Calingasan N Y, Gandy S E, Baker H, Sheu K F, Kim K S, Wisniewski H M, Gibson G E
Cornell University Medical College, Burke Medical Research Institute, White Plains, NY 10605, USA.
Brain Res. 1995 Apr 17;677(1):50-60. doi: 10.1016/0006-8993(95)00136-e.
Thiamine deficiency (TD) is a classical model of impaired cerebral oxidation. As in Alzheimer's disease (AD), TD is characterized by selective neuronal loss, decreased activities of thiamine pyrophosphate-dependent enzymes, cholinergic deficits and memory loss. Amyloid beta-protein (A beta), a approximately 4 kDa fragment of the beta-amyloid precursor protein (APP), accumulates in the brains of patients with AD or Down's syndrome. In the current study, we examined APP and A beta immunoreactivity in the brains of thiamine-deficient rats. Animals received thiamine-deficient diet ad libitum and daily injections of the thiamine antagonist, pyrithiamine. Immunocytochemical staining and immunoblotting utilized a rabbit polyclonal antiserum against human APP645-694 (numbering according to APP695 isoform). Three, 6 and 9 days of TD did not appear to damage any brain region nor change APP-like immunoreactivity. However, 13 days of TD led to pathological lesions mainly in the thalamus, mammillary body, inferior colliculus and some periventricular areas. While immunocytochemistry and thioflavine S histochemistry failed to show fibrillar beta-amyloid, APP-like immunoreactivity accumulated in aggregates of swollen, abnormal neurites and perikarya along the periphery of the infarct-like lesion in the thalamus and medial geniculate nucleus. Immunoblotting of the thalamic region around the lesion revealed increased APP-like holoprotein immunoreactivity. APP-like immunoreactive neurites were scattered in the mammillary body and medial vestibular nuclei where the lesion did not resemble infarcts. In the inferior colliculus, increased perikaryal APP-like immunostaining occurred in neurons surrounding necrotic areas. Regions without apparent pathological lesions showed no alteration in APP-like immunoreactivity. Thus, the oxidative insult associated with cell loss, hemorrhage and infarct-like lesions during TD leads to altered APP metabolism. This is the first report to show a relationship between changes in APP expression, oxidative metabolism and selective cell damage caused by nutritional/cofactor deficiency. This model appears useful in defining the role of APP in the reponse to central nervous system injury, and may also be relevant to the pathophysiology of Wernicke-Korsakoff syndrome and AD.
硫胺素缺乏（TD）是脑氧化受损的经典模型。与阿尔茨海默病（AD）一样，TD的特征是选择性神经元丢失、硫胺素焦磷酸依赖性酶活性降低、胆碱能缺陷和记忆丧失。淀粉样β蛋白（Aβ）是β淀粉样前体蛋白（APP）的一个约4 kDa的片段，在AD患者或唐氏综合征患者的大脑中积累。在本研究中，我们检测了硫胺素缺乏大鼠大脑中的APP和Aβ免疫反应性。动物随意接受硫胺素缺乏饮食，并每日注射硫胺素拮抗剂吡硫胺素。免疫细胞化学染色和免疫印迹使用了针对人APP645 - 694（根据APP695同工型编号）的兔多克隆抗血清。TD 3天、6天和9天似乎未损伤任何脑区，也未改变APP样免疫反应性。然而，TD 13天导致主要在丘脑、乳头体、下丘和一些脑室周围区域出现病理损伤。虽然免疫细胞化学和硫黄素S组织化学未能显示出纤维状β淀粉样蛋白，但APP样免疫反应性在丘脑和内侧膝状核梗死样病变周边肿胀、异常的神经突和核周体聚集体中积累。病变周围丘脑区域的免疫印迹显示APP样全蛋白免疫反应性增加。APP样免疫反应性神经突散在于乳头体和内侧前庭核，这些部位的病变不像梗死灶。在下丘，坏死区域周围的神经元中核周体APP样免疫染色增加。没有明显病理损伤的区域APP样免疫反应性没有改变。因此，TD期间与细胞丢失、出血和梗死样病变相关的氧化损伤导致APP代谢改变。这是首次报道显示APP表达变化、氧化代谢与营养/辅助因子缺乏引起的选择性细胞损伤之间的关系。该模型似乎有助于确定APP在中枢神经系统损伤反应中的作用，也可能与韦尼克 - 科萨科夫综合征和AD的病理生理学相关。
