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Science. 2009 Mar 13;323(5920):1473-7. doi: 10.1126/science.1168979.

A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis.

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1
Division of Neurology and Neuropathology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.

Abstract

beta-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673-->valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced beta-amyloid (Abeta) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Abeta aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer's disease.

PMID:
19286555
PMCID:
PMC2728497
DOI:
10.1126/science.1168979
[Indexed for MEDLINE]
Free PMC Article
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