Letter | Published:

Human umbilical cord plasma proteins revitalize hippocampal function in aged mice

Nature volume 544, pages 488492 (27 April 2017) | Download Citation


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & Neural plasticity in the ageing brain. Nature Rev. Neurosci. 7, 30–40 (2006)

  2. 2.

    , , & Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature 340, 474–476 (1989)

  3. 3.

    et al. Long-term potentiation and the induction of c-fos mRNA and proteins in the dentate gyrus of unanesthetized rats. Neurosci. Lett. 101, 274–280 (1989)

  4. 4.

    et al. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nature Neurosci. 4, 289–296 (2001)

  5. 5.

    et al. Altered hippocampal transcript profile accompanies an age-related spatial memory deficit in mice. Learn. Mem. 11, 253–260 (2004)

  6. 6.

    et al. Transcriptional mechanisms of hippocampal aging. Exp. Gerontol. 39, 1613–1622 (2004)

  7. 7.

    , & Gene-expression profile of the ageing brain in mice. Nature Genet. 25, 294–297 (2000)

  8. 8.

    et al. Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J. Neurosci. 23, 3807–3819 (2003)

  9. 9.

    et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005)

  10. 10.

    et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153, 828–839 (2013)

  11. 11.

    et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344, 649–652 (2014)

  12. 12.

    et al. Systemic regulation of the age-related decline of pancreatic β-cell replication. Diabetes 62, 2843–2848 (2013)

  13. 13.

    et al. Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin. Nature Commun. 6, 7131 (2015)

  14. 14.

    et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630–634 (2014)

  15. 15.

    et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011)

  16. 16.

    et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Med. 20, 659–663 (2014)

  17. 17.

    , & Blood-borne revitalization of the aged brain. JAMA Neurol. 72, 1191–1194 (2015)

  18. 18.

    et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J. Immunol. 174, 6477–6489 (2005)

  19. 19.

    , , & Attenuation of c-Fos basal expression in the cerebral cortex of aged rat. Neuroreport 9, 2733–2736 (1998)

  20. 20.

    et al. Thy1-hAPPLond/Swe+ mouse model of Alzheimer’s disease displays broad behavioral deficits in sensorimotor, cognitive and social function. Brain Behav. 2, 142–154 (2012)

  21. 21.

    , , , & BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice. Nature Neurosci. 18, 1464–1473 (2015)

  22. 22.

    et al. Genome-wide identification and characterization of functional neuronal activity-dependent enhancers. Nature Neurosci. 17, 1330–1339 (2014)

  23. 23.

    , , , & Permanent genetic access to transiently active neurons via TRAP: targeted recombination in active populations. Neuron 78, 773–784 (2013)

  24. 24.

    , , , & Prox1 postmitotically defines dentate gyrus cells by specifying granule cell identity over CA3 pyramidal cell fate in the hippocampus. Development 139, 3051–3062 (2012)

  25. 25.

    et al. GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice. J. Alzheimers Dis. 21, 507–518 (2010)

  26. 26.

    et al. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335, 1503–1506 (2012)

  27. 27.

    , , , & Prepulse inhibition and fear-potentiated startle are altered in tissue inhibitor of metalloproteinase-2 (TIMP-2) knockout mice. Brain Res. 1051, 81–89 (2005)

  28. 28.

    , , & Tissue inhibitor of metalloproteinase-2(TIMP-2)-deficient mice display motor deficits. J. Neurobiol. 66, 82–94 (2006)

  29. 29.

    , & The dual role of the extracellular matrix in synaptic plasticity and homeostasis. Nature Rev. Neurosci. 11, 735–746 (2010)

  30. 30.

    & Tissue inhibitor of metalloproteinases-2 is expressed in the interstitial matrix in adult mouse organs and during embryonic development. Mol. Biol. Cell 8, 1513–1527 (1997)

  31. 31.

    et al. In vivo assessment of behavioral recovery and circulatory exchange in the peritoneal parabiosis model. Sci. Rep. 6, 29015 (2016)

  32. 32.

    et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci. Transl. Med. 3, 89ra57 (2011)

  33. 33.

    ., ., ., & in The Omics: Applications in Neuroscience (ed ) 183–191 (Oxford Univ. Press, 2014)

  34. 34.

    , , & Open source clustering software. Bioinformatics 20, 1453–1454 (2004)

  35. 35.

    Java Treeview—extensible visualization of microarray data. Bioinformatics 20, 3246–3248 (2004)

  36. 36.

    , & Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl Acad. Sci. USA 98, 5116–5121 (2001)

  37. 37.

    , , , & Relative contribution of endogenous neurotrophins in hippocampal long-term potentiation. J. Neurosci. 19, 7983–7990 (1999)

  38. 38.

    , , , & Determinants of BDNF-induced hippocampal synaptic plasticity: role of the Trk B receptor and the kinetics of neurotrophin delivery. Learn. Mem. 3, 188–196 (1996)

  39. 39.

    , & Male and female C57BL/6 mice respond differently to diazepam challenge in avoidance learning tasks. Pharmacol. Biochem. Behav. 72, 13–21 (2002)

  40. 40.

    & Sensitivity to foot shock in autoimmune NZB × NZW F1 hybrid mice. Physiol. Behav. 56, 849–853 (1994)

  41. 41.

    & Visual cliff behavior of mice as a function of genetic differences in eye characteristics. Psychon. Sci. 4, 35–36 (1966)

  42. 42.

    et al. Selective discrimination learning impairments in mice expressing the human Huntington’s disease mutation. J. Neurosci. 19, 10428–10437 (1999)

  43. 43.

    et al. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346, 89–93 (2014)

  44. 44.

    , & The Scalable Brain Atlas: instant Web-based access to public brain atlases and related content. Neuroinformatics 13, 353–366 (2015)

  45. 45.

    et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445, 168–176 (2007)

  46. 46.

    et al. Development and validation of an immuno-PET tracer as a companion diagnostic agent for antibody-drug conjugate therapy to target the CA6 epitope. Radiology 276, 191–198 (2015)

  47. 47.

    et al. Comparison of 64Cu-complexing bifunctional chelators for radioimmunoconjugation: labeling efficiency, specific activity, and in vitro/in vivo stability. Bioconjug. Chem. 23, 1029–1039 (2012)

  48. 48.

    et al. Microfluidic radiolabeling of biomolecules with PET radiometals. Nucl. Med. Biol. 40, 42–51 (2013)

  49. 49.

    et al. New positron emission tomography (PET) radioligand for imaging σ-1 receptors in living subjects. J. Med. Chem. 55, 8272–8282 (2012)

  50. 50.

    et al. Comparative in vivo stability of copper-64-labeled cross-bridged and conventional tetraazamacrocyclic complexes. J. Med. Chem. 47, 1465–1474 (2004)

  51. 51.

    & Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25, 402–408 (2001)

Download references


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


  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


  1. Search for Joseph M. Castellano in:

  2. Search for Kira I. Mosher in:

  3. Search for Rachelle J. Abbey in:

  4. Search for Alisha A. McBride in:

  5. Search for Michelle L. James in:

  6. Search for Daniela Berdnik in:

  7. Search for Jadon C. Shen in:

  8. Search for Bende Zou in:

  9. Search for Xinmin S. Xie in:

  10. Search for Martha Tingle in:

  11. Search for Izumi V. Hinkson in:

  12. Search for Martin S. Angst in:

  13. Search for Tony Wyss-Coray in:


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

PDF files

  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.

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.