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Astrocytic APOE4 genotype-mediated negative impacts on synaptic architecture in human pluripotent stem cell model.
Watanabe, Hirotaka; Murakami, Rei; Tsumagari, Kazuya; Morimoto, Satoru; Hashimoto, Tadafumi; Imaizumi, Kent; Sonn, Iki; Yamada, Kaoru; Saito, Yuko; Murayama, Shigeo; Iwatsubo, Takeshi; Okano, Hideyuki.
Afiliação
  • Watanabe H; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: hwatanabe@keio.jp.
  • Murakami R; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Research Fellow of Japan Society for the Promotion of Science (JSPS), Tokyo 102-0083, Japan.
  • Tsumagari K; Center for Integrated Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
  • Morimoto S; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
  • Hashimoto T; Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
  • Imaizumi K; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
  • Sonn I; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Research Fellow of Japan Society for the Promotion of Science (JSPS), Tokyo 102-0083, Japan.
  • Yamada K; Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
  • Saito Y; Department of Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo 173-0015, Japan.
  • Murayama S; Department of Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo 173-0015, Japan; Brain Bank for Neurodevelopmental, Neurological and Psychiatric Disorders, United Graduate School of Child Development, Osaka University, Osaka
  • Iwatsubo T; Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
  • Okano H; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: hidokano@keio.jp.
Stem Cell Reports ; 18(9): 1854-1869, 2023 09 12.
Article em En | MEDLINE | ID: mdl-37657448
The APOE4 genotype is the strongest risk factor for the pathogenesis of sporadic Alzheimer's disease (AD), but the detailed molecular mechanism of APOE4-mediated synaptic impairment remains to be determined. In this study, we generated a human astrocyte model carrying the APOE3 or APOE4 genotype using human induced pluripotent stem cells (iPSCs) in which isogenic APOE4 iPSCs were genome edited from healthy control APOE3 iPSCs. Next, we demonstrated that the astrocytic APOE4 genotype negatively affects dendritic spine dynamics in a co-culture system with primary neurons. Transcriptome analysis revealed an increase of EDIL3, an extracellular matrix glycoprotein, in human APOE4 astrocytes, which could underlie dendritic spine reduction in neuronal cultures. Accordingly, postmortem AD brains carrying the APOE4 allele have elevated levels of EDIL3 protein deposits within amyloid plaques. Together, these results demonstrate the novel deleterious effect of human APOE4 astrocytes on synaptic architecture and may help to elucidate the mechanism of APOE4-linked AD pathogenesis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco Pluripotentes / Células-Tronco Pluripotentes Induzidas Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco Pluripotentes / Células-Tronco Pluripotentes Induzidas Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article