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 Aβ 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 Aβ 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.
journal_name
Alzheimers Res Therjournal_title
Alzheimer's research & therapyauthors
Kapadia M,Mian MF,Ma D,Hutton CP,Azam A,Narkaj K,Cao C,Brown B,Michalski B,Morgan D,Forsythe P,Zovkic IB,Fahnestock M,Sakic Bdoi
10.1186/s13195-020-00745-9subject
Has Abstractpub_date
2021-01-20 00:00:00pages
30issue
1issn
1758-9193pii
10.1186/s13195-020-00745-9journal_volume
13pub_type
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,评审
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journal_title:Alzheimer's research & therapy
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
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journal_title:Alzheimer's research & therapy
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journal_title:Alzheimer's research & therapy
pub_type: 已发布勘误
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journal_title:Alzheimer's research & therapy
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,随机对照试验
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journal_title:Alzheimer's research & therapy
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journal_title:Alzheimer's research & therapy
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journal_title:Alzheimer's research & therapy
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,评审
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pub_type: 杂志文章
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journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,多中心研究,随机对照试验
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pub_type: 杂志文章,多中心研究,随机对照试验
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