Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Ward 12-369, Chicago, IL, 60611, USA.
Neurotox Res. 2019 Apr;35(3):621-634. doi: 10.1007/s12640-019-0005-9. Epub 2019 Feb 7.
Alzheimer's disease (AD) is the most common cause of progressive decline of memory function in aged humans. To study about a disease mechanism and progression, animal models for the specific disease are needed. For AD, although highly valid animal models exist, none of the existing models recapitulates all aspects of human AD. The pathogenic mechanisms involved in AD are diverse and thus it is difficult to recapitulate human AD in model organisms. Intracerebroventricular (ICV) injection of okadaic acid (OKA), a protein phosphatase 2A (PP2A) inhibitor, in rats causes neurotoxicity associated with neurofibrillary degeneration. However, this model lacks amyloid pathology as observed in AD. We aimed at combining two different treatments and hence producing a better animal model of AD which may mimic most of the neuropathological, neurobehavioral, and neurochemical changes observed in AD. For this, OKA (200 ng) was microinjected bilaterally into the hippocampus of male Wistar rats followed by exposure of same rats to hypoxic conditions (10%) for 3 days. The result of which, the combination model exhibited tau hyperphosphorylation along with Aβ upregulation as evident by western blotting and immunohistochemistry. The observed changes were accompanied with dysfunction of neurotransmitter system, i.e., decreased acetylcholine activity and expression. This combinatorial model also exhibited cognitive deficiency which was assessed by Morris water maze and avoidance tests along with enhanced oxidative stress which is thought to be a major player in AD pathogenesis. Taken together, we established an easily reproducible and reliable rat model for sporadic dementia of Alzheimer's type in rats which allows effective testing of new therapeutic strategies.
阿尔茨海默病（AD）是老年人记忆功能进行性下降的最常见原因。为了研究疾病机制和进展，需要针对特定疾病的动物模型。对于 AD，虽然存在高度有效的动物模型，但没有一种现有的模型能再现人类 AD 的所有方面。AD 涉及的发病机制多种多样，因此很难在模型生物中再现人类 AD。向大鼠的侧脑室（ICV）内注射蛋白磷酸酶 2A（PP2A）抑制剂 okadaic 酸（OKA）会引起与神经纤维变性相关的神经毒性。然而，这种模型缺乏 AD 中观察到的淀粉样蛋白病理学。我们的目的是结合两种不同的治疗方法，从而产生一种更好的 AD 动物模型，该模型可能模拟 AD 中观察到的大多数神经病理学、神经行为和神经化学变化。为此，将 OKA（200ng）双侧微注射到雄性 Wistar 大鼠的海马中，然后使相同的大鼠暴露于低氧条件（10%）3 天。结果，组合模型表现出 tau 过度磷酸化，同时 Aβ 上调，这可以通过 Western 印迹和免疫组织化学来证明。观察到的变化伴随着神经递质系统功能障碍，即乙酰胆碱活性和表达降低。这种组合模型还表现出认知缺陷，这可以通过 Morris 水迷宫和回避测试来评估，同时还伴有氧化应激增强，这被认为是 AD 发病机制中的主要因素。综上所述，我们在大鼠中建立了一种易于重现和可靠的散发性阿尔茨海默病痴呆大鼠模型，可有效测试新的治疗策略。
