Immunosuppression prevents neuronal atrophy in lupus-prone mice:

Šakić, Boris; Kolb, Bryan; Whishaw, Ian Q.; Gorny, Grazyna; Szechtman, Henry; Denburg, Judah A.

doi:10.1016/s0165-5728(00)00364-7

Cited by 49 publications

(9 citation statements)

References 53 publications

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“…Some evidence does suggest a role for serum autoantibody levels in NP-SLE, as mice with more severe peripheral and behavioral manifestations of SLE also have more pronounced changes in hippocampal and cortical morphology and increased indices of cell death [163–166]. This can be prevented with doses of cyclophosphamide that reduce serum autoantibody titers [165], although CSF levels of autoantibodies were not assessed. However, IgG levels in serum, but not CSF, are positively correlated with spleen weight, suggesting that central autoimmune processes are relatively independent from systemic manifestations [167].…”

Section: Cns Mechanisms and Pathologymentioning

confidence: 99%

The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

Gulinello

Putterman

2011

Journal of Biomedicine and Biotechnology

107

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To date, CNS disease and neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. In this review, we focus on a specific mouse model of lupus and the ways in which this model reflects some of the most common manifestations and potential mechanisms of human NP-SLE. The mouse MRL lymphoproliferation strain (a.k.a. MRL/lpr) spontaneously develops the hallmark serological markers and peripheral pathologies typifying lupus in addition to displaying the cognitive and affective dysfunction characteristic of NP-SLE, which may be among the earliest symptoms of lupus. We suggest that although NP-SLE may share common mechanisms with peripheral organ pathology in lupus, especially in the latter stages of the disease, the immunologically privileged nature of the CNS indicates that early manifestations of particularly mood disorders maybe derived from some unique mechanisms. These include altered cytokine profiles that can activate astrocytes, microglia, and alter neuronal function before dysregulation of the blood-brain barrier and development of clinical autoantibody titres.

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Section: Cns Mechanisms and Pathologymentioning

confidence: 99%

The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

Gulinello

Putterman

2011

Journal of Biomedicine and Biotechnology

107

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“…It should be noted that neurological defects present in aged lpr (Fas KO , only 10% normal expression) and gld (FasL KO ) mice, have both an immunological and neurological etiology. As they approach adulthood, Fas KO and FasL KO mice develop extensive peripheral autoimmune disease, followed by the acquisition of neuropathy characterized by extensive inflammation (Ma et al, 2006), accelerating neuronal apoptosis and depletion, brain atrophy, and behavioral degeneration (Sakic et al, 1992, 2000a,b, 2002; Watanabe-Fukunaga et al, 1992; Takahashi et al, 1994; Ballok et al 2003a, 2004a; Anderson et al, 2006; Ma et al, 2006; Sled et al, 2009). The neuronal effect of aberrant Fas/FasL expression has been predominantly studied on mice of the MRL-lpr background, which spontaneously develop age-dependent autoimmune disease similar to human autoimmune systemic lupus erythematosus (SLE) combined with lymphadenopathy (Sakic et al, 2002).…”

Section: The Neurological Role Of Fasl and Its Receptormentioning

confidence: 99%

The role of tumor necrosis factor receptor superfamily members in mammalian brain development, function and homeostasis

Twohig

Cuff

Yong

et al. 2011

Reviews in the Neurosciences

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Tumor necrosis factor receptor superfamily (TNFRSF) members were initially identified as immunological mediators, and are still commonly perceived as immunological molecules. However, our understanding of the diversity of TNFRSF members' roles in mammalian physiology has grown significantly since the first discovery of TNFRp55 (TNFRSF1) in 1975. In particular, the last decade has provided evidence for important roles in brain development, function and the emergent field of neuronal homeostasis. Recent evidence suggests that TNFRSF members are expressed in an overlapping regulated pattern during neuronal development, participating in the regulation of neuronal expansion, growth, differentiation and regional pattern development. This review examines evidence for non-immunological roles of TNFRSF members in brain development, function and maintenance under normal physiological conditions. In addition, several aspects of brain function during inflammation will also be described, when illuminating and relevant to the non-immunological role of TNFRSF members. Finally, key questions in the field will be outlined.

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“…The alkylating agent cyclophosphamide (CY) is effective in arresting systemic autoimmunity via its metabolite phosphoramide mustard, which is formed in cells with low levels of aldehyde dehydrogenase and leads to apoptosis by forming DNA crosslinks. Given that chronic exposure to CY prevents neurodegeneration and normalizes behavior in autoimmune mice [55,[96][97][98], an identical, well-established protocol that does not involve injection-induced stress was chosen as a treatment modality in the current study. To provide consistency and comparability across studies, previously used behavioral, cellular and molecular variables [53,65] were analyzed.…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Chronic Immunosuppression on Behavioral, Epigenetic and Alzheimer’s Disease-Associated Markers in 3xTg-AD Mice

Kapadia

Mian

et al. 2020

Preprint

Self Cite

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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. 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. 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. 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.

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Immunosuppression prevents neuronal atrophy in lupus-prone mice:

Cited by 49 publications

References 53 publications

The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

The role of tumor necrosis factor receptor superfamily members in mammalian brain development, function and homeostasis

Differential Effects of Chronic Immunosuppression on Behavioral, Epigenetic and Alzheimer’s Disease-Associated Markers in 3xTg-AD Mice

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