Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

Article type: Research Article

Authors: Marchese, Monica^a | Cowan, David^b | Head, Elizabeth^f | Ma, Donglai^c | Karimi, Khalil^b | Ashthorpe, Vanessa^e | Kapadia, Minesh^d | Zhao, Hui^d | Davis, Paulina^f | Sakic, Boris^{d; *}

Affiliations: [a] Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada | [b] Department of Medicine, McMaster University, Hamilton, ON, Canada | [c] Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada | [d] Department of Psychiatry & Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada | [e] Central Animal Facility, McMaster University, Hamilton, ON, Canada | [f] Department of Molecular & Biomedical Pharmacology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

Correspondence: [*] Correspondence to: Boris Sakic, Ph.D., Department of Psychiatry and Behavioral Neurosciences, McMaster University, The Brain-Body Institute, St. Joseph's Healthcare T-3307, 50 Charlton Avenue East, Hamilton, Ontario, L8N 4A6, Canada. Tel.: +1 905 518 7833; Fax: +1 905 540 6593; E-mail: sakic@mcmaster.ca.

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. Conclusion: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.

Keywords: Alzheimer's disease, amyloidosis, anxiety, autoimmunity, hepatomegaly, inflammation, mild cognitive impairment, olfaction, splenomegaly, 3xTg-AD model

DOI: 10.3233/JAD-131490

Journal: Journal of Alzheimer's Disease, vol. 39, no. 1, pp. 191-210, 2014