Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan-si, Gyeongsangnam-do 626-870, Republic of Korea.
Int J Mol Med. 2013 Mar;31(3):577-82. doi: 10.3892/ijmm.2013.1233. Epub 2013 Jan 8.
Hypercholesterolemia is a known risk factor for Alzheimer's disease (AD). In the present study, we investigated whether diet-induced hypercholesterolemia affects AD-like pathologies such as amyloid β-peptide (Aβ) deposition, tau pathology, inflammation and cognitive impairment, using an Aβ25-35-injected AD-like pathological mouse model. Hypercholesterolemia was induced by providing apolipoprotein E knock out (Apo E KO) mice with a high-fat diet for 4 weeks prior to Aβ25-35 injection and for 4 weeks following Aβ25-35 injection, for a total of 8 weeks of treatment. Our data showed that intracerebroventricular injection of C57BL/6J mice with Aβ25-35 resulted in increased immunoreactivity of Aβ and phosphorylated-tau (p-tau), which was accompanied by enhanced microglial CD11b-like immunoreactivity in the brain. Moreover, hypercholesterolemia slightly increased Aβ and p-tau levels and microglial activation in the vehicle group, while further increasing the Aβ and p-tau levels and microglial activation in Aβ25-35-injected mice. Consistent with the neuropathological analysis, hypercholesterolemia resulted in significant spatial learning and memory deficits in Aβ25-35-injected mice as revealed by water maze testing. Collectively, these findings demonstrated that hypercholesterolemia accelerated Aβ accumulation and tau pathology, which was accompanied by microglial activation and subsequent aggravation of memory impairment induced by Aβ25-35. Thus, we suggest that the modulation of cholesterol can be used to reduce the risk of developing AD.
高胆固醇血症是阿尔茨海默病（AD）的已知危险因素。在本研究中，我们使用 Aβ25-35 注射的 AD 样病理小鼠模型，研究了饮食诱导的高胆固醇血症是否会影响 AD 样病理学，如淀粉样β肽（Aβ）沉积、tau 病理学、炎症和认知障碍。通过在 Aβ25-35 注射前 4 周和 Aβ25-35 注射后 4 周为载脂蛋白 E 敲除（ApoE KO）小鼠提供高脂肪饮食来诱导高胆固醇血症，总共进行 8 周的治疗。我们的数据表明，向 C57BL/6J 小鼠脑室内注射 Aβ25-35 导致 Aβ和磷酸化 tau（p-tau）的免疫反应性增加，这伴随着大脑中小胶质细胞 CD11b 样免疫反应性的增强。此外，高胆固醇血症略微增加了载体组中 Aβ 和 p-tau 水平以及小胶质细胞的激活，而在 Aβ25-35 注射的小鼠中进一步增加了 Aβ 和 p-tau 水平以及小胶质细胞的激活。与神经病理学分析一致，水迷宫测试显示，高胆固醇血症导致 Aβ25-35 注射小鼠出现显著的空间学习和记忆缺陷。总的来说，这些发现表明，高胆固醇血症加速了 Aβ 的积累和 tau 病理学，伴随着小胶质细胞的激活以及随后的 Aβ25-35 诱导的记忆障碍的加重。因此，我们建议调节胆固醇可以降低患 AD 的风险。
