1 Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
2 Department of Physiology, University of Kentucky, Lexington, KY, USA.
ASN Neuro. 2017 Nov-Dec;9(6):1759091417742296. doi: 10.1177/1759091417742296.
High plasma levels of homocysteine, termed hyperhomocysteinemia, are a risk factor for vascular cognitive impairment and dementia, which is the second leading cause of dementia. While hyperhomocysteinemia induces microhemorrhages and cognitive decline in mice, the specific effect of hyperhomocysteinemia on each cell type remains unknown. We took separate cultures of astrocytes, microglia, endothelial cells, and neuronal cells and treated each with moderate levels of homocysteine for 24, 48, 72, and 96 hr. We then determined the gene expression changes for cell-specific markers and neuroinflammatory markers including the matrix metalloproteinase 9 system. Astrocytes had decreased levels of several astrocytic end feet genes, such as aquaporin 4 and an adenosine triphosphate (ATP)-sensitive inward rectifier potassium channel at 72 hr, as well as an increase in matrix metalloproteinase 9 at 48 hr. Gene changes in microglia indicated a peak in proinflammatory markers at 48 hr followed by a peak in the anti-inflammatory marker, interleukin 1 receptor antagonist, at 72 hr. Endothelial cells had reduced occludin expression at 72 hr, while kinases and phosphatases known to alter tau phosphorylation states were increased in neuronal cells. This suggests that hyperhomocysteinemia induces early proinflammatory changes in microglia and astrocytic changes relevant to their interaction with the vasculature. Overall, the data show how hyperhomocysteinemia could impact Alzheimer's disease and vascular cognitive impairment and dementia.
高同型半胱氨酸血症（血同）又称高同型半胱氨酸血症，是血管性认知障碍和痴呆（痴呆的第二大病因）的一个风险因素。虽然血同会导致小鼠微出血和认知能力下降，但血同对每种细胞类型的具体影响尚不清楚。我们分别培养星形胶质细胞、小胶质细胞、内皮细胞和神经元细胞，并将每种细胞用中等水平的同型半胱氨酸处理 24、48、72 和 96 小时。然后，我们测定了细胞特异性标志物和神经炎症标志物（包括基质金属蛋白酶 9 系统）的基因表达变化。星形胶质细胞在 72 小时时几种星形胶质细胞终足基因的水平下降，如水通道蛋白 4 和三磷酸腺苷（ATP）敏感内向整流钾通道，而基质金属蛋白酶 9 在 48 小时时增加。小胶质细胞的基因变化表明，在 48 小时时促炎标志物达到峰值，然后在 72 小时时抗炎标志物白细胞介素 1 受体拮抗剂达到峰值。内皮细胞在 72 小时时封闭蛋白表达减少，而改变 tau 磷酸化状态的激酶和磷酸酶在神经元细胞中增加。这表明高同型半胱氨酸血症会引起小胶质细胞的早期促炎变化，以及与血管相互作用相关的星形胶质细胞变化。总的来说，这些数据表明高同型半胱氨酸血症如何影响阿尔茨海默病和血管性认知障碍和痴呆。
