Loading…

ADAM10 Missense Mutations Potentiate [beta]-Amyloid Accumulation by Impairing Prodomain Chaperone Function

The generation of Aβ, the main component of senile plaques in Alzheimer's disease (AD), is precluded by [alpha]-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, tha...

Full description

Saved in:
Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2013-10, Vol.80 (2), p.385
Main Authors: Suh, Jaehong, Choi, Se Hoon, Romano, Donna M, Gannon, Moira A, Lesinski, Andrea N, Kim, Doo Yeon, Tanzi, Rudolph E
Format: Article
Language:English
Subjects:
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The generation of Aβ, the main component of senile plaques in Alzheimer's disease (AD), is precluded by [alpha]-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 [alpha]-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 [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.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2013.08.035