APP Osaka Mutation in Familial Alzheimer's Disease-Its Discovery, Phenotypes, and Mechanism of Recessive Inheritance

Alzheimer's disease is believed to begin with synaptic dysfunction caused by soluble A beta oligomers. When this oligomer hypothesis was proposed in 2002, there was no direct evidence that A beta oligomers actually disrupt synaptic function to cause cognitive impairment in humans. In patient brains, both soluble and insoluble A beta species always coexist, and therefore it is difficult to determine which pathologies are caused by A beta oligomers and which are caused by amyloid fibrils. Thus, no validity of the oligomer hypothesis was available until the Osaka mutation was discovered. This mutation, which was found in a Japanese pedigree of familial Alzheimer's disease, is the deletion of codon 693 of APP gene, resulting in mutant A beta lacking the 22nd glutamate. Only homozygous carriers suffer from dementia. In vitro studies revealed that this mutation has a very unique character that accelerates A beta oligomerization but does not form amyloid fibrils. Model mice expressing this mutation demonstrated that all pathologies of Alzheimer's disease can be induced by A beta oligomers alone. In this review, we describe the story behind the discovery of the Osaka mutation, summarize the mutant's phenotypes, and propose a mechanism of its recessive inheritance.