Letter

Human umbilical cord plasma proteins revitalize hippocampal function in aged mice

Received:
Accepted:
Published online:

Abstract

Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation1, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation2,3,4 and downregulated in the aged brain5,6,7,8. In addition to revitalizing other aged tissues9,10,11,12,13, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters14,15,16, although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown17. We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.

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Acknowledgements

We thank clinical staff for human blood-plasma collection/coordination, C. Guenthner, L. Luo for TRAP-FOS breeders, T. Rando for discussion, Stanford Translational Applications Service Center/Protein and Nucleic Acid facilities for whole-genome microarrays, H. Zhang for mice for depletion experiments. This work was funded by the Jane Coffin Childs Postdoctoral Fellowship-Simons Foundation (J.M.C), Veterans Affairs (T.W.-C.), anonymous (T.W.-C.), the Glenn Foundation for Medical Research (T.W.-C.), the Stanford Brain Rejuvenation Project, and the National Institute on Aging (K99AG051711 (J.M.C.), AG045034 (T.W.-C.), DP1AG053015 (T.W.-C.) and AG040877 (K.I.M.)).

Author information

Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA

    • Joseph M. Castellano
    • , Kira I. Mosher
    • , Rachelle J. Abbey
    • , Alisha A. McBride
    • , Michelle L. James
    • , Daniela Berdnik
    • , Jadon C. Shen
    • , Izumi V. Hinkson
    •  & Tony Wyss-Coray
  2. Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA

    • Joseph M. Castellano
    • , Kira I. Mosher
    • , Rachelle J. Abbey
    • , Alisha A. McBride
    • , Daniela Berdnik
    • , Jadon C. Shen
    • , Izumi V. Hinkson
    •  & Tony Wyss-Coray
  3. Neuroscience Graduate Program, Stanford University School of Medicine, Stanford, California 94305, USA

    • Kira I. Mosher
    •  & Tony Wyss-Coray
  4. Center for Tissue Regeneration, Repair and Restoration, V.A. Palo Alto Healthcare System, Palo Alto, California 94304, USA

    • Rachelle J. Abbey
    • , Alisha A. McBride
    • , Daniela Berdnik
    • , Jadon C. Shen
    • , Izumi V. Hinkson
    •  & Tony Wyss-Coray
  5. Molecular Imaging Program at Stanford, Radiology, Stanford University School of Medicine, Stanford, California 94305, USA

    • Michelle L. James
  6. AfaSci Research Laboratories, Redwood City, California 94063, USA

    • Bende Zou
    •  & Xinmin S. Xie
  7. Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California 94305, USA

    • Xinmin S. Xie
    • , Martha Tingle
    •  & Martin S. Angst

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Contributions

J.M.C. and T.W.-C. designed research. J.M.C., K.I.M., D.B., and J.C.S. performed protein microarray experiments. J.M.C., R.J.A., and A.A.M. performed behaviour, staining/microscopy. J.M.C. performed biochemical assays; I.V.H. developed silver stain protocol. J.M.C. and M.L.J. performed radiolabelling/autoradiography experiments. J.M.C., B.Z., and X.S.X. performed LTP experiments. M.T. and M.S.A. provided human samples. J.M.C. analysed data and wrote the manuscript. T.W.-C. supervised study.

Competing interests

T.W.-C. is co-founder of Alkahest, Inc. T.W.-C., J.M.C., M.S.A. are Alkahest shareholders. Stanford filed patent applications covering a method treating aging-associated conditions by young plasma (PCT/US2014/068897; co-inventors: T.W.-C., J.M.C., M.S.A.) or TIMP2 (PCT/US2016/036032; co-inventors: T.W.-C., J.M.C.).

Corresponding author

Correspondence to Tony Wyss-Coray.

Reviewer Information Nature thanks H. Eichenbaum and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

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  1. 1.

    Supplementary Information

    This file contains Supplementary Figure 1, the uncropped scans of the western blots, Ponceau S stains, and silver gel depicted in the main and Extended Data Figures and Supplementary Table 1, a list of human and mouse plasma protein microarray antibodies.

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