Department of Animal Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
Department of Animal Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Aug 30;94:109661. doi: 10.1016/j.pnpbp.2019.109661. Epub 2019 May 29.
Neuronal apoptosis and impaired hippocampal neurogenesis are major players in cognitive/memory dysfunctions including Alzheimer's disease (AD). Interferon beta (IFNβ) is a cytokine with anti-apoptotic and neuroprotective properties on the central nervous system (CNS) cells which specifically affects neural progenitor cells (NPCs) even in the adult brain. In this study, we examined the effect of IFNβ on memory impairment as well as hippocampal neurogenesis and apoptosis in a rat model of AD. AD model was induced by lentiviral-mediated overexpression of mutant APP in the hippocampus of adult rats. Intranasal (IN) administration of IFNβ (0.5 μg/kg and 1 μg/kg doses) was started from day 23 after virus injection and continued every other day to the final day of experiments. The expression levels of APP, neurogenesis (Nestin, Ki67, DCX, and Reelin) and apoptosis (Bax/Bcl-2 ratio, cleaved-caspase-3 and seladin-1) markers were evaluated by immunohistochemistry, real-time PCR, immunofluorescence and western blotting. Moreover, thioflavin T and Nissl stainings were used to assess Aβ plaque levels and neuronal degeneration in the hippocampus, respectively. Our results showed that IFNβ treatment reduced APP expression and Aβ plaque formation, and concomitantly ameliorated spatial learning and memory deficits examined in Y-maze and Morris water maze tests. Moreover, in parallel with reducing apoptosis and neural loss in the hippocampal subfields, IFNβ decreased ectopic neurogenesis in the CA1 and CA3 regions of the AD rat hippocampus. However, IFNβ increased neurogenesis in the dentate gyrus neurogenic niche. Our findings suggest that IFNβ exerts neuroprotective effects at least partly by inhibition of apoptosis and modulation of neurogenesis. Taken together, IFNβ can be a promising therapeutic approach to improve cognitive performance in AD-like neurodegenerative context.
神经元凋亡和海马神经发生受损是包括阿尔茨海默病（AD）在内的认知/记忆功能障碍的主要原因。干扰素β（IFNβ）是一种细胞因子，对中枢神经系统（CNS）细胞具有抗凋亡和神经保护作用，特别是在成年大脑中，它可以影响神经祖细胞（NPC）。在这项研究中，我们研究了 IFNβ 对 AD 大鼠模型中记忆障碍以及海马神经发生和凋亡的影响。AD 模型通过慢病毒介导的 APP 突变体在成年大鼠海马中的过表达来诱导。IFNβ（0.5μg/kg 和 1μg/kg 剂量）的鼻腔内（IN）给药从病毒注射后第 23 天开始，每天一次，持续到实验的最后一天。通过免疫组织化学、实时 PCR、免疫荧光和 Western blot 评估 APP、神经发生（Nestin、Ki67、DCX 和 Reelin）和凋亡（Bax/Bcl-2 比值、cleaved-caspase-3 和 seladin-1）标志物的表达水平。此外，还使用硫黄素 T 和尼氏染色分别评估海马中的 Aβ 斑块水平和神经元变性。我们的结果表明，IFNβ 治疗可降低 APP 表达和 Aβ 斑块形成，同时改善 Y 迷宫和 Morris 水迷宫测试中观察到的空间学习和记忆缺陷。此外，IFNβ 通过减少海马亚区的凋亡和神经丢失，降低 AD 大鼠海马 CA1 和 CA3 区的异位神经发生。然而，IFNβ 增加了齿状回神经发生龛中的神经发生。我们的研究结果表明，IFNβ 通过抑制细胞凋亡和调节神经发生发挥神经保护作用。总之，IFNβ 可能是改善 AD 样神经退行性变认知表现的一种有前途的治疗方法。
