Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado, USA.
Center for Healthy Aging, Colorado State University, Fort Collins, Colorado, USA.
J Gerontol A Biol Sci Med Sci. 2022 Sep 1;77(9):1766-1774. doi: 10.1093/gerona/glac073.
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.
年龄增长是大多数慢性疾病（包括阿尔茨海默病，AD）的主要风险因素。目前用于研究脑衰老和 AD 的临床前模型主要是转基因模型，这些模型携带的突变旨在模拟与人类脑衰老/AD 相关的脑病理学（例如，通过增加淀粉样前体蛋白、β 淀粉样蛋白 [Aβ] 和/或磷酸化 tau 的产生，这些都是 AD 的关键病理介质）。虽然这些模型可能提供 AD 病理生理过程的见解，但没有一个模型能完全再现该疾病及其与年龄的强依赖性，并且将临床前结果和治疗方法转化为人类的成功有限。在这里，我们描述了 2 种非转基因豚鼠（GP）模型，即标准的 PigmEnTed（PET）品系和研究较少的邓金-哈特利（DH）品系，它们可能自然模拟人类大脑衰老和 AD 的关键特征。我们表明，PET GP 中的脑衰老在转录组上与人类脑衰老相似，而较老的 DH 脑在转录组上与人类 AD 更相似。这两种品系/模型随着年龄的增长，神经丝轻链（NFL，神经元损伤的标志物）也会增加，而 DH 动物的 S100 钙结合蛋白 B（S100β）、离子钙结合衔接分子 1（Iba1）和 Aβ以及磷酸化 tau 的含量更高，这些都是神经炎症相关 AD 的重要标志物。总的来说，我们的结果表明，PET 和 DH GP 都可能分别是研究脑衰老和 AD 的有用非转基因模型。
