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J Neurosci:降低磷酸化蛋白1水平减少β-淀粉样蛋白毒性

来源:生物谷 2013-10-16 20:56

2013年10月17日讯 /生物谷BIOON/--在Marco Prado博士的带领下,Western大学一项新的研究已经确定大脑试图保护自己免受阿尔茨海默氏病(AD)毒性蛋白影响的机制。

Prado和他的同事们已经对有关朊蛋白作用做了大量的工作。他们发现,β-淀粉样蛋白肽的毒性是AD的主要元凶之一,通过抑制β-淀粉样蛋白肽与朊蛋白相互作用,可以减少其毒性。

当一种蛋白质--应力诱导磷酸化蛋白1(STI1)与朊蛋白作用后,能防止β-淀粉样肽的相互作用,起到保护神经元作用。现在,这项研究发表在Journal of Neuroscience杂志上。

有趣的是,当我们研究AD患者大脑时,我们看到的是,STI1水平提高。研究人员测试了STI1在小鼠神经元的水平,分析增加或减少STI1的水平会发生什么。

当水STI1平下降,β-淀粉样蛋白对神经攻击变得更加敏感,STI1增加时,β-淀粉样蛋白的毒性减轻。

Prado说: AD是非常复杂的疾病,但如何能够帮助大脑抵抗毒素也许能治愈疾病。(生物谷Bioon.com)

Forebrain Deletion of the Vesicular Acetylcholine Transporter Results in Deficits in Executive Function, Metabolic, and RNA Splicing Abnormalities in the Prefrontal Cortex

Benjamin Kolisnyk,et al.

One of the key brain regions in cognitive processing and executive function is the prefrontal cortex (PFC), which receives cholinergic input from basal forebrain cholinergic neurons. We evaluated the contribution of synaptically released acetylcholine (ACh) to executive function by genetically targeting the vesicular acetylcholine transporter (VAChT) in the mouse forebrain. Executive function was assessed using a pairwise visual discrimination paradigm and the 5-choice serial reaction time task (5-CSRT). In the pairwise test, VAChT-deficient mice were able to learn, but were impaired in reversal learning, suggesting that these mice present cognitive inflexibility. Interestingly, VAChT-targeted mice took longer to reach criteria in the 5-CSRT. Although their performance was indistinguishable from that of control mice during low attentional demand, increased attentional demand revealed striking deficits in VAChT-deleted mice. Galantamine, a cholinesterase inhibitor used in Alzheimer's disease, significantly improved the performance of control mice, but not of VAChT-deficient mice on the 5-CSRT. In vivo magnetic resonance spectroscopy showed altered levels of two neurochemical markers of neuronal function, taurine and lactate, suggesting altered PFC metabolism in VAChT-deficient mice. The PFC of these mice displayed a drastic reduction in the splicing factor heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1), whose cholinergic-mediated reduction was previously demonstrated in Alzheimer's disease. Consequently, several key hnRNPA2/B1 target transcripts involved in neuronal function present changes in alternative splicing in VAChT-deficient mice, including pyruvate kinase M, a key enzyme involved in lactate metabolism. We propose that VAChT-targeted mice can be used to model and to dissect the neurochemical basis of executive abnormalities.

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