Characterization of microtubule-associated protein tau isoforms and Alzheimer's disease-like pathology in normal sheep (Ovis aries): relevance to their potential as a model of Alzheimer's disease.
Characterization of microtubule-associated protein tau isoforms and Alzheimer's disease-like pathology in normal sheep (Ovis aries): relevance to their potential as a model of Alzheimer's disease.
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DOI：
10.1007/s00018-022-04572-z
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发表时间：
2022-10-21
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--
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阿尔茨海默病是一种慢性神经退行性疾病，占所有痴呆症的80%。以记忆和认知功能的恶化为特征，关键的神经病理学特征是β-淀粉样蛋白和过度磷酸化tau蛋白的积累，分别为“斑块”和“缠结”。然而，尽管进行了广泛的研究，阿尔茨海默病中聚集体形成的确切机制仍然难以捉摸，这些聚集体对疾病进展的贡献也是如此。重要的是，最近对目前阿尔茨海默病动物模型的评估表明，啮齿动物模型不能完全重现该疾病在人类中发生的病理复杂性。因此，越来越多的注意力正在支付给物种，可能成为良好的替代啮齿动物研究阿尔茨海默氏病的分子病理学。绵羊（Ovis aries）就是这样一个物种，尽管到目前为止，很少有关于绵羊阿尔茨海默病的分子研究。在这里，我们研究了22只绵羊的阿尔茨海默病相关的组织病理学特征，使用抗β-淀粉样蛋白（Abcam 12267和mOC 64）和磷酸化特异性抗tau（AT 8和S396）抗体。我们鉴定了许多与早期阿尔茨海默病样病理学一致的β-淀粉样蛋白和tau蛋白的神经元内聚集体。我们证实了两个3-重复（1 N3 R，2N 3R）和两个4-重复（1 N4 R，2N 4 R）tau亚型在绵羊脑中的表达，这是由于两个tau外显子的选择性剪接。最后，我们调查了30只绵羊的丝氨酸396残基的磷酸化状态，并报告该残基的磷酸化开始于2岁的绵羊。总之，这些数据表明，绵羊表现出自然发生的β-淀粉样蛋白和tau病理，反映了阿尔茨海默病早期阶段发生的病理。这是验证绵羊作为一种可行的大型动物物种来模拟阿尔茨海默病的重要一步。在线版本包含补充材料，可通过10.1007/s 00018 -022-04572-z获得。
Alzheimer’s disease is a chronic neurodegenerative disease that accounts for up to 80% of all dementias. Characterised by deteriorations of memory and cognitive function, the key neuropathological features are accumulations of β-amyloid and hyperphosphorylated tau, as ‘plaques’ and ‘tangles’, respectively. Despite extensive study, however, the exact mechanism underlying aggregate formation in Alzheimer’s disease remains elusive, as does the contribution of these aggregates to disease progression. Importantly, a recent evaluation of current Alzheimer’s disease animal models suggested that rodent models are not able to fully recapitulate the pathological intricacies of the disease as it occurs in humans. Therefore, increasing attention is being paid to species that might make good alternatives to rodents for studying the molecular pathology of Alzheimer’s disease. The sheep (Ovis aries) is one such species, although to date, there have been few molecular studies relating to Alzheimer’s disease in sheep. Here, we investigated the Alzheimer’s disease relevant histopathological characteristics of 22 sheep, using anti-β-amyloid (Abcam 12267 and mOC64) and phosphorylation specific anti-tau (AT8 and S396) antibodies. We identified numerous intraneuronal aggregates of both β-amyloid and tau that are consistent with early Alzheimer’s disease-like pathology. We confirmed the expression of two 3-repeat (1N3R, 2N3R) and two 4-repeat (1N4R, 2N4R) tau isoforms in the ovine brain, which result from the alternative splicing of two tau exons. Finally, we investigated the phosphorylation status of the serine396 residue in 30 sheep, and report that the phosphorylation of this residue begins in sheep aged as young as 2 years. Together, these data show that sheep exhibit naturally occurring β-amyloid and tau pathologies, that reflect those that occur in the early stages of Alzheimer’s disease. This is an important step towards the validation of the sheep as a feasible large animal species in which to model Alzheimer’s disease. The online version contains supplementary material available at 10.1007/s00018-022-04572-z.
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影响因子：
12.7
作者：
Braak, Heiko;Del Tredici, Kelly
通讯作者：
Del Tredici, Kelly
影响因子：
14
作者：
通讯作者：
--
影响因子：
2.3
作者：
Calderon-Garciduenas, Ana Laura;Duyckaerts, Charles
通讯作者：
Duyckaerts, Charles
影响因子：
4.2
作者：
Edler MK;Sherwood CC;Meindl RS;Hopkins WD;Ely JJ;Erwin JM;Mufson EJ;Hof PR;Raghanti MA
通讯作者：
Raghanti MA
DOI：
10.1097/00005072-198811000-00006
发表时间：
1988-11-01
影响因子：
3.2
作者：
CORK, LC;POWERS, RE;PRICE, DL
通讯作者：
PRICE, DL