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铝与家族性阿尔茨海默氏病的神经病理学密切相关 精选

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铝与家族性阿尔茨海默氏病的神经病理学密切相关

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IOS出版社(IOS Press202149日提供资料,一项新的研究继续支持越来越多的证据表明,铝与阿尔茨海默氏病(Alzheimer's disease简称AD)的发病机理有关。英国基尔大学(Keele University)研究人员发现铝与磷酸化Tau蛋白共存,磷酸化Tau蛋白是AD的早期引发剂。相关研究结果于202149日已经在《阿尔茨海默氏病杂志》(Journal of Alzheimer's Disease Reports)网站发表——Matthew John Mold, Adam O’Farrell, Benjamin Morris, Christopher Exley. Aluminum and Tau in Neurofibrillary Tangles in Familial Alzheimer’s Disease. Journal of Alzheimer's Disease Reports, 2021; 5 (1): 283-294. DOI: 10.3233/ADR-210011. Published: 09 April 2021. https://content.iospress.com/articles/journal-of-alzheimers-disease-reports/adr210011

发表在《阿尔茨海默氏病报告》杂志网站的此项新研究基于同一组的两项较早发表的研究(包括Mold et al., 2020, Journal of Alzheimer's Disease)。新的数据表明,铝与磷酸化的Tau蛋白共存,并以缠结的形式存在于早发或家族性阿尔茨海默氏病的大脑神经元中。基尔大学Lennard-Jones实验室Birchall中心(Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, UK)首席研究员Matthew John Mold博士解释说:这些缠结的存在与神经元细胞死亡有关,观察到这些缠结中的铝可能突出铝在其形成中的作用。

较早的研究突出了家族性AD大脑组织中铝和淀粉样蛋白βamyloid-β)的广泛共定位。研究人员在当前研究中使用了高度选择性的免疫标记方法,并结合了铝特异性荧光显微镜技术。在同一个哥伦比亚家族性AD捐献者队列中,发现与铝共存的缠结中的磷酸化Tau蛋白与铝共存。对于铝在AD中的作用,有趣的是,也许有意义的是,铝与Tau蛋白的明确联系不像淀粉样βamyloid-β)一样容易被识别。在这些组织中,与淀粉样Tau蛋白相比,铝的聚集体多于Tau蛋白,后者主要是细胞内的。合著者克里斯托弗·埃克斯利(Christopher Exley)教授指出。

《阿尔茨海默病杂志》主编乔治·佩里(George Perry)博士评论道:“近半个世纪以来,铝的积累一直与阿尔茨海默病有关,但这是博士们细致具体的研究。Matthew John Mold博士和克里斯托弗·埃克斯利博士正在定义铝和其他多价金属的确切分子相互作用,这可能是阿尔茨海默病病理形成的关键。

Matthew John Mold博士说:“新的数据可能表明,铝与细胞外老年斑的结合先于细胞内Tau蛋白的聚集。这些与淀粉样蛋白β和Tau蛋白的关系,可能解释了与未诊断为神经退行性疾病的患者相比,在家族性AD患者的脑组织中观察到的高水平铝。”“已知Tau蛋白和淀粉样β蛋白协同作用产生AD神经毒性,我们的数据为铝在这一过程中的作用提供了新的证据。上述介绍仅供参考,更多信息敬请注意浏览原文或者相关报道

Abstract

Background:

Familial Alzheimer’s disease (fAD) is driven by genetic predispositions affecting the expression and metabolism of the amyloid-β protein precursor. Aluminum is a non-essential yet biologically-reactive metal implicated in the etiology of AD. Recent research has identified aluminum intricately and unequivocally associated with amyloid-β in senile plaques and, more tentatively, co-deposited with neuropil-like threads in the brains of a Colombian cohort of donors with fAD.

Objective:

Herein, we have assessed the co-localization of aluminum to immunolabelled phosphorylated tau to probe the potential preferential binding of aluminum to senile plaques or neurofibrillary tangles in the same Colombian kindred.

Methods:

Herein, we have performed phosphorylated tau-specific immunolabelling followed by aluminum-specific fluorescence microscopy of the identical brain tissue sections via a sequential labelling method.

Results:

Aluminum was co-localized with immunoreactive phosphorylated tau in the brains of donors with fAD. While aluminum was predominantly co-located to neurofibrillary tangles in the temporal cortex, aluminum was more frequently co-deposited with cortical senile plaques.

Conclusion:

These data suggest that the co-deposition of aluminum with amyloid-β precedes that with neurofibrillary tangles. Extracellularly deposited amyloid-β may also be more immediately available to bind aluminum versus intracellular aggregates of tau. Therapeutic approaches to reduce tau have demonstrated the amelioration of its synergistic interactions with amyloid-β, ultimately reducing tau pathology and reducing neuronal loss. These data support the intricate associations of aluminum in the neuropathology of fAD, of which its subsequent reduction may further therapeutic benefits observed in ongoing clinical trials in vivo.




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