title: 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 individuals. 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 brain. 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.
authors.affiliation: 1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA. [3] Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California, USA.
authors.forename: Lucas K
authors.initials: LK
authors.lastname: Smith
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Yingbo
authors.initials: Y
authors.lastname: He
authors.affiliation: 1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [2] Department of Biochemistry, Dankook University College of Medicine, Cheonan, Korea.
authors.forename: Jeong-Soo
authors.initials: JS
authors.lastname: Park
authors.affiliation: 1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA. [3] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [4] Neuroscience Graduate Program, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Gregor
authors.initials: G
authors.lastname: Bieri
authors.affiliation: 1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA.
authors.forename: Cedric E
authors.initials: CE
authors.lastname: Snethlage
authors.affiliation: 1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA. [3] Neuroscience Graduate Program, University of California San Francisco, San Francisco, California, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Lin
authors.affiliation: 1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Gontier
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Wabl
authors.affiliation: 1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA.
authors.forename: Kristopher E
authors.initials: KE
authors.lastname: Plambeck
authors.affiliation: 1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA. [3] Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Udeochu
authors.affiliation: 1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA. [3] Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, California, USA.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Wheatley
authors.affiliation: 1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Bouchard
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital Bern, Bern, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggel
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ramya
authors.initials: R
authors.lastname: Narasimha
authors.affiliation: 1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [2] Neuroscience Graduate Program, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Grant
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jian
authors.identifier: 0000000220648467
authors.initials: J
authors.lastname: Luo
authors.affiliation: 1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [2] Neuroscience Graduate Program, Stanford University School of Medicine, Stanford, California, USA. [3] Center for Tissue Regeneration, Repair and Restoration, Veterans' Affairs (VA) Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.affiliation: 1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA. [3] Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California, USA. [4] Neuroscience Graduate Program, University of California San Francisco, San Francisco, California, USA. [5] Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, California, USA. [6] California Institute for Quantitative Biosciences (QB3), San Francisco, California, USA.
authors.forename: Saul A
authors.initials: SA
authors.lastname: Villeda
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D000818:Animals; D003071:Cognition; D006801:Humans; D008285:Major Histocompatibility Complex / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D055495:Neurogenesis; D001613:beta 2-Microglobulin / Q000502:physiology*
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; C486171:Tap1 protein, mouse; D001613:beta 2-Microglobulin