Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada; St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba, Canada.
St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba, Canada.
Exp Neurol. 2018 May;303:29-37. doi: 10.1016/j.expneurol.2018.01.013. Epub 2018 Feb 2.
Secreted amyloid precursor protein alpha (sAPPα) is a potent neurotrophin in the CNS but a dedicated receptor has not been found. However, protein interactions involving amyloid beta (Aβ), a peptide cleaved from the same parent peptide as sAPPα, indicate that insulin receptors (IRs) could be a target of amyloid peptides. In this study, in vitro analysis of cortical neuronal cultures revealed that exogenous sAPPα increased IR phosphorylation in the absence of insulin. Furthermore, in an APP overexpressing mouse model, sAPPα bound IRs in the cortex with significantly greater binding in hypoinsulinemic animals. To further examine the effects of sAPPα on the diabetic brain, we next rendered sAPPα overexpressing mice insulin depleted and found that sAPPα blocked aberrant tau phosphorylation (T231) in cortical tissue after 16 weeks diabetes. sAPPα overexpression also prevented hyperphosphorylation of AKT/GSK3 and activation of the unfolded protein response (UPR). In total, these data show sAPPα binds and activates neuronal IRs and that sAPPα has a protective effect on diabetic brain tissue.
分泌的淀粉样前体蛋白α（sAPPα）是中枢神经系统中的一种强效神经营养因子，但尚未发现其专用受体。然而，涉及淀粉样β（Aβ）的蛋白相互作用，Aβ是与 sAPPα 相同前体肽切割而来的肽，表明胰岛素受体（IRs）可能是淀粉样肽的靶标。在这项研究中，体外分析皮质神经元培养物表明，外源性 sAPPα 在没有胰岛素的情况下增加了 IR 的磷酸化。此外，在 APP 过表达的小鼠模型中，sAPPα 在皮质中与 IR 结合，在低胰岛素血症动物中结合显著增加。为了进一步研究 sAPPα 对糖尿病大脑的影响，我们接下来使 sAPPα 过表达的小鼠胰岛素耗竭，并发现 sAPPα 在糖尿病 16 周后阻止了皮质组织中异常的 tau 磷酸化（T231）。sAPPα 的过表达还阻止了 AKT/GSK3 的过度磷酸化和未折叠蛋白反应（UPR）的激活。总的来说，这些数据表明 sAPPα 结合并激活神经元 IRs，并且 sAPPα 对糖尿病脑组织具有保护作用。
