Guo Jing, Xu Cheng, Ni Shaozhou, Zhang Shujuan, Li Qihang, Zeng Peng, Pi Guilin, Liu Enjie, Sun Dong-Sheng, Liu Yanchao, Wang Zhouyi, Chen Haote, Yang Ying, Wang Jian-Zhi
Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Hubei Provincial Key Laboratory of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
Department of Emergency, Zhongnan Hospital of Wuhan University, Wuhan, China.
J Alzheimers Dis. 2019;68(1):367-381. doi: 10.3233/JAD-180978.
Hyperhomocysteinemia is an independent risk factor of Alzheimer's disease (AD), which is not diagnosed for many years before onset due to lack of peripherally detectable early biomarkers. Visual dysfunction is prevalent in AD patients and correlates with the severity of cognitive defects. Importantly, alterations in eyes can be non-invasively detected. To search for early biomarkers in eyes from high risk factors of AD, we injected homocysteine (Hcy) into the rats via vena caudalis for 3, 7, and 14 days, respectively, and characterized the chronological order of the AD-like pathologies appearing in retina and the hippocampus during the progression of hyperhomocysteinemia, and their correlations with cognitive impairment. We found that administration of Hcy for 14 days, but not 3 or 7 days, induced hyperhomocysteinemia, although a gradually increased blood Hcy level was detected. In retina and/or the hippocampus, significant loss of retinal ganglion cells and stenosis of retinal arteries with the AD-like tau and amyloid-β (Aβ) pathologies and memory deficit were shown only in the 14-day Hcy group. Interestingly, accumulation of Ser262 hyperphosphorylated tau (pS262-tau) but not Aβ with decreased methylation of protein phosphatase-2A catalytic subunit (M-PP2Ac) and increased de-methylated PP2Ac (DM-PP2Ac) was detected in retina of the 3-day Hcy group, in which the retinal pathologies were preceded by those of the hippocampus. These findings suggest that elevated pS262-tau and DM-PP2Ac and reduced M-PP2Ac in retina may serve as surveillance biomarkers for diagnosis of the hyperhomocysteinemia-induced AD in the early stage.
高同型半胱氨酸血症是阿尔茨海默病（AD）的独立危险因素，由于缺乏外周可检测的早期生物标志物，在发病前多年无法诊断。视觉功能障碍在AD患者中很普遍，并且与认知缺陷的严重程度相关。重要的是，眼睛的改变可以通过非侵入性检测到。为了从AD的高危因素中寻找眼睛中的早期生物标志物，我们分别通过尾静脉向大鼠注射同型半胱氨酸（Hcy）3天、7天和14天，并确定在高同型半胱氨酸血症进展过程中视网膜和海马中出现的AD样病理变化的时间顺序，以及它们与认知障碍的相关性。我们发现，给予Hcy 14天可诱导高同型半胱氨酸血症，而给予3天或7天则不会，尽管检测到血液中Hcy水平逐渐升高。在视网膜和/或海马中，仅在14天Hcy组中出现了视网膜神经节细胞的显著丢失、视网膜动脉狭窄以及AD样tau和淀粉样β（Aβ）病理变化和记忆缺陷。有趣的是，在3天Hcy组的视网膜中检测到Ser262磷酸化tau（pS262-tau）的积累，但未检测到Aβ的积累，同时蛋白磷酸酶2A催化亚基的甲基化降低（M-PP2Ac），去甲基化的PP2Ac（DM-PP2Ac）增加，其中视网膜病变先于海马病变。这些发现表明，视网膜中pS262-tau和DM-PP2Ac升高以及M-PP2Ac降低可能作为早期诊断高同型半胱氨酸血症诱导的AD的监测生物标志物。
