LeBlanc A C, Papadopoulos M, Bélair C, Chu W, Crosato M, Powell J, Goodyer C G
Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada.
J Neurochem. 1997 Mar;68(3):1183-90. doi: 10.1046/j.1471-4159.1997.68031183.x.
Increased production of amyloid beta peptide (A beta) is highly suspected to play a major role in Alzheimer's disease (AD) pathogenesis. Because A beta deposits in AD senile plaques appear uniquely in the brain and are fairly restricted to humans, we assessed amyloid precursor protein (APP) metabolism in primary cultures of the cell types associated with AD senile plaques: neurons, astrocytes, and microglia. We find that neurons secrete 40% of newly synthesized APP, whereas glia secrete only 10%. Neuronal and astrocytic APP processing generates five C-terminal fragments similar to those observed in human adult brain, of which the most amyloidogenic higher-molecular-weight fragments are more abundant. The level of amyloidogenic 4-kDa A beta exceeds that of nonamyloidogenic 3-kDa A beta in both neurons and astrocytes. In contrast, microglia make more of the smallest C-terminal fragment and no detectable A beta. We conclude that human neurons and astrocytes generate higher levels of amyloidogenic fragments than microglia and favor amyloidogenic processing compared with previously studied culture systems. Therefore, we propose that the higher amyloidogenic processing of APP in neurons and astrocytes, combined with the extended lifespan of individuals, likely promotes AD pathology in aging humans.
淀粉样β肽（Aβ）产量增加被高度怀疑在阿尔茨海默病（AD）发病机制中起主要作用。由于AD老年斑中的Aβ沉积物仅在大脑中独特出现且相当局限于人类，我们评估了与AD老年斑相关的细胞类型（神经元、星形胶质细胞和小胶质细胞）原代培养物中的淀粉样前体蛋白（APP）代谢。我们发现神经元分泌新合成APP的40%，而胶质细胞仅分泌10%。神经元和星形胶质细胞的APP加工产生五个C末端片段，类似于在人类成人大脑中观察到的片段，其中最具淀粉样变性的高分子量片段更为丰富。在神经元和星形胶质细胞中，具有淀粉样变性的4 kDa Aβ水平超过了非淀粉样变性的3 kDa Aβ水平。相比之下，小胶质细胞产生更多最小的C末端片段，且未检测到Aβ。我们得出结论，与先前研究的培养系统相比，人类神经元和星形胶质细胞产生的淀粉样变性片段水平高于小胶质细胞，并且更倾向于淀粉样变性加工。因此，我们提出神经元和星形胶质细胞中APP更高的淀粉样变性加工，与个体寿命延长相结合，可能会促进衰老人类的AD病理。
