The amyloidogenic potential and behavioral correlates of stress
The amyloidogenic potential and behavioral correlates of stress
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DOI：
10.1038/sj.mp.4002101
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发表时间：
2009-01-01
影响因子：
11
通讯作者：
Almeida, O. F. X.
中科院分区：
文献类型：
--
作者：
Catania, C.;Sotiropoulos, I.;Almeida, O. F. X.
阿尔茨海默病（AD）患者基础皮质醇水平升高的观察提示了这样的假设，即应激和糖皮质激素（GC）可能有助于AD的发展和/或维持。与这一假设相一致，我们发现，应激和GC引起大鼠海马和前额皮质中淀粉样前体肽的错误加工，导致肽C-末端片段99（C99）水平增加，其进一步的蛋白水解裂解导致淀粉样β（A β）的产生。我们还表明，外源性A β可以再现的压力和GC对C99生产的影响，并强调的历史显着增强的C99诱导的A β和GC的影响。以前的工作表明A β在破坏突触功能和认知行为中的作用，据报道，AD患者表现出高度焦虑的迹象。在这里，行为分析显示，像压力和GC一样，A β给药会导致空间记忆缺陷，而压力和GC会加剧空间记忆缺陷;此外，A β、压力和GC会诱导过度焦虑状态。鉴于C99和A β的内在特性包括神经危害和行为障碍，我们的研究结果表明压力和GC在AD的发病机制中发挥着因果作用，并证明压力性生活事件和GC治疗可以对AD的发病过程产生累积影响。发展和进展。
Observations of elevated basal cortisol levels in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids (GC) may contribute to the development and/or maintenance of AD. Consistent with that hypothesis, we show that stress and GC provoke misprocessing of amyloid precursor peptide in the rat hippocampus and prefrontal cortex, resulting in increased levels of the peptide C-terminal fragment 99 (C99), whose further proteolytic cleavage results in the generation of amyloid-beta (A beta). We also show that exogenous A beta can reproduce the effects of stress and GC on C99 production and that a history of stress strikingly potentiates the C99-inducing effects of A beta and GC. Previous work has indicated a role for A beta in disruption of synaptic function and cognitive behaviors, and AD patients reportedly show signs of heightened anxiety. Here, behavioral analysis revealed that like stress and GC, A beta administration causes spatial memory deficits that are exacerbated by stress and GC; additionally, A beta, stress and GC induced a state of hyperanxiety. Given that the intrinsic properties of C99 and A beta include neuroendangerment and behavioral impairment, our findings suggest a causal role for stress and GC in the etiopathogenesis of AD, and demonstrate that stressful life events and GC therapy can have a cumulative impact on the course of AD development and progression.