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 disease, 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.

Vaccines targeting the primary amino acid sequence and conformational epitope of amyloid‐β had distinct effects on neuropathology and cognitive deficits in EAE/AD mice

“…Notably, our EAE/AD model exhibited considerable neuroinflammation following Aβ immunization, even without myelin basic protein induction. This suggests that Aβ, acting as a self‐protein, can induce autoimmune reactions in EAE/AD mice, which is consistent with previous reports (Marchese et al, 2014; Sardi et al, 2011; Wang et al, 2014). In contrast, AOE1 immunization did not promote neuroinflammation or detrimental immune responses.…”

Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice

“…[24][25][26]77 However, several recent studies indicate that 3XTg AD mice show significant anxiety. 29,30 Thus, we speculate that tauopathies may play a more important role in inducing mental disorder than b-amyloid during the course of AD. Nevertheless, the amyloid pathology has also been consistently linked with GABA neuromodulation; the model produced in the present study is actually more closely related to a "pure tauopathy" than AD.…”

“…22,23 In the AD-related APP or APP/PS1 models, some show anxiety, 24,25 others do not, [26][27][28] whereas the 3XTg mice, which overexpress tau and APP/PS1, show significant anxiety behaviors, 29,30 suggesting a more intimate connection between tau and anxiety. In transgenic mice with conditional expression of N-terminal tau in nesting-positive cells, the anxiety behavior was also shown, 31 which provides direct evidence supporting the role of tau in anxiety.…”

The preventive effects of edible folic acid on cardiomyocyte apoptosis and survival in early onset triple‐transgenic Alzheimer's disease model mice

“…AD is a significant economic, medical, and social burden globally due to prolonged life expectancy, the escalating incidence of the disease, and lack of effective treatments. According to a recent report about AD, more than 36 million people have been affected worldwide . The neuropathological hallmarks of AD are filamentous intracellular aggregates (neurofibrillary tangles) of hyperphosphorylated tau protein and extracellular deposits (plaques) of amyloid‐β peptide (Aβ) .…”