title: Aberrant T-lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein-α: implications for autism.
abstract: Abnormalities in T-lymphocyte populations and function are observed in autism. Soluble amyloid precursor protein α (sAPP-α) is elevated in some patients with autism and is known to be produced by immune cells. In light of the well-established role of sAPP-α in proliferation, growth, and survival of neurons, we hypothesized an analogous role in the immune system. Thus, we explored whether sAPP-α could modulate immune development and function, especially aspects of the pinnacle cell of the adaptive arm of the immune system: the T cell. To do this, we generated mice overexpressing human sAPP-α and characterized elements of T-cell development, signal transduction, cytokine production, and innate/adaptive immune functions. Here, we report that transgenic sAPP-α-overexpressing (TgsAPP-α) mice displayed increased proportions of CD8(+) T cells, while effector memory T cells were decreased in the thymus. Overall apoptotic signal transduction was decreased in the thymus, an effect that correlated with dramatic elevations in Notch1 activation; while active-caspase-3/total-caspase-3 and Bax/Bcl-2 ratios were decreased. Greater levels of IFN-γ, IL-2, and IL-4 were observed after ex vivo challenge of TgsAPP-α mouse splenocytes with T-cell mitogen. Finally, after immunization, splenocytes from TgsAPP-α mice displayed decreased levels IFN-γ, IL-2, and IL-4, as well as suppressed ZAP70 activation, after recall antigen stimulation. Given elevated levels of circulating sAPP-α in some patients with autism, sAPP-α could potentially drive aspects of immune dysfunction observed in these patients, including dysregulated T-cell apoptosis, aberrant PI3K/AKT signaling, cytokine alterations, and impaired T-cell recall stimulation.
authors.affiliation: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Neurosciences, College of Medicine, University of South Florida, 3515 E. Fletcher Ave. Tampa, FL 33613, USA.
authors.forename: Antoinette R
authors.initials: AR
authors.lastname: Bailey
authors.forename: Huayan
authors.initials: H
authors.lastname: Hou
authors.forename: Demian F
authors.initials: DF
authors.lastname: Obregon
authors.forename: Jun
authors.initials: J
authors.lastname: Tian
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zou
authors.forename: William V
authors.initials: WV
authors.lastname: Nikolic
authors.forename: Michael
authors.initials: M
authors.lastname: Bengtson
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Tanya
authors.initials: T
authors.lastname: Murphy
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000097:blood / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001321:Autistic Disorder / Q000097:blood / Q000276:immunology*; D015153:Blotting, Western; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007109:Immunity / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051881:Receptor, Notch1 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D017252:CD3 Complex; D007376:Interleukin-2; D051881:Receptor, Notch1; D015847:Interleukin-4; D007371:Interferon-gamma
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