Characterization of Early Alzheimer's Disease-Like Pathological Alterations in Non-Human Primates with Aging: A Pilot Study.
Characterization of Early Alzheimer's Disease-Like Pathological Alterations in Non-Human Primates with Aging: A Pilot Study.
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DOI：
10.3233/jad-215303
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发表时间：
2022
影响因子：
4
通讯作者：
Ma, Tao
中科院分区：
文献类型：
--
作者：
Jester, Hannah M.;Gosrani, Saahj P.;Ding, Huiping;Zhou, Xueyan;Ko, Mei-Chuan;Ma, Tao
散发性或迟发性阿尔茨海默病（LOAD）是一种多因素的神经退行性疾病，衰老是最常见的危险因素。非人灵长类动物（NHP）在神经解剖学和神经发育等方面与人类非常相似，是研究LOAD的理想模型。最近的研究揭示了老年NHP中的AD样病理学。在这项初步研究中，我们利用了6只食蟹猴的脑样本，这些食蟹猴被分为两组：中年（平均年龄14.81岁）和老年（平均年龄19.33岁）。我们调查了NHP中是否存在AD样脑病理。采用免疫组织化学方法检测脑组织Aβ病理变化及神经元密度。我们应用生物化学测定来测量AD中指示的tau磷酸化和多种信号传导途径。我们进行了电子显微镜实验，以研究突触后密度和线粒体形态学的改变，在脑NHP。我们在老年NHP的前额叶皮层（但不在海马）中发现了多种AD样病理改变，包括tau蛋白过度磷酸化，AMP活化蛋白激酶（AMPK）活性增加，蛋白磷酸酶2A（PP2A）表达减少，线粒体形态受损和突触后密度形成。这些发现可能有助于了解LOAD发展的因素，特别是在从中年到老年的早期过渡阶段。未来的努力是必要的，以阐明潜在的区域（也许是细胞）的脆弱性与老化和功能相关的NHP的这种病理变化的机制。
Sporadic or late onset Alzheimer’s disease (LOAD) is a multifactorial neurodegenerative disease with aging the most known risk factor. Non-human primates (NHPs) may serve as an excellent model to study LOAD because of their close similarity to humans in many aspects including neuroanatomy and neurodevelopment. Recent studies reveal AD-like pathology in old NHPs. In this pilot study, we took advantage of brain samples from 6 Cynomolgus macaques that were divided into two groups: middle aged (average age 14.81 years) and older (average age 19.33 years). We investigated whether AD-like brain pathologies are present in the NHPs. We used immunohistochemical method to examine brain Aβ pathology and neuron density. We applied biochemical assays to measure tau phosphorylation and multiple signaling pathways indicated in AD. We performed electron microscopy experiments to study alterations of postsynaptic density and mitochondrial morphology in the brain of NHPs. We found multiple AD-like pathological alteration in the prefrontal cortex (but not in the hippocampus) of the older NHPs including tau hyperphosphorylation, increased activity of AMP-activated protein kinase (AMPK), decreased expression of protein phosphatase 2A (PP2A), impairments in mitochondrial morphology, and postsynaptic densities formation. These findings may provide insights into the factors contributing to the development of LOAD, particularly during the early stage transitioning from middle to old age. Future endeavors are warranted to elucidate mechanisms underlying the regional (and perhaps cellular) vulnerability with aging and the functional correlation of such pathological changes in NHPs.