Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, Japan; Geriatrics and Vascular Medicine, Tokyo Medical and Dental University, Japan.
Aging Neuroscience Research Team, Tokyo Metropolitan Institute of Gerontology, Japan.
Arch Biochem Biophys. 2019 Mar 15;663:120-128. doi: 10.1016/j.abb.2019.01.003. Epub 2019 Jan 8.
Vitamin C (l-ascorbic acid, VC) and vitamin E (α-tocopherol, VE) play important physiological roles as endogenous antioxidants in many tissues and organs. However, their roles in the brain remain entirely elusive. We established senescence marker protein 30 (SMP30)/α-tocopherol transfer protein (αTTP) double knockout (DKO) mice as a novel VC and VE double-deficiency model and examined the effect of VC and VE double-deficiency on brain functions.
DKO and wild-type (WT) mice were divided into the following two groups: mice in the CE (+) group were supplied with sufficient amounts of VC and VE and mice in the CE (-) group were deficient in both VC and VE. After 8 weeks of CE (+) or CE (-) treatments, a battery of behavioral experiments was conducted to analyze cognitive functions, including memory, through the Morris water maze and Pavlovian fear conditioning tasks.
The plasma VC and VE levels in DKO-CE (-) mice and VE level in WT-CE (-) mice were almost completely depleted after 8 weeks of the deficient treatment. The behavioral study revealed that the general behaviors, including locomotor activity and anxiety level, were not influenced by the CE (-) treatment in DKO and WT mice. However, in the Pavlovian fear conditioning task, DKO-CE (-) mice showed impaired conditioned fear memory compared with that of DKO-CE (+) mice. Furthermore, increased mRNA expression was observed in inflammatory-related genes, such as IL-6, TNFα, F4/80, and Mcp-1, in the hippocampus of DKO-CE (-) mice.
The findings of this study provide evidence that VC and VE deficiency led to impaired conditioned fear memory possibly caused by neuroinflammation in the brain.
维生素 C（L-抗坏血酸，VC）和维生素 E（α-生育酚，VE）作为许多组织和器官中内源性抗氧化剂，发挥着重要的生理作用。然而，它们在大脑中的作用仍然完全难以捉摸。我们建立了衰老标志物蛋白 30（SMP30）/α-生育酚转移蛋白（αTTP）双重敲除（DKO）小鼠作为一种新型 VC 和 VE 双重缺乏模型，并研究了 VC 和 VE 双重缺乏对大脑功能的影响。
DKO 和野生型（WT）小鼠分为以下两组：CE（+）组的小鼠给予足够量的 VC 和 VE，CE（-）组的小鼠 VC 和 VE 均缺乏。CE（+）或 CE（-）处理 8 周后，进行一系列行为学实验，通过 Morris 水迷宫和巴甫洛夫恐惧条件反射任务分析认知功能，包括记忆。
8 周缺乏治疗后，DKO-CE（-）小鼠的血浆 VC 和 VE 水平和 WT-CE（-）小鼠的 VE 水平几乎完全耗尽。行为研究表明，CE（-）处理对 DKO 和 WT 小鼠的一般行为，包括运动活性和焦虑水平没有影响。然而，在巴甫洛夫恐惧条件反射任务中，与 DKO-CE（+）小鼠相比，DKO-CE（-）小鼠的条件性恐惧记忆受损。此外，在 DKO-CE（-）小鼠的海马体中观察到炎症相关基因（如 IL-6、TNFα、F4/80 和 Mcp-1）的 mRNA 表达增加。
本研究结果提供了证据，表明 VC 和 VE 缺乏导致条件性恐惧记忆受损，可能是由于大脑中的神经炎症所致。
