Molecular mechanism of sporadic Alzheimer's disease onset

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Amyloid beta (Ab) oligomer is a major causative factor of Alzheimer's disease (AD). Compared to familialAD (FAD), it remains unclear how neurotoxic Ab species is generated and/or what mechanism can increase the generation of Ab in sporadic AD (SAD). To reveal this, first I focused on the axonal transport of APP, which is a precursor protein of Ab and functions as kinesin-1 cargo, because disturbed anterograde transport of APP alters Ab generation. We revealed how APP connect with kinesin-1 motor mediated by JIP1b. Sexond I analyzed gamma-secretase malfunction in SAD patient. In FAD who carry mutations of causative gene, gamma-cleavage are altered. We found altered gamma-cleaved peptide in SAD patients, in other words, alcadein fragment in CSF are altered in SAD. These analyses support an idea that SAD is generated by several causes to induce a quantitative and/or qualitative change of Ab production, and results are useful to develop the tailor-made therapies.