title: CD45 deficiency drives amyloid-β peptide oligomers and neuronal loss in Alzheimer's disease mice.
abstract: Converging lines of evidence indicate dysregulation of the key immunoregulatory molecule CD45 (also known as leukocyte common antigen) in Alzheimer's disease (AD). We report that transgenic mice overproducing amyloid-β peptide (Aβ) but deficient in CD45 (PSAPP/CD45(-/-) mice) faithfully recapitulate AD neuropathology. Specifically, we find increased abundance of cerebral intracellular and extracellular soluble oligomeric and insoluble Aβ, decreased plasma soluble Aβ, increased abundance of microglial neurotoxic cytokines tumor necrosis factor-α and interleukin-1β, and neuronal loss in PSAPP/CD45(-/-) mice compared with CD45-sufficient PSAPP littermates (bearing mutant human amyloid precursor protein and mutant human presenilin-1 transgenes). After CD45 ablation, in vitro and in vivo studies demonstrate an anti-Aβ phagocytic but proinflammatory microglial phenotype. This form of microglial activation occurs with elevated Aβ oligomers and neural injury and loss as determined by decreased ratio of anti-apoptotic Bcl-xL to proapoptotic Bax, increased activated caspase-3, mitochondrial dysfunction, and loss of cortical neurons in PSAPP/CD45(-/-) mice. These data show that deficiency in CD45 activity leads to brain accumulation of neurotoxic Aβ oligomers and validate CD45-mediated microglial clearance of oligomeric Aβ as a novel AD therapeutic target.
authors.affiliation: Department of Psychiatry and Behavioral Medicine, University of South Florida, Tampa, FL 33613, USA.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Huayan
authors.initials: H
authors.lastname: Hou
authors.forename: Kavon
authors.initials: K
authors.lastname: Rezai-Zadeh
authors.forename: Brian
authors.initials: B
authors.lastname: Giunta
authors.forename: Amanda
authors.initials: A
authors.lastname: Ruscin
authors.forename: Carmelina
authors.initials: C
authors.lastname: Gemma
authors.forename: Jingji
authors.initials: J
authors.lastname: Jin
authors.forename: Natasa
authors.initials: N
authors.lastname: Dragicevic
authors.forename: Patrick
authors.initials: P
authors.lastname: Bradshaw
authors.forename: Suhail
authors.initials: S
authors.lastname: Rasool
authors.forename: Charles G
authors.initials: CG
authors.lastname: Glabe
authors.forename: Jared
authors.initials: J
authors.lastname: Ehrhart
authors.forename: Paula
authors.initials: P
authors.lastname: Bickford
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Demian
authors.initials: D
authors.lastname: Obregon
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000686:Amyloidosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D055503:Protein Multimerization; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053583:Interleukin-1beta; D010446:Peptide Fragments; D053764:Presenilin-1; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse