阻断BCL2预防阿尔茨海默病小鼠模型的致死性牛头病

IF 1.3 4区 医学 Q3 ANATOMY & MORPHOLOGY
Gerard J Nuovo, Madison Rice, Nicola Zanesi, Dwitiya Sawant, Candice Crilly, Esmerina Tili
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引用次数: 0

摘要

阿尔茨海默病(AD)研究的一个主要目标是减少异常tau负担。通过对死于阿尔茨海默病的人的脑组织进行多光谱分析,证明tau蛋白过度磷酸化的神经元积累了许多BCL2家族的蛋白质,包括那些阻止细胞更新的蛋白质(如BCL2, MCL1, BCLXL)和那些促进细胞更新的蛋白质(如NOXA, PUMA, BAK, BAX)。一个带有人源化高磷酸化tau蛋白的AD小鼠模型被用来验证这样一种假设,即将这种平衡转移到促细胞周转环境将减少tau负担,并伴随临床改善。在这里,我们发现,在使用fda批准的阻断BCL2的药物venetoclax治疗后,因中枢神经系统病变而在11至15个月死亡的AD小鼠模型中,tau负荷明显减少。免疫组化检测显示,venetoclax治疗后脑和脊髓神经元中过度磷酸化tau蛋白阳性的目标神经元数量减少94.5%,改良Bielchowsky染色显示减少98.1%。在记录的神经原纤维缠结(nft)明显并且伴随神经炎症减少后,venetoclax治疗开始。与未经治疗的小鼠相比,接受治疗的小鼠直到13个月时都很健壮,而未经治疗的小鼠在临床和尸检中都显示出明确的脑和脊髓损伤证据。我们的结论是,即使在发病后,不可避免的异常tau蛋白沉积也可以通过阻断人类AD的nft中丰富的一种抗细胞周转蛋白的药物来预防。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The Prevention of Fatal Tauopathy in a Mouse Model of Alzheimer Disease by Blocking BCL2.

A major goal in Alzheimer disease (AD) research is the reduction of the abnormal tau burden. Using multispectral analyses on brain tissues from humans who died of AD it was documented that neurons with hyperphosphorylated tau protein accumulate many proteins of the BCL2 family, including those that block cell turnover (eg, BCL2, MCL1, BCLXL) and those that promote cell turnover (eg, NOXA, PUMA, BAK, BAX). A mouse model of AD with the humanized hyperphosphorylated tau protein was used to test the hypothesis that shifting this balance to a pro-cell turnover milieu would reduce the tau burden with concomitant clinical improvement. Here, we show that a mouse model of AD with death at 11 to 15 months due to CNS tauopathy had a marked reduction in the tau burden after treatment with the FDA-approved drug venetoclax, which blocks BCL2. The reduction of the number of target neurons positive for hyperphosphorylated tau protein after venetoclax treatment in the brain and spinal cord neurons was 94.5% as determined by immunohistochemistry and 98.1% as documented with the modified Bielchowsky stain. The venetoclax treatment began after documented neurofibrillary tangles (NFTs) were evident and there was a concomitant reduction in neuroinflammation. The treated mice were robust until sacrificed at 13 months as compared with the untreated mice that showed unequivocal evidence of brain and spinal cord damage both clinically and at autopsy. We conclude that otherwise inexorable abnormal tau protein deposition, even after initiation, can be prevented by a drug that blocks one anti-cell turnover protein abundant in the NFTs of human AD.

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来源期刊
Applied Immunohistochemistry & Molecular Morphology
Applied Immunohistochemistry & Molecular Morphology ANATOMY & MORPHOLOGY-MEDICAL LABORATORY TECHNOLOGY
CiteScore
3.20
自引率
0.00%
发文量
153
期刊介绍: ​Applied Immunohistochemistry & Molecular Morphology covers newly developed identification and detection technologies, and their applications in research and diagnosis for the applied immunohistochemist & molecular Morphologist. Official Journal of the International Society for Immunohistochemisty and Molecular Morphology​.
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