■目前的证据表明微血管疾病与阿尔茨海默病(AD)有关。脑血管疾病与心血管疾病相关,约40%的AD患者并发。蛋白激酶C(PKC)ε激活剂DCPLA可以刺激人抗原(Hu)R,从而阻止降解并促进线粒体Mn-超氧化物歧化酶(MnSOD)和血管内皮生长因子-A(VEGF)mRNA的翻译。
■诱发脑微梗死,我们用微珠(20μm口径)注射三转基因(3×Tg)和野生型(WT)对照小鼠颈总动脉,有或没有DCPLA-ME(甲酯)2周。经过水迷宫训练,16个月大的小鼠在海马CA1区的单个细胞或微血管水平进行共聚焦免疫组织化学检查,对于空间记忆存储很重要,通过西方印迹在背侧海马中。
■在没有脑微梗死的3×Tg小鼠中,(轻度)氧化应激和缺氧诱导因子(HIF)-1α加速增加,但是VEGF的减少,线粒体转录因子A(TFAM),MnSOD与毛细血管丢失有关。小动脉的变化不太明显。然而,在3×Tg小鼠脑微梗死,小动脉直径及其壁细胞的增加与强氧化DNA损伤8-羟基-2'-脱氧鸟苷(8-OHdG)有关,凋亡(裂解的半胱天冬酶3),和持续缺氧(HIF-1α和VEGF/PKCε/细胞外信号调节激酶或ERK通路增加)。微闭塞增强了突触标记spinophilin的丢失,星形细胞数,星形胶质细胞-血管耦合区和轴突脱髓鞘。DCPLA-ME可预防空间记忆缺陷;强氧化应激相关的凋亡;持续缺氧(通过减少HIF-1α和VEGF);和小动脉壁的过度细胞修复,毛细管周围空间扩张,神经胶质血管破坏,和脱髓鞘.
■总而言之,在3×Tg小鼠脑微梗死,持续缺氧(HIF-1α和VEGF信号增加)以小动脉壁增厚为主,DCPLA对持续缺氧有保护作用。
UNASSIGNED: Current evidence suggests that
microvessel disease is involved in Alzheimer\'s disease (AD). Cerebrovascular disease correlates with cardiovascular disease and is complicated in ≈40% of AD patients. The protein kinase C (PKC) ε activator DCPLA can stimulate human antigen (Hu) R that prevents degradation and promotes the translation of mitochondrial Mn-superoxide dismutase (MnSOD) and vascular endothelial growth factor-A (VEGF) mRNAs.
UNASSIGNED: To induce brain microinfarcts, we injected triple transgenic (3×Tg) and wild-type (WT) control mice with microbeads (20 μm caliber) into common carotid arteries, with or without the DCPLA-ME (methyl-ester) for 2 weeks. After water maze training, mice at 16 months old were examined for confocal immunohistochemistry at a single cell or
microvessel level in the hippocampal CA1 area, important for spatial memory storage, and in the dorsal hippocampus by western blots.
UNASSIGNED: In 3×Tg mice without cerebral microinfarcts, an accelerating age-related increase in (mild) oxidative stress and hypoxia inducible factor (HIF)-1α, but a reduction in VEGF, mitochondrial transcription factor A (TFAM), and MnSOD were associated with capillary loss. The change was less pronounced in arterioles. However, in 3×Tg mice with cerebral microinfarcts, increasing arteriolar diameter and their wall cells were related with the strong oxidative DNA damage 8-hydroxy-2\'-deoxyguanosine (8-OHdG), apoptosis (cleaved caspase 3), and sustained hypoxia (increased HIF-1α and VEGF/PKCε/extracellular signal regulated kinase or ERK pathway). Microocclusion enhanced the loss of the synaptic marker spinophilin, astrocytic number, and astrocyte-vascular coupling areas and demyelination of axons. DCPLA-ME prevented spatial memory defect; strong oxidative stress-related apoptosis; sustained hypoxia (by reducing HIF-1α and VEGF); and exaggerated cell repair in arteriolar walls, pericapillary space dilation, neuro-glial-vascular disruption, and demyelination.
UNASSIGNED: In conclusion, in 3×Tg mice with cerebral microinfarcts, sustained hypoxia (increased HIF-1α and VEGF signals) is dominant with arteriolar wall thickening, and DCPLA has a protective effect on sustained hypoxia.