Mattson M P, Cheng B, Culwell A R, Esch F S, Lieberburg I, Rydel R E
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230.
Neuron. 1993 Feb;10(2):243-54. doi: 10.1016/0896-6273(93)90315-i.
The beta-amyloid precursor protein (beta APP) is a membrane-spanning glycoprotein that is the source of the beta-amyloid peptide (beta AP) which accumulates as senile plaques in the brains of patients with Alzheimer's disease. beta APP is normally processed such that a cleavage occurs within the beta AP, liberating secreted forms of beta APP (APPss) from the cell. The neuronal functions of these forms are unknown. We now report that APPss have a potent neuroprotective action in cultured rat hippocampal and septal neurons and in human cortical neurons. APPs695 and APPs751 protected neurons against hypoglycemic damage, and the neuroprotection was abolished by antibodies to a specific region common to both APPs695 and APPs751. APPss caused a rapid and prolonged reduction in [Ca2+]i and prevented the rise in [Ca2+]i that normally mediated hypoglycemic damage. APPss also protected neurons against glutamate neurotoxicity, effectively raising the excitotoxic threshold. APPss may normally play excitoprotective and neuromodulatory roles. Alternative processing of APPss in Alzheimer's disease may contribute to neuronal degeneration by compromising the normal function of APPss and by promoting the deposition of beta AP.
β-淀粉样前体蛋白（β-APP）是一种跨膜糖蛋白，是β-淀粉样肽（β-AP）的来源，β-AP在阿尔茨海默病患者大脑中以老年斑形式积累。β-APP通常进行加工处理，使得在β-AP内发生切割，从细胞中释放出分泌形式的β-APP（APPss）。这些形式的神经元功能尚不清楚。我们现在报告，APPss在培养的大鼠海马和隔区神经元以及人类皮层神经元中具有强大的神经保护作用。APPs695和APPs751保护神经元免受低血糖损伤，并且针对APPs695和APPs751共有的特定区域的抗体可消除这种神经保护作用。APPss导致细胞内钙离子浓度（[Ca2+]i）迅速且持续降低，并防止通常介导低血糖损伤的[Ca2+]i升高。APPss还保护神经元免受谷氨酸神经毒性作用，有效提高兴奋毒性阈值。APPss可能正常发挥兴奋保护和神经调节作用。阿尔茨海默病中APPss的异常加工处理可能通过损害APPss的正常功能以及促进β-AP的沉积而导致神经元变性。
