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Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer’s disease

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  • Sang Su Kwak

    (Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School)

  • Kevin J. Washicosky

    (Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School)

  • Emma Brand

    (Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School)

  • Djuna Maydell

    (Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School)

  • Jenna Aronson

    (Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School
    Massachusetts Institute of Technology)

  • Susan Kim

    (Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School)

  • Diane E. Capen

    (Center for Systems Biology and Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital, Harvard Medical School)

  • Murat Cetinbas

    (Massachusetts General Hospital)

  • Ruslan Sadreyev

    (Massachusetts General Hospital)

  • Shen Ning

    (Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School
    Graduate Program for Neuroscience, Boston University School of Medicine)

  • Enjana Bylykbashi

    (Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School)

  • Weiming Xia

    (Geriatric Research Education and Clinical Center, Edith Nourse Rogers Memorial Veterans Hospital
    Boston University School of Medicine)

  • Steven L. Wagner

    (University of California, San Diego)

  • Se Hoon Choi

    (Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School)

  • Rudolph E. Tanzi

    (Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School)

  • Doo Yeon Kim

    (Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School)

Abstract

The relationship between amyloid-β (Aβ) species and tau pathology in Alzheimer’s disease (AD) is not fully understood. Here, we provide direct evidence that Aβ42/40 ratio, not total Aβ level, plays a critical role in inducing neurofibrillary tangles (NTFs) in human neurons. Using 3D-differentiated clonal human neural progenitor cells (hNPCs) expressing varying levels of amyloid β precursor protein (APP) and presenilin 1 (PS1) with AD mutations, we show that pathogenic tau accumulation and aggregation are tightly correlated with Aβ42/40 ratio. Roles of Aβ42/40 ratio on tau pathology are also confirmed with APP transmembrane domain (TMD) mutant hNPCs, which display differential Aβ42/40 ratios without mutant PS1. Moreover, naïve hNPCs co-cultured with APP TMD I45F (high Aβ42/40) cells, not with I47F cells (low Aβ42/40), develop robust tau pathology in a 3D non-cell autonomous cell culture system. These results emphasize the importance of reducing the Aβ42/40 ratio in AD therapy.

Suggested Citation

  • Sang Su Kwak & Kevin J. Washicosky & Emma Brand & Djuna Maydell & Jenna Aronson & Susan Kim & Diane E. Capen & Murat Cetinbas & Ruslan Sadreyev & Shen Ning & Enjana Bylykbashi & Weiming Xia & Steven L, 2020. "Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer’s disease," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15120-3
    DOI: 10.1038/s41467-020-15120-3
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    Cited by:

    1. Yifan He & Yang Feng & Xinyuan Song, 2023. "Variable selection for high‐dimensional generalized linear model with block‐missing data," Scandinavian Journal of Statistics, Danish Society for Theoretical Statistics;Finnish Statistical Society;Norwegian Statistical Association;Swedish Statistical Association, vol. 50(3), pages 1279-1297, September.

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