Anti-amyloidogenicactivity of a mutant form of Aβ: a new strategy for Alzheimer therapy

Amyloid-β precursor protein (APP) mutations cause familial Alzheimer’s disease with virtually complete penetrance. We found an APP mutation (A673V) that causes disease only in the homozygous state, while heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced amyloid β (Aβ) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Aβ 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.