ADAM10 missense mutations potentiate beta-amyloid accumulation by impairing prodomain chaperone function.
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Suh J, Choi SH, Romano DM, Gannon MA, Lesinski AN, Kim DY, Tanzi RE
ADAM10 missense mutations potentiate beta-amyloid accumulation by impairing prodomain chaperone function.
Neuron. 2013 Oct 16;80(2):385-401. doi: 10.1016/j.neuron.2013.08.035. Epub 2013 Sep 19.
- PubMed ID
- 24055016 [ View in PubMed]
- Abstract
The generation of Abeta, the main component of senile plaques in Alzheimer's disease (AD), is precluded by alpha-secretase cleavage within the Abeta domain of the amyloid precursor protein (APP). We identified two rare mutations (Q170H and R181G) in the prodomain of the metalloprotease, ADAM10, that cosegregate with late-onset AD (LOAD). Here, we addressed the pathogenicity of these mutations in transgenic mice expressing human ADAM10 in brain. In Tg2576 AD mice, both mutations attenuated alpha-secretase activity of ADAM10 and shifted APP processing toward beta-secretase-mediated cleavage, while enhancing Abeta plaque load and reactive gliosis. We also demonstrated ADAM10 expression potentiates adult hippocampal neurogenesis, which is reduced by the LOAD mutations. Mechanistically, both LOAD mutations impaired the molecular chaperone activity of ADAM10 prodomain. Collectively, these findings suggest that diminished alpha-secretase activity, owing to LOAD ADAM10 prodomain mutations, leads to AD-related pathology, strongly supporting ADAM10 as a promising therapeutic target for this devastating disease.