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APP Osaka Mutation in Familial Alzheimer's Disease-Its Discovery, Phenotypes, and Mechanism of Recessive Inheritance
Takami Tomiyama1, Hiroyuki Shimada2
1Department of Translational Neuroscience, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
Abstract:
Alzheimer's disease is believed to begin with synaptic dysfunction caused by soluble Aβ oligomers. When this oligomer hypothesis was proposed in 2002, there was no direct evidence that Aβ oligomers actually disrupt synaptic function to cause cognitive impairment in humans. In patient brains, both soluble and insoluble Aβ species always coexist, and therefore it is difficult to determine which pathologies are caused by Aβ 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 Aβ lacking the 22nd glutamate. Only homozygous carriers suffer from dementia. In vitro studies revealed that this mutation has a very unique character that accelerates Aβ oligomerization but does not form amyloid fibrils. Model mice expressing this mutation demonstrated that all pathologies of Alzheimer's disease can be induced by Aβ 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.
Insights
The Osaka mutation provides the first direct evidence that amyloid-beta (Aβ) oligomers, not fibrils, cause Alzheimer's disease cognitive decline. This discovery validates the Aβ oligomer hypothesis, advancing our understanding of Alzheimer's pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Alzheimer's disease (AD) pathogenesis is linked to amyloid-beta (Aβ) oligomers causing synaptic dysfunction.
- Direct evidence linking Aβ oligomers to human cognitive impairment was lacking.
- Coexistence of soluble and insoluble Aβ species in patients complicated etiological studies.
Purpose of the Study:
- To investigate the role of Aβ oligomers in Alzheimer's disease.
- To validate the Aβ oligomer hypothesis using a unique genetic mutation.
- To elucidate the mechanism of recessive inheritance in familial Alzheimer's disease.
Main Methods:
- Discovery and characterization of the Osaka mutation (APP gene codon 693 deletion).
- In vitro studies on Aβ oligomerization and fibril formation.
- Analysis of Alzheimer's disease pathologies in model mice expressing the Osaka mutation.
Main Results:
- The Osaka mutation accelerates Aβ oligomerization but prevents amyloid fibril formation.
- Homozygous carriers of the Osaka mutation develop dementia.
- Aβ oligomers alone were sufficient to induce all observed Alzheimer's disease pathologies in model mice.
Conclusions:
- The Osaka mutation provides definitive evidence for Aβ oligomers as the primary cause of Alzheimer's disease.
- This finding validates the Aβ oligomer hypothesis, shifting focus from amyloid fibrils.
- The study elucidates a mechanism for recessive inheritance in familial Alzheimer's disease driven by Aβ oligomers.
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