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The Journal of Neuroscience, September 17, 2003, 23(24):8513-8525

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Analysis of Neurons Created from Wild-Type and Alzheimer's Mutation Knock-In Embryonic Stem Cells by a Highly Efficient Differentiation Protocol

Yoichiro Abe,^1 * Keisuke Kouyama,^1 * Taisuke Tomita,² Yusuke Tomita,¹ Norimitsu Ban,¹ Mikiro Nawa,¹ Masaaki Matsuoka,¹ Takako Niikura,¹ Sadakazu Aiso,¹ Yoshiko Kita,¹ Takeshi Iwatsubo,² and Ikuo Nishimoto¹

¹Departments of Pharmacology and Anatomy, KEIO University School of Medicine, Tokyo 160-8582, Japan, and ²Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan

It is impossible to obtain and amplify live neurons from Alzheimer's disease (AD) patients. To establish the neurons harboring AD abnormality, we constructed mouse embryonic stem (ES) cells, in which the AD-causative V642I mutation was introduced to the endogenous amyloid precursor protein (APP) gene, in combination with a protocol to efficiently differentiate ES cells into postmitotic neurons without using a cell sorter. By this protocol, ES cells differentiated into >90% of the central type of adult postmitotic neurons. Neurons derived from V642I–APP knock-in ES cells were indistinguishable from wild-type ES-derived neurons, as determined by the expression of various markers for neuronal differentiation. Notably, V642I–APP knock-in ES cell-derived neurons exhibited significantly increased secretion of A42 without AD-related hyperphosphorylation of tau, indicating that the direct output of the AD-causative mutation is increased A42 secretion. In this study, we analyze created neurons with wild-type and AD genotypes and propose a new strategy for generating neurons for any dominantly inherited neurodegenerative diseases. The strategy can be applied to create human neurons with AD or any other neurodegenerative disease by using human ES cells.

Key words: embryonic stem cell; postmitotic neuron; differentiation; Alzheimer's disease; gene knock-in; sharable neuron with disease genotype; amyloid precursor protein; amyloid- protein; tau

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Received Nov 26, 2002; revised July 21, 2003; accepted July 22, 2003.

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