Other
11 Authors
- Nikolic WV,
- Mori T,
- Hou H,
- Obregon DF,
- Zhu Y,
- Bengtson M,
- Bailey AR,
- Tan J,
- Murphy T,
- Zou Q,
- Tian J
| First Author | Bailey AR | Year | 2012 |
| Journal | FASEB J | Volume | 26 |
| Issue | 3 | Pages | 1040-51 |
| PubMed ID | 22085641 | Mgi Jnum | J:182808 |
| Mgi Id | MGI:5316919 | Doi | 10.1096/fj.11-195438 |
| Citation | Bailey AR, et al. (2012) Aberrant T-lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein-alpha: implications for autism. FASEB J 26(3):1040-51 |
| abstractText | Abnormalities in T-lymphocyte populations and function are observed in autism. Soluble amyloid precursor protein alpha (sAPP-alpha) 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-alpha in proliferation, growth, and survival of neurons, we hypothesized an analogous role in the immune system. Thus, we explored whether sAPP-alpha 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-alpha and characterized elements of T-cell development, signal transduction, cytokine production, and innate/adaptive immune functions. Here, we report that transgenic sAPP-alpha-overexpressing (TgsAPP-alpha) 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-gamma, IL-2, and IL-4 were observed after ex vivo challenge of TgsAPP-alpha mouse splenocytes with T-cell mitogen. Finally, after immunization, splenocytes from TgsAPP-alpha mice displayed decreased levels IFN-gamma, IL-2, and IL-4, as well as suppressed ZAP70 activation, after recall antigen stimulation. Given elevated levels of circulating sAPP-alpha in some patients with autism, sAPP-alpha 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. |
