title: The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function.
abstract: The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive-innate immunity cross talk and accelerated disease progression.
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, CA 92697; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA 92697;
authors.forename: Samuel E
authors.identifier: http://orcid.org/0000-0002-3012-6945
authors.initials: SE
authors.lastname: Marsh
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, CA 92697; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA 92697;
authors.forename: Edsel M
authors.initials: EM
authors.lastname: Abud
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;
authors.forename: Anita
authors.initials: A
authors.lastname: Lakatos
authors.affiliation: Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA 92697; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697;
authors.forename: Alborz
authors.initials: A
authors.lastname: Karimzadeh
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Yeung
authors.affiliation: Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA 92647.
authors.forename: Hayk
authors.initials: H
authors.lastname: Davtyan
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, CA 92697; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA 92697;
authors.forename: Gianna M
authors.initials: GM
authors.lastname: Fote
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;
authors.forename: Lydia
authors.initials: L
authors.lastname: Lau
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697;
authors.forename: Jason G
authors.initials: JG
authors.lastname: Weinger
authors.affiliation: Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA 92697; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697;
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Lane
authors.affiliation: Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA 92697; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697;
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Inlay
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Poon
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, CA 92697; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA 92697; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697; mblurton@uci.edu.
authors.forename: Mathew
authors.initials: M
authors.lastname: Blurton-Jones
mesh_terms: D000222:Adaptation, Physiological; D000544:Alzheimer Disease / Q000276:immunology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D017628:Microglia / Q000473:pathology*; D010587:Phagocytosis
chemical_list: D016229:Amyloid beta-Peptides; D007074:Immunoglobulin G
keywords: Alzheimer’s; IgG; amyloid; inflammation; microglia