which are particularly relevant in the central nervous system. The ADAM10 gene has been identified in genome-wide association studies of patients with AD; mutations have been reported in families with strong functional support but incomplete segregation; and haploinsufficiency has been reported in a family carrying a nonsense mutation. However, genetic studies of AD cohorts have not identified causal variants. ADAM10 levels in biological fluids show conflicting results, except in platelets, where patients with AD consistently exhibit reduced levels. Stimulation of ADAM10 as a therapeutic target offers new opportunities through various components and such measures as physical exercise. However, only one (positive) clinical trial has been published to date, using the retinoid acitretin.

ADAM10 plays a fundamental role in brain function, and sufficient studies support its involvement in AD pathogenesis. There are only isolated examples of ADAM10 mutations as a genetic cause, but these encourage continued screening in familial AD. ADAM10 levels in platelets could be considered as a biomarker. The enhancement of ADAM10 expression in AD remains a therapeutic target that requires further research.