Autoimmune manifestations in the 3xtg-ad model of alzheimer's disease

Monica Marchese, David Cowan, Elizabeth Head, Donglai Ma, Khalil Karimi, Vanessa Ashthorpe, Minesh Kapadia, Hui Zhao, Paulina Davis, Boris Sakic*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

71 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)191-210
Number of pages20
JournalJournal of Alzheimer's Disease
Issue number1
Publication statusPublished - 2014
Externally publishedYes


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


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