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Neuron. 2013 Oct 16;80(2):385-401. doi: 10.1016/j.neuron.2013.08.035. Epub 2013 Sep 19.

ADAM10 missense mutations potentiate β-amyloid accumulation by impairing prodomain chaperone function.

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Genetics and Aging Research Unit, MassGeneral Institute of Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.


The generation of Aβ, the main component of senile plaques in Alzheimer's disease (AD), is precluded by α-secretase cleavage within the Aβ 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 α-secretase activity of ADAM10 and shifted APP processing toward β-secretase-mediated cleavage, while enhancing Aβ 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 α-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.

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