title: Autoimmune manifestations in the 3xTg-AD model of Alzheimer's disease.
abstract: BACKGROUND
  Immune system activation is frequently reported in patients with Alzheimer's disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration.
  
  
  OBJECTIVE
  The present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology.
  
  
  METHODS
  A broad battery of tests was employed to assess behavioral performance and autoimmune/inflammatory markers in 3xTg-AD (AD) mice and wild type controls from 1.5 to 12 months of age.
  
  
  RESULTS
  Aged AD mice displayed severe manifestations of systemic autoimmune/inflammatory dise6ase, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double-negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired "cognitive" flexibility in the first 6 months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at an older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-β or tau pathology.
  
  
  CONCLUSIONS
  The results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior. Consequently, 3xTg-AD mice may be a useful model in elucidating the role of immune system in the etiology of AD.
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada.
authors.forename: Monica
authors.initials: M
authors.lastname: Marchese
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Cowan
authors.affiliation: Department of Molecular & Biomedical Pharmacology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Donglai
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Khalil
authors.initials: K
authors.lastname: Karimi
authors.affiliation: Central Animal Facility, McMaster University, Hamilton, ON, Canada.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ashthorpe
authors.affiliation: Department of Psychiatry & Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada.
authors.forename: Minesh
authors.initials: M
authors.lastname: Kapadia
authors.affiliation: Department of Psychiatry & Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Molecular & Biomedical Pharmacology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
authors.forename: Paulina
authors.initials: P
authors.lastname: Davis
authors.affiliation: Department of Psychiatry & Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada.
authors.forename: Boris
authors.initials: B
authors.lastname: Sakic
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000974:Antibodies, Antinuclear / Q000378:metabolism*; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D006400:Hematocrit; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D013163:Splenomegaly / Q000150:complications; D013601:T-Lymphocytes / Q000473:pathology
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D015415:Biomarkers
keywords: 3xTg-AD model; Alzheimer's disease; amyloidosis; anxiety; autoimmunity; hepatomegaly; inflammation; mild cognitive impairment; olfaction; splenomegaly