title: Age-dependent increase of blood-brain barrier permeability and neuron-binding autoantibodies in S100B knockout mice.
abstract: S100B is a calcium-sensor protein that impacts multiple signal transduction pathways. It is widely considered to be an important biomarker for several neuronal diseases as well as blood-brain barrier (BBB) breakdown. In this report, we demonstrate a BBB deficiency in mice that lack S100B through detection of leaked Immunoglobulin G (IgG) in the brain parenchyma. IgG leaks and IgG-binding to selected neurons were observed in S100B knockout (S100BKO) mice at 6 months of age but not at 3 months. By 9 months, IgG leaks persisted and the density of IgG-bound neurons increased significantly. These results reveal a chronic increase in BBB permeability upon aging in S100BKO mice for the first time. Moreover, coincident with the increase in IgG-bound neurons, autoantibodies targeting brain proteins were detected in the serum via western blots. These events were concurrent with compromise of neurons, increase of activated microglia and lack of astrocytic activation as evidenced by decreased expression of microtubule-associated protein type 2 (MAP2), elevated number of CD68 positive cells and unaltered expression of glial fibrillary acidic protein (GFAP) respectively. Results suggest a key role for S100B in maintaining BBB functional integrity and, further, propose the S100BKO mouse as a valuable model system to explore the link between chronic functional compromise of the BBB, generation of brain-reactive autoantibodies and neuronal dysfunctions.
authors.affiliation: Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ 08084, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ 08084, USA.
authors.forename: Eric V
authors.initials: EV
authors.lastname: Brown
authors.affiliation: Biomarker Discovery Center, New Jersey Institute for Successful Aging, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA; Department of Geriatrics and Gerontology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA.
authors.forename: Nimish K
authors.initials: NK
authors.lastname: Acharya
authors.affiliation: Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USA.
authors.forename: Denah M
authors.initials: DM
authors.lastname: Appelt
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON, Canada M6J 3X5.
authors.forename: Alexander
authors.initials: A
authors.lastname: Marks
authors.affiliation: Biomarker Discovery Center, New Jersey Institute for Successful Aging, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA; Department of Geriatrics and Gerontology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nagele
authors.affiliation: Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ 08084, USA; Department of Cell Biology, Rowan School of Osteopathic Medicine, Stratford, NJ 08084, USA. Electronic address: vvenkat2007@gmail.com.
authors.forename: Venkat
authors.initials: V
authors.lastname: Venkataraman
mesh_terms: D000367:Age Factors; D000818:Animals; D001323:Autoantibodies / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000276:immunology / Q000378:metabolism*; D010539:Permeability; D064568:S100 Calcium Binding Protein beta Subunit / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D064568:S100 Calcium Binding Protein beta Subunit; C579159:S100b protein, mouse
keywords: Aging; Autoantibodies; Blood–brain barrier; Neurodegenerative disease; S100B