Presenilin-1 P264L Knock-In Mutation: Differential Effects on Aβ Production, Amyloid Deposition, and Neuronal Vulnerability
Presenilin-1 P264L Knock-In Mutation: Differential Effects on Aβ Production, Amyloid Deposition, and Neuronal Vulnerability
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Presenilin-1 P264L 敲入突变：对 Aβ 生成、淀粉样蛋白沉积和神经元脆弱性的不同影响
作者：
R. Siman;A. Reaume;M. Savage;S. Trusko;Yin;R. Scott;D. Flood
早老素-1 （PS-1）基因突变与家族性阿尔茨海默病（FAD）之间的致病机制尚不确定，但已经提出包括神经元对变性的敏感性增加和β-淀粉样前体蛋白（APP）的淀粉样变性加工增强。我们通过使用Cre-lox系统的基因靶向来研究这一问题，将fad相关的P264L突变引入内源性小鼠PS-1基因，这种方法维持了对表达的正常调控控制。源自PS-1纯合突变敲入小鼠的初级皮质神经元表现出与PS-1野生型相似的基底神经变性。Staurosporine和a - β1 - 42诱导细胞凋亡，且PS-1敲入突变不改变细胞的剂量依赖性和最大死亡程度。同样，谷氨酸诱导的神经元坏死不受PS-1P264L突变的影响。通过基础和毒素诱导的caspase和calpain激活、凋亡和坏死信号的生化指标分别证实了PS-1P264L突变的缺乏作用。为了分析PS-1P264L敲入突变对APP加工和ad型神经病理发展的影响，我们建立了携带PS-1和APP突变的小鼠系。与对神经元易感性没有影响相反，PS-1P264L纯合突变小鼠培养的皮质神经元分泌Aβ42的速度增加，而分泌Aβ40的速度减少。此外，PS-1敲入突变选择性地增加了小鼠大脑中的a β42水平，加速了淀粉样蛋白沉积及其伴随的反应性胶质瘤的发生，即使是单个突变等位基因也是如此。我们得出结论，在正常水平下表达fad相关突变体PS-1通常不会增加皮质神经元对变性的敏感性。相反，APP淀粉样变性过程的增强可能对ps -1相关FAD的发病机制至关重要。
The pathogenic mechanism linking presenilin-1 (PS-1) gene mutations to familial Alzheimer's disease (FAD) is uncertain, but has been proposed to include increased neuronal sensitivity to degeneration and enhanced amyloidogenic processing of the β-amyloid precursor protein (APP). We investigated this issue by using gene targeting with the Cre-lox system to introduce an FAD-linked P264L mutation into the endogenous mouse PS-1 gene, an approach that maintains normal regulatory controls over expression. Primary cortical neurons derived from PS-1 homozygous mutant knock-in mice exhibit basal neurodegeneration similar to their PS-1 wild-type counterparts. Staurosporine and Aβ1–42 induce apoptosis, and neither the dose dependence nor maximal extent of cell death is altered by the PS-1 knock-in mutation. Similarly, glutamate-induced neuronal necrosis is unaffected by the PS-1P264L mutation. The lack of effect of the PS-1P264L mutation is confirmed by measures of basal- and toxin-induced caspase and calpain activation, biochemical indices of apoptotic and necrotic signaling, respectively. To analyze the influence of the PS-1P264L knock-in mutation on APP processing and the development of AD-type neuropathology, we created mouse lines carrying mutations in both PS-1 and APP. In contrast to the lack of effect on neuronal vulnerability, cortical neurons cultured from PS-1P264L homozygous mutant mice secrete Aβ42 at an increased rate, whereas secretion of Aβ40 is reduced. Moreover, the PS-1 knock-in mutation selectively increases Aβ42 levels in the mouse brain and accelerates the onset of amyloid deposition and its attendant reactive gliosis, even as a single mutant allele. We conclude that expression of an FAD-linked mutant PS-1 at normal levels does not generally increase cortical neuronal sensitivity to degeneration. Instead, enhanced amyloidogenic processing of APP likely is critical to the pathogenesis of PS-1-linked FAD.
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DOI：
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发表时间：
1998
期刊：
The American journal of pathology
影响因子：
--
作者：
S. Frautschy;Fusheng Yang;Michael Irrizarry;B. Hyman;T. Saido;K. Hsiao;G. Cole
通讯作者：
S. Frautschy;Fusheng Yang;Michael Irrizarry;B. Hyman;T. Saido;K. Hsiao;G. Cole
影响因子：
--
作者：
Olney, JW;Wozniak, DF;Farber, NB
通讯作者：
Farber, NB
DOI：
10.1073/pnas.96.2.742
发表时间：
1999-01-19
影响因子：
11.1
作者：
Greenfield, JP;Tsai, J;Xu, HX
通讯作者：
Xu, HX
影响因子：
56.9
作者：
SUZUKI, N;CHEUNG, TT;YOUNKIN, SG
通讯作者：
YOUNKIN, SG
影响因子：
56.9
作者：
CAI, XD;GOLDE, TE;YOUNKIN, SG
通讯作者：
YOUNKIN, SG