Dataset Information

Differential effects of chronic immunosuppression on behavioral, epigenetic, and Alzheimer's disease-associated markers in 3xTg-AD mice.

ABSTRACT:

Background

Circulating autoantibodies and sex-dependent discrepancy in prevalence are unexplained phenomena of Alzheimer's disease (AD). Using the 3xTg-AD mouse model, we reported that adult males show early manifestations of systemic autoimmunity, increased emotional reactivity, enhanced expression of the histone variant macroH2A1 in the cerebral cortex, and loss of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain their AD-like phenotype. This study examines the link between immunity and other traits of the current 3xTg-AD model.

Methods

Young 3xTg-AD and wild-type mice drank a sucrose-laced 0.4?mg/ml solution of the immunosuppressant cyclophosphamide on weekends for 5?months. After behavioral phenotyping at 2 and 6?months of age, we assessed organ mass, serologic markers of autoimmunity, molecular markers of early AD pathology, and expression of genes associated with neurodegeneration.

Results

Chronic immunosuppression prevented hematocrit drop and reduced soluble A? in 3xTg-AD males while normalizing the expression of histone variant macroH2A1 in 3xTg-AD females. This treatment also reduced hepatosplenomegaly, lowered autoantibody levels, and increased the effector T cell population while decreasing the proportion of regulatory T cells in both sexes. Exposure to cyclophosphamide, however, neither prevented reduced brain mass and BDNF expression nor normalized increased tau and anxiety-related behaviors.

Conclusion

The results suggest that systemic autoimmunity increases soluble A? production and affects transcriptional regulation of macroH2A1 in a sex-related manner. Despite the complexity of multisystem interactions, 3xTg-AD mice can be a useful in vivo model for exploring the regulatory role of autoimmunity in the etiology of AD-like neurodegenerative disorders.

SUBMITTER: Kapadia M

PROVIDER: S-EPMC7818784 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Differential effects of chronic immunosuppression on behavioral, epigenetic, and Alzheimer's disease-associated markers in 3xTg-AD mice.

Kapadia Minesh M Mian M Firoz MF Ma Donglai D Hutton Craig P CP Azam Amber A Narkaj Klotilda K Cao Chuanhai C Brown Breanna B Michalski Bernadeta B Morgan David D Forsythe Paul P Zovkic Iva B IB Fahnestock Margaret M Sakic Boris B

Alzheimer's research & therapy 20210120 1

<h4>Background</h4>Circulating autoantibodies and sex-dependent discrepancy in prevalence are unexplained phenomena of Alzheimer's disease (AD). Using the 3xTg-AD mouse model, we reported that adult males show early manifestations of systemic autoimmunity, increased emotional reactivity, enhanced expression of the histone variant macroH2A1 in the cerebral cortex, and loss of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain their AD-like phenotype. Th ...[more]

PMID: 33472690

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Project description:Psychosis and/or aggression are common problems in dementia, and when severe or persistent, cause considerable patient distress and disability, caregiver stress, and early institutionalization. In 2005, the Food and Drug Administration (FDA) determined that atypical antipsychotics were associated with a significantly greater mortality risk compared to placebo, which prompted the addition of an FDA black-box warning. The American College of Neuropsychopharmacology (ACNP) White Paper, 2008, reviewed this issue and made clinical and research recommendations regarding the use of antipsychotics in dementia patients with psychosis and/or agitation. Increased mortality risk has also been described in cerebrovascular adverse events in elderly users of antipsychotics. In the present work, at the translational level, we used male 3xTg-AD mice (PS1M146V, APPSwe, tauP301L) at advanced stages of the disease reported to have worse survival than females, to study the behavioral effects of a low chronic dose of risperidone (0.1 mg/kg, s.c., 90 days, from 13 to 16 months of age) and its impact on long-term survival, as compared to mice with normal aging. Animals were behaviorally assessed for cognitive and BPSD (behavioral and psychological symptoms of dementia)-like symptoms in naturalistic and experimental conditions (open-field test, T-maze, social interaction, Morris water maze, and marble test) before and after treatment. Weight, basal glucose levels, and IPGTT (i.p. glucose tolerance test) were also recorded. Neophobia in the corner test was used for behavioral monitoring. Survival curves were recorded throughout the experiment until natural death. The benefits of risperidone were limited, both at cognitive and BPSD-like level, and mostly restricted to burying, agitation/vibrating tail, and other social behaviors. However, the work warns about a clear early mortality risk window during the treatment and long-lasting impact on survival. Reduced life expectancy and life span were observed in the 3xTg-AD mice, but total lifespan (36 months) recorded in C57BL/6 × 129Sv counterparts with normal aging was also truncated to 28 months in those with treatment. Sarcopenia at time of death was found in all groups, but was more severe in wild-type animals treated with risperidone. Therefore, the 3xTg-AD mice and their non-transgenic counterparts can be useful to delimitate critical time windows and for studying the physio-pathogenic factors and underlying causal events involved in this topic of considerable public health significance.

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Dataset Information

Differential effects of chronic immunosuppression on behavioral, epigenetic, and Alzheimer's disease-associated markers in 3xTg-AD mice.

Background

Methods

Results

Conclusion

Publications

Differential effects of chronic immunosuppression on behavioral, epigenetic, and Alzheimer's disease-associated markers in 3xTg-AD mice.

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