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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Hedden, T. & Gabrieli, J.D. Insights into the ageing mind: a view from cognitive neuroscience. Nat. Rev. Neurosci. 5, 87–96 (2004).
Mattson, M.P. & Magnus, T. Ageing and neuronal vulnerability. Nat. Rev. Neurosci. 7, 278–294 (2006).
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).
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).
Katsimpardi, L. et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630–634 (2014).
Villeda, S.A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).
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).
Ruckh, J.M. et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10, 96–103 (2012).
Conboy, I.M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).
Brack, A.S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007).
Laviano, A. Young blood. N. Engl. J. Med. 371, 573–575 (2014).
Bouchard, J. & Villeda, S.A. Aging and brain rejuvenation as systemic events. J. Neurochem. 132, 5–19 (2015).
Zijlstra, M. et al. β2-microglobulin–deficient mice lack CD4–8+ cytolytic T cells. Nature 344, 742–746 (1990).
Lee, H. et al. Synapse elimination and learning rules co-regulated by MHC class I H2-Db. Nature 509, 195–200 (2014).
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).
Boulanger, L.M. & Shatz, C.J. Immune signalling in neural development, synaptic plasticity and disease. Nat. Rev. Neurosci. 5, 521–531 (2004).
Shatz, C.J. MHC class I: an unexpected role in neuronal plasticity. Neuron 64, 40–45 (2009).
Huh, G.S. et al. Functional requirement for class I MHC in CNS development and plasticity. Science 290, 2155–2159 (2000).
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).
Glynn, M.W. et al. MHCI negatively regulates synapse density during the establishment of cortical connections. Nat. Neurosci. 14, 442–451 (2011).
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).
Corlin, D.B. et al. Quantification of cleaved β2-microglobulin in serum from patients undergoing chronic hemodialysis. Clin. Chem. 51, 1177–1184 (2005).
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).
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).
Carrette, O. et al. A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer's disease. Proteomics 3, 1486–1494 (2003).
Clelland, C.D. et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325, 210–213 (2009).
Kitamura, T. et al. Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell 139, 814–827 (2009).
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).
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).
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).
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).
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).
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).
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).
Adelson, J.D. et al. Neuroprotection from stroke in the absence of MHCI or PirB. Neuron 73, 1100–1107 (2012).
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).
Couillard-Despres, S. et al. In vivo optical imaging of neurogenesis: watching new neurons in the intact brain. Mol. Imaging 7, 28–34 (2008).
Mosher, K.I. et al. Neural progenitor cells regulate microglia functions and activity. Nat. Neurosci. 15, 1485–1487 (2012).
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).
Zhang, J. et al. CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases. Am. J. Clin. Pathol. 129, 526–529 (2008).
Li, G. et al. Cerebrospinal fluid concentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects. PLoS ONE 4, e5424 (2009).
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.).
The authors declare no competing financial interests.
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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
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