ADAM10 missense mutations potentiate β-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 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.
Genetics and Aging Research Unit, MassGeneral Institute of Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Jaehong
J
Suh
Se Hoon
SH
Choi
Donna M
DM
Romano
Moira A
MA
Gannon
Andrea N
AN
Lesinski
Doo Yeon
DY
Kim
Rudolph E
RE
Tanzi
D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005911:Gliosis / Q000473:pathology; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics; D058225:Plaque, Amyloid / Q000378:metabolism
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D018832:Molecular Chaperones; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human