LeBlanc A C, Koutroumanis M, Goodyer C G
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada H3A 2T6.
J Neurosci. 1998 Apr 15;18(8):2907-13. doi: 10.1523/JNEUROSCI.18-08-02907.1998.
Overexpression and altered metabolism of amyloid precursor protein (APP) resulting in increased 4 kDa amyloid beta peptide (Abeta) production are believed to play a major role in Alzheimer's disease (AD). Therefore, reducing Abeta production in the brain is a possible therapy for AD. Because AD pathology is fairly restricted to the CNS of humans, we have established human cerebral primary neuron cultures to investigate the metabolism of APP. In many cell lines and rodent primary neuron cultures, phorbol ester activation of protein kinase C (PKC) increases the release of the secreted large N-terminal fragment of amyloid precursor protein (sAPP) and decreases Abeta release (; ; ). In contrast, we find that PKC activation in human primary neurons increases the rate of sAPP release and the production of APP C-terminal fragments and 4 kDa Abeta. Our results indicate species- and cell type-specific regulation of APP metabolism. Therefore, our results curtail the use of PKC activators in controlling human brain Abeta levels.
淀粉样前体蛋白（APP）的过表达和代谢改变导致4 kDa淀粉样β肽（Aβ）生成增加，这被认为在阿尔茨海默病（AD）中起主要作用。因此，减少大脑中Aβ的生成是治疗AD的一种可能方法。由于AD病理学相当局限于人类中枢神经系统（CNS），我们建立了人脑原代神经元培养物来研究APP的代谢。在许多细胞系和啮齿动物原代神经元培养物中，佛波酯激活蛋白激酶C（PKC）可增加淀粉样前体蛋白分泌性大N端片段（sAPP）的释放并减少Aβ释放（；；）。相反，我们发现人原代神经元中PKC激活会增加sAPP释放速率以及APP C端片段和4 kDa Aβ的生成。我们的结果表明APP代谢存在物种和细胞类型特异性调控。因此，我们的结果限制了PKC激活剂在控制人脑Aβ水平方面的应用。
