Abstract

Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals1,2,3,4. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain5,6. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

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Acknowledgements

We thank D.R. Galasko (University of California San Diego), J.A. Kaye (Oregon Health Sciences University), G. Li (Veterans Affairs Northwest Network Mental Illness Research, Education and Clinical Center), E.R. Peskind (University of Washington and Veterans Affairs Northwest Network Mental Illness Research, Education and Clinical Center), and J.F. Quinn (Oregon Health Sciences University) for generously providing human plasma and CSF samples. We are grateful to numerous unnamed human subjects and staff for their contributions. We thank D. Dubal and M. Thomson for critically reading manuscript. This work was funded by a California Institute for Regenerative Medicine (CIRM) fellowship (K.L.), a National Science Foundation fellowship (J.U.), a National Research Service Award fellowship (1F31-AG050415, E.G.W.), Anonymous (T.W.-C.), Veterans Affairs (T.W.-C.), the National Institute on Aging (AG027505, T.W.-C.), CIRM (T.W.-C.), the Sandler Foundation (S.A.V.), a gift from Marc and Lynne Benioff, (S.A.V.), the University of California San Francisco Clinical and Translational Science Institute (UL1-TR000004, S.A.V.), and the US National Institutes of Health Director's Independence Award (DP5-OD12178, S.A.V.).

Author information

Author notes

    • Lucas K Smith
    • , Yingbo He
    • , Jeong-Soo Park
    • , Gregor Bieri
    •  & Cedric E Snethlage

    These authors contributed equally to this work.

Affiliations

  1. Department of Anatomy, University of California San Francisco, San Francisco, California, USA.

    • Lucas K Smith
    • , Gregor Bieri
    • , Cedric E Snethlage
    • , Karin Lin
    • , Geraldine Gontier
    • , Kristopher E Plambeck
    • , Joe Udeochu
    • , Elizabeth G Wheatley
    • , Jill Bouchard
    •  & Saul A Villeda
  2. The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA.

    • Lucas K Smith
    • , Gregor Bieri
    • , Cedric E Snethlage
    • , Karin Lin
    • , Geraldine Gontier
    • , Kristopher E Plambeck
    • , Joe Udeochu
    • , Elizabeth G Wheatley
    • , Jill Bouchard
    •  & Saul A Villeda
  3. Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California, USA.

    • Lucas K Smith
    • , Joe Udeochu
    •  & Saul A Villeda
  4. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.

    • Yingbo He
    • , Jeong-Soo Park
    • , Gregor Bieri
    • , Rafael Wabl
    • , Ramya Narasimha
    • , Jacqueline L Grant
    • , Jian Luo
    •  & Tony Wyss-Coray
  5. Department of Biochemistry, Dankook University College of Medicine, Cheonan, Korea.

    • Jeong-Soo Park
  6. Neuroscience Graduate Program, Stanford University School of Medicine, Stanford, California, USA.

    • Gregor Bieri
    • , Jacqueline L Grant
    •  & Tony Wyss-Coray
  7. Neuroscience Graduate Program, University of California San Francisco, San Francisco, California, USA.

    • Karin Lin
    •  & Saul A Villeda
  8. Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, California, USA.

    • Elizabeth G Wheatley
    •  & Saul A Villeda
  9. Department of Rheumatology, Immunology and Allergology, University Hospital Bern, Bern, Switzerland.

    • Alexander Eggel
  10. Center for Tissue Regeneration, Repair and Restoration, Veterans' Affairs (VA) Palo Alto Health Care System, Palo Alto, California, USA.

    • Tony Wyss-Coray
  11. California Institute for Quantitative Biosciences (QB3), San Francisco, California, USA.

    • Saul A Villeda

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Contributions

L.K.S., J-S.P., G.B., C.E.S. and S.A.V. performed pharmacological studies. L.K.S., Y.H., J-S.P., C.E.S. and S.A.V. analyzed knockout studies. L.K.S., G.B., C.E.S., K.L. and S.A.V. performed behavioral studies. L.K.S., C.E.S., K.L., G.G., K.E.P., J.U. and J.L. performed parabiosis studies. L.K.S. performed biochemical studies. Y.H. and J.-S.P. performed in vitro studies. A.E. and S.A.V. analyzed human data. R.W., E.G.W., J.B., R.N. and J.L.G. assisted in histological analysis. G.B. generated schematics. S.A.V. and T.W.-C. developed the concept. S.A.V. wrote the manuscript and supervised the study. All authors had the opportunity to discuss results and comment on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Saul A Villeda.

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DOI

https://doi.org/10.1038/nm.3898