Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

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.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Systemic B2M increases with age and impairs hippocampal-dependent cognitive function and neurogenesis.
Figure 2: B2M expression increases in the aging hippocampus and impairs hippocampal-dependent cognitive function and neurogenesis.
Figure 3: Reducing MHC I surface expression mitigates the negative effects of heterochronic parabiosis on neurogenesis.
Figure 4: Absence of B2M enhances hippocampal-dependent cognitive function and neurogenesis in aged animals.

References

  1. 1

    Hedden, T. & Gabrieli, J.D. Insights into the ageing mind: a view from cognitive neuroscience. Nat. Rev. Neurosci. 5, 87–96 (2004).

    CAS  Article  Google Scholar 

  2. 2

    Mattson, M.P. & Magnus, T. Ageing and neuronal vulnerability. Nat. Rev. Neurosci. 7, 278–294 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3

    Small, S.A., Schobel, S.A., Buxton, R.B., Witter, M.P. & Barnes, C.A. A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat. Rev. Neurosci. 12, 585–601 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4

    Rao, M.S., Hattiangady, B. & Shetty, A.K. The window and mechanisms of major age-related decline in the production of new neurons within the dentate gyrus of the hippocampus. Aging Cell 5, 545–558 (2006).

    CAS  Article  Google Scholar 

  5. 5

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Ruckh, J.M. et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10, 96–103 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10

    Brack, A.S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11

    Laviano, A. Young blood. N. Engl. J. Med. 371, 573–575 (2014).

    Article  CAS  Google Scholar 

  12. 12

    Bouchard, J. & Villeda, S.A. Aging and brain rejuvenation as systemic events. J. Neurochem. 132, 5–19 (2015).

    CAS  Article  Google Scholar 

  13. 13

    Zijlstra, M. et al. β2-microglobulin–deficient mice lack CD4–8+ cytolytic T cells. Nature 344, 742–746 (1990).

    CAS  Article  Google Scholar 

  14. 14

    Lee, H. et al. Synapse elimination and learning rules co-regulated by MHC class I H2-Db. Nature 509, 195–200 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15

    Loconto, J. et al. Functional expression of murine V2R pheromone receptors involves selective association with the M10 and M1 families of MHC class Ib molecules. Cell 112, 607–618 (2003).

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Boulanger, L.M. & Shatz, C.J. Immune signalling in neural development, synaptic plasticity and disease. Nat. Rev. Neurosci. 5, 521–531 (2004).

    CAS  Article  Google Scholar 

  17. 17

    Shatz, C.J. MHC class I: an unexpected role in neuronal plasticity. Neuron 64, 40–45 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18

    Huh, G.S. et al. Functional requirement for class I MHC in CNS development and plasticity. Science 290, 2155–2159 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    Goddard, C.A., Butts, D.A. & Shatz, C.J. Regulation of CNS synapses by neuronal MHC class I. Proc. Natl. Acad. Sci. USA 104, 6828–6833 (2007).

    Article  Google Scholar 

  20. 20

    Glynn, M.W. et al. MHCI negatively regulates synapse density during the establishment of cortical connections. Nat. Neurosci. 14, 442–451 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Murray, A.M. Cognitive impairment in the aging dialysis and chronic kidney disease populations: an occult burden. Adv. Chronic Kidney Dis. 15, 123–132 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22

    Corlin, D.B. et al. Quantification of cleaved β2-microglobulin in serum from patients undergoing chronic hemodialysis. Clin. Chem. 51, 1177–1184 (2005).

    CAS  Article  Google Scholar 

  23. 23

    McArthur, J.C. et al. The diagnostic utility of elevation in cerebrospinal fluid β2-microglobulin in HIV-1 dementia. Multicenter AIDS Cohort Study. Neurology 42, 1707–1712 (1992).

    CAS  Article  Google Scholar 

  24. 24

    Brew, B.J., Dunbar, N., Pemberton, L. & Kaldor, J. Predictive markers of AIDS dementia complex: CD4 cell count and cerebrospinal fluid concentrations of β2-microglobulin and neopterin. J. Infect. Dis. 174, 294–298 (1996).

    CAS  Article  Google Scholar 

  25. 25

    Carrette, O. et al. A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer's disease. Proteomics 3, 1486–1494 (2003).

    CAS  Article  Google Scholar 

  26. 26

    Clelland, C.D. et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325, 210–213 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27

    Kitamura, T. et al. Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell 139, 814–827 (2009).

    CAS  Article  Google Scholar 

  28. 28

    Zhang, C.L., Zou, Y., He, W., Gage, F.H. & Evans, R.M. A role for adult TLX-positive neural stem cells in learning and behaviour. Nature 451, 1004–1007 (2008).

    CAS  Article  Google Scholar 

  29. 29

    Drapeau, E. et al. Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc. Natl. Acad. Sci. USA 100, 14385–14390 (2003).

    CAS  Article  Google Scholar 

  30. 30

    Merrill, D.A., Karim, R., Darraq, M., Chiba, A.A. & Tuszynski, M.H. Hippocampal cell genesis does not correlate with spatial learning ability in aged rats. J. Comp. Neurol. 459, 201–207 (2003).

    Article  Google Scholar 

  31. 31

    Bizon, J.L. & Gallagher, M. Production of new cells in the rat dentate gyrus over the lifespan: relation to cognitive decline. Eur. J. Neurosci. 18, 215–219 (2003).

    CAS  Article  Google Scholar 

  32. 32

    Seib, D.R. et al. Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline. Cell Stem Cell 12, 204–214 (2013).

    CAS  Article  Google Scholar 

  33. 33

    Van Kaer, L., Ashton-Rickardt, P.G., Ploegh, H.L. & Tonegawa, S. TAP1 mutant mice are deficient in antigen presentation, surface class I molecules, and CD4–8+ T cells. Cell 71, 1205–1214 (1992).

    CAS  Article  Google Scholar 

  34. 34

    Laguna Goya, R., Tyers, P. & Barker, R.A. Adult neurogenesis is unaffected by a functional knock-out of MHC class I in mice. Neuroreport 21, 349–353 (2010).

    CAS  Article  Google Scholar 

  35. 35

    Adelson, J.D. et al. Neuroprotection from stroke in the absence of MHCI or PirB. Neuron 73, 1100–1107 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36

    Jeck, W.R., Siebold, A.P. & Sharpless, N.E. Review: a meta-analysis of GWAS and age-associated diseases. Aging Cell 11, 727–731 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Couillard-Despres, S. et al. In vivo optical imaging of neurogenesis: watching new neurons in the intact brain. Mol. Imaging 7, 28–34 (2008).

    CAS  Article  Google Scholar 

  38. 38

    Mosher, K.I. et al. Neural progenitor cells regulate microglia functions and activity. Nat. Neurosci. 15, 1485–1487 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Alamed, J., Wilcock, D.M., Diamond, D.M., Gordon, M.N. & Morgan, D. Two-day radial-arm water maze learning and memory task; robust resolution of amyloid-related memory deficits in transgenic mice. Nat. Protoc. 1, 1671–1679 (2006).

    CAS  Article  Google Scholar 

  40. 40

    Zhang, J. et al. CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases. Am. J. Clin. Pathol. 129, 526–529 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Li, G. et al. Cerebrospinal fluid concentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects. PLoS ONE 4, e5424 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

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

Affiliations

Authors

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.

Corresponding author

Correspondence to Saul A Villeda.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–14 & Supplementary Table 1 (PDF 1800 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Smith, L., He, Y., Park, JS. et al. β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nat Med 21, 932–937 (2015). https://doi.org/10.1038/nm.3898

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing