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JAD:研究发现蛋白激酶Cε或为阿尔兹海默症提供新型药物靶点

  1. 蛋白体
  2. 蛋白激酶
  3. 阿尔兹海默

来源:生物谷 2016-08-25 15:31

JAD:研究发现蛋白激酶Cε或为阿尔兹海默症提供新型药物靶点

阿尔茨海默

2014年8月26日讯 /生物谷BIOON/ --长期以来,阿尔兹海默症药物开发都一直困扰着科学家和药物开发者,可以说这一领域是当今医药产业的重灾区,许多医药巨头都曾在此备尝苦果。

一般而言,阿尔兹海默症主要是由于脑部积聚了大量的β淀粉样蛋白体而影响脑部正常机能的,因此长期以来大部分科学家就将研究重心放在了这种淀粉样蛋白体上。如今美国西弗吉尼亚大学布兰切特洛克菲勒神经科学研究所的科学家在阿尔兹海默症上又有新进展。研究人员发现阿尔兹海默症的发作与脑部一种名为PKCε的酶有关。研究发现在脑部海马体和颞叶端中这种蛋白酶的表达水平明显降低,而海马体和颞叶端则是早期阿尔兹海默症患者的主要发病区。并且PKCε的表达水平与淀粉样蛋白的积累有直接关系。此外PKCε的水平也与阿尔兹海默症的严重程度相关。

研究人员另一个发现是在阿尔兹海默症患者皮肤样本中,PKCε的表达量也显着降低,患者病情越严重,皮肤中PKCε的水平也越低。这一结果将有助于新型阿尔兹海默症药物和鉴定方法。(生物谷Bioon.com)

生物谷推荐的英文摘要:

Journal of Alzheimer's Disease DOI 10.3233/JAD-141221

PKCε Deficits in Alzheimer's Disease Brains and Skin Fibroblasts

Tapan K. Khan, Abhik Sen, Jarin Hongpaisan, Chol S. Lim, Thomas J. Nelson, Daniel L. Alkon

In Alzheimer's disease (AD) transgenic mice, activation of synaptogenic protein kinase C ε (PKCε) was found to prevent synaptotoxic amyloid-β (Aβ)-oligomer elevation, PKCε deficits, early synaptic loss, cognitive deficits, and amyloid plaque formation. In humans, to study the role of PKCε in the pathophysiology of AD and to evaluate its possible use as an early AD-biomarker, we examined PKCε and Aβ in the brains of autopsy-confirmed AD patients (n = 20) and age-matched controls (AC, n = 19), and in skin fibroblast samples from AD (n = 14), non-AD dementia patients (n = 14), and AC (n = 22). Intraneuronal Aβ levels were measured immunohistochemically (using an Aβ-specific antibody) in hippocampal pyramidal cells of human autopsy brains. PKCε was significantly lower in the hippocampus and temporal pole areas of AD brains, whereas Aβ levels were significantly higher. The ratio of PKCε to Aβ in individual CA1 pyramidal cells was markedly lower in the autopsy AD brains versus controls. PKCε was inversely correlated with Aβ levels in controls, whereas in AD patients, PKCε showed no significant correlation with Aβ. In autopsy brains, PKCε decreased as the Braak score increased. Skin fibroblast samples from AD patients also demonstrated a deficit in PKCε compared to controls and an AD-specific change in the Aβ-oligomer effects on PKCε. Together, these data demonstrate that the relationship between Aβ levels and PKCε is markedly altered in AD patients' brains and skin fibroblasts, reflecting a loss of protective effect of PKCε against toxic Aβ accumulation. These changes of PKCε levels in human skin fibroblasts may provide an accurate, non-invasive peripheral AD biomarker.

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