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ApoE4 Gene Variant and Alzheimer’s Disease Risk

Journal Club April 2018

 

Dr. Oliver Medvedik hosts the April 2018 edition of Journal Club, our monthly livestreamed event where we review and discuss the latest scientific research publications relating to life extension and aging. This month, we discuss the gene variant ApoE4, which raises the risk of Alzheimer’s disease [1].

Abstract

Efforts to develop drugs for Alzheimer’s disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD, we demonstrated that ApoE4-expressing neurons had higher levels of tau phosphorylation, unrelated to their increased production of amyloid-ฮฒ (Aฮฒ) peptides, and that they displayed GABAergic neuron degeneration. ApoE4 increased Aฮฒ production in human, but not in mouse, neurons. Converting ApoE4 to ApoE3 by gene editing rescued these phenotypes, indicating the specific effects of ApoE4. Neurons that lacked APOE behaved similarly to those expressing ApoE3, and the introduction of ApoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from ApoE4. Treatment of ApoE4-expressing neurons with a small-molecule structure corrector ameliorated the detrimental effects, thus showing that correcting the pathogenic conformation of ApoE4 is a viable therapeutic approach for ApoE4-related AD.

Literature
[1] Wang, C., Najm, R., Xu, Q., Jeong, D. E., Walker, D., Balestra, M. E., Yoon, S. Y., Yuan, H., Li, G., Miller, Z. A., Miller, B. L., Malloy, M. J., & Huang, Y. (2018). Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nature medicine,ย 24(5), 647โ€“657. https://doi.org/10.1038/s41591-018-0004-z
CategoryNews
About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri โ€“ Google AR and Dinorah Delfin โ€“ Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
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