A novel APP mutation (E693Δ): characterization and implication in the Aβ oligomer hypothesis

Takami Tomiyama

Department of Neuroscience, Osaka City University Graduate School of Medicine

Based on experimental models, soluble Aβ oligomers have been proposed to initiate synaptic and cognitive dysfunction in Alzheimer's disease. However, there is no direct evidence in humans that this mechanism can cause Alzheimer's disease. We recently identified a novel APP mutation (E693Δ) in Japanese pedigrees showing Alzheimer's disease. This mutation produces variant Aβ with a unique aggregation property of enhanced oligomerization but no fibrillization. The mutant Aβ inhibited hippocampal long-term potentiation in rats in vivo and induced synaptic alteration in mouse hippocampal slices more potently than wild-type Aβ. Amyloid imaging with a PET tracer Pittsburgh compound-B demonstrated little amyloid deposition in the patient's brain. These results suggest that the E693Δ mutation causes disease by enhanced formation of synaptotoxic Aβ oligomers in the absence of fibril formation. Our findings may provide genetic validation in humans for the Aβ oligomer hypothesis.

Address correspondence to Dr. Takami Tomiyama, Department of Neuroscience, Osaka City University Graduate School of Medicine (1-4-3 Asahimachi, Abeno-ku, Osaka 5454-8585, Japan)