Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector
| Autor: | Heidi Yuan, Qin Xu, Dah-Eun Jeong, Ramsey Najm, Maureen E. Balestra, Zachary A. Miller, Yadong Huang, Mary J. Malloy, Bruce L. Miller, Gang Li, Chengzhong Wang, David Walker, Seo Yeon Yoon |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Apolipoprotein E Aging Apolipoprotein E4 Apolipoprotein E3 Neurodegenerative Alzheimer's Disease Medical and Health Sciences Genome editing 2.1 Biological and endogenous factors Protein Isoforms Aetiology Phosphorylation GABAergic Neurons Induced pluripotent stem cell Cells Cultured Neurons Gene Editing Cultured Homozygote General Medicine Phenotype Small molecule Cell biology Neurological lipids (amino acids peptides and proteins) Animal studies Cells Induced Pluripotent Stem Cells Immunology tau Proteins Biology General Biochemistry Genetics and Molecular Biology Article Cell Line Small Molecule Libraries 03 medical and health sciences Alzheimer Disease mental disorders Genetics Acquired Cognitive Impairment Humans Amyloid beta-Peptides Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Stem Cell Research Brain Disorders 030104 developmental biology Cell culture Nerve Degeneration APOE Gene Product Dementia human activities |
| Zdroj: | Wang, C; Najm, R; Xu, Q; Jeong, D-E; Walker, D; Balestra, ME; et al.(2018). Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. NATURE MEDICINE, 24(5), 647-+. doi: 10.1038/s41591-018-0004-z. UCSF: Retrieved from: http://www.escholarship.org/uc/item/796161bm Nature medicine, vol 24, iss 5 Nature medicine |
| Popis: | 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-β (Aβ) peptides, and that they displayed GABAergic neuron degeneration. ApoE4 increased Aβ 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. |
| Databáze: | OpenAIRE |
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