Nontransgenic Guinea Pig Strains Exhibit Hallmarks of Human Brain Aging and Alzheimer's Disease.
Nontransgenic Guinea Pig Strains Exhibit Hallmarks of Human Brain Aging and Alzheimer's Disease.
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非转基因豚鼠品系表现出人类大脑衰老和阿尔茨海默病的特征。
DOI：
10.1093/gerona/glac073
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
LaRocca,ThomasJ
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作者：
Wahl,Devin;Moreno,JulieA;Santangelo,KellyS;Zhang,Qian;Afzali,MaryamF;Walsh,MaureenA;Musci,RobertV;Cavalier,AlyssaN;Hamilton,KarynL;LaRocca,ThomasJ
老年是大多数慢性疾病的主要危险因素，包括阿尔茨海默病（AD）。目前研究脑老化和AD的临床前模型主要是转基因的，并且含有旨在反映与人脑老化/AD相关的脑病理的突变（例如，通过增加淀粉样前体蛋白、淀粉样β [Aβ]和/或磷酸化tau的产生，所有这些都是AD的关键病理介质）。尽管这些模型可以提供关于AD病理生理过程的见解，但没有一个完全概括了该疾病及其强烈的年龄依赖性，并且在将临床前结果和治疗转化为人类方面的成功有限。在这里，我们描述了2个非转基因豚鼠（GP）模型，一个标准的PigmEnTed（PET）品系，和较少研究的Dunkin-Hartley（DH）品系，它们可能自然地模仿人类大脑老化和AD的关键特征。我们发现，PET GP中的脑老化在转录组学上与人类脑老化相似，而老年DH脑在转录组学上与人类AD更相似。两种品系/模型还显示出随着年龄增长神经丝轻链（NFL，神经元损伤的标志物）增加，DH动物显示出更高的S100钙结合蛋白B（S100β）、离子化钙结合衔接分子1（Iba 1）以及Aβ和磷酸化tau-，这些都是神经炎症相关AD的重要标志物。总的来说，我们的研究结果表明，PET和DH GP可能是有用的，非转基因模型，分别研究脑老化和AD。
Older age is the primary risk factor for most chronic diseases, including Alzheimer’s disease (AD). Current preclinical models to study brain aging and AD are mainly transgenic and harbor mutations intended to mirror brain pathologies associated with human brain aging/AD (eg, by increasing production of the amyloid precursor protein, amyloid beta [Aβ], and/or phosphorylated tau, all of which are key pathological mediators of AD). Although these models may provide insight on pathophysiological processes in AD, none completely recapitulate the disease and its strong age-dependence, and there has been limited success in translating preclinical results and treatments to humans. Here, we describe 2 nontransgenic guinea pig (GP) models, a standard PigmEnTed (PET) strain, and lesser-studied Dunkin-Hartley (DH) strain, that may naturally mimic key features of brain aging and AD in humans. We show that brain aging in PET GP is transcriptomically similar to human brain aging, whereas older DH brains are transcriptomically more similar to human AD. Both strains/models also exhibit increased neurofilament light chain (NFL, a marker of neuronal damage) with aging, and DH animals display greater S100 calcium-binding protein B (S100β), ionized calcium-binding adapter molecule 1 (Iba1), and Aβ and phosphorylated tau—which are all important markers of neuroinflammation-associated AD. Collectively, our results suggest that both the PET and DH GP may be useful, nontransgenic models to study brain aging and AD, respectively.