Aging renders the brain vulnerable to amyloid β-protein neurotoxicity
Aging renders the brain vulnerable to amyloid β-protein neurotoxicity
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DOI：
10.1038/nm0798-827
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发表时间：
1998-07-01
期刊：
影响因子：
82.9
通讯作者：
Yankner, BA
中科院分区：
文献类型：
--
作者：
Geula, C;Wu, CK;Yankner, BA
脑中淀粉样β蛋白（A β）的纤维状沉积物的形成是阿尔茨海默病（1.2）（AD）的病理学标志。一个中心问题是A β是否在AD的神经退行性过程中发挥直接作用（参考文献10）。3、4）。体外A β纤维形式的神经毒性表明A β参与神经变性过程（5-11）。然而，在大脑中形成淀粉样蛋白沉积的A β前体蛋白转基因小鼠没有显示出AD中发现的神经元损失或tau磷酸化的程度（参考文献10）。12-16）。在这里，我们表明，微量注射斑块等效浓度的纤维，但不可溶，A β在老年恒河猴大脑皮层的结果在深刻的神经元损失，tau蛋白磷酸化和小胶质细胞增殖。在斑块等效浓度下的原纤维A β在年轻成年恒河猴脑中没有毒性。体内β毒性也具有高度的物种特异性;老年恒河猴的毒性大于老年绒猴，老年大鼠的毒性不显著。这些结果表明，体内AB神经毒性是衰老大脑的病理反应，这在高等灵长类动物中最为明显。因此，长寿可能会导致人类对阿尔茨海默病的独特易感性，使大脑容易受到A β神经毒性的影响。
The formation of fibrillar deposits of amyloid beta protein (A beta) in the brain is a pathological hallmark of Alzheimer's disease(1.2) (AD). A central question is whether A beta plays a direct role in the neurodegenerative process in AD (refs. 3,4). The involvement of A beta in the neurodegenerative process is suggested by the neurotoxicity of the fibrillar form of A beta in vitro(5-11). However, mice transgenic for the A beta precursor protein that develop amyloid deposits in the brain do not show the degree of neuronal loss or tau phosphorylation found in AD (refs. 12-16). Here we show that microinjection of plaque-equivalent concentrations of fibrillar, but not soluble, A beta in the aged rhesus monkey cerebral cortex results in profound neuronal loss, tau phosphorylation and microglial proliferation. Fibrillar A beta at plaque-equivalent concentrations is not toxic in the young adult rhesus brain. A beta toxicity in vivo is also highly species-specific; toxicity is greater in aged rhesus monkeys than in aged marmoset monkeys, and is not significant in aged rats. These results suggest that AB neurotoxicity in vivo is a pathological response of the aging brain, which is most pronounced in higher order primates. Thus, longevity may contribute to the unique susceptibility of humans to Alzheimer's disease by rendering the brain vulnerable to A beta neurotoxicity.