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Aberrant T‐lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein‐α: implications for autism

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.—Bailey, A. R., Hou, H., Obregon, D. F., Tian, J., Zhu, Y., Zou, Q., Nikolic, W. V., Bengtson, M., Mori, T., Murphy, T., Tan, J. Aberrant T‐lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein‐α: implications for autism. FASEB J. 26, 1040‐1051 (2012). www.fasebj.org