A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland.
Kuopio University Hospital, PL100, 70029 KYS, Kuopio, Finland.
Aging Dis. 2014 Apr 1;5(2):76-87. doi: 10.14336/AD.2014.050076. eCollection 2014 Apr.
Cerebral ischemia is a risk factor for Alzheimer's disease (AD). Moreover, recent evidence indicates that it is a two-way street as the incidence rate of stroke is significantly higher in AD patients than those without the disease. Here we investigated the interaction of ischemic brain insults and AD in 9-month-old ApdE9 mice, which show full-blown accumulation of Aβ deposits and microgliosis in the brain. Permanent occlusion of the middle cerebral artery (pMCAo) resulted in 36% larger infarct in ApdE9 mice compared to their wild-type (wt) controls. This was not due to differences in endothelium-dependent vascular reactivity. Treatment with human intravenous immunoglobulin (IVIG) reduced the infarct volumes and abolished the increased vulnerability of ApdE9 mice to pMCAo induced brain ischemia. When the mice were exposed to global brain ischemia (GI), an insult of hippocampal cells, ApdE9 mice showed increased neuronal loss in CA2 and CA3 subregions compared to their wt controls. GI was associated with increased microgliosis, astrogliosis, infiltration of blood-derived monocytic cells, and neurogenesis without clear differences between the genotypes. IVIG treatment prevented the GI-induced neuron loss in hippocampal CA1 and CA3 regions in ApdE9 mice. IVIG treatment increased microgliosis in wt but not in ApdE9 mice. Finally, GI induced 60% reduction in the hippocampal Aβ burden in ApdE9 mice, which was not affected by IVIG treatment. The results indicate that the AD pathology with Aβ deposits and microgliosis increases ischemic vulnerability in various brain areas. Moreover, IVIG treatment may be beneficial especially in patients suffering from both acute ischemic insult and AD.
脑缺血是阿尔茨海默病（AD）的一个风险因素。此外，最近的证据表明，这是一个双向的过程，因为 AD 患者中风的发病率明显高于没有这种疾病的患者。在这里，我们研究了缺血性脑损伤和 AD 在 9 个月大的 ApdE9 小鼠中的相互作用，这些小鼠的大脑中显示出 Aβ 沉积和小胶质细胞增生的全面积累。大脑中动脉永久性闭塞（pMCAo）导致 ApdE9 小鼠的梗死体积比其野生型（wt）对照增加 36%。这并不是由于内皮依赖性血管反应性的差异。用人类静脉注射免疫球蛋白（IVIG）治疗可减少梗死体积，并消除 ApdE9 小鼠对 pMCAo 诱导的脑缺血的易感性增加。当小鼠暴露于全脑缺血（GI）时，海马细胞的一种损伤，ApdE9 小鼠与 wt 对照相比，CA2 和 CA3 亚区的神经元丢失增加。GI 与小胶质细胞增生、星形胶质细胞增生、血液来源的单核细胞浸润和神经发生增加有关，但基因型之间没有明显差异。IVIG 治疗可预防 ApdE9 小鼠海马 CA1 和 CA3 区的 GI 诱导的神经元丢失。IVIG 治疗增加了 wt 小鼠的小胶质细胞增生，但不增加 ApdE9 小鼠的小胶质细胞增生。最后，GI 诱导 ApdE9 小鼠海马 Aβ 负荷减少 60%，IVIG 治疗对其没有影响。结果表明，AD 病理学伴 Aβ 沉积和小胶质细胞增生增加了各种脑区的缺血易感性。此外，IVIG 治疗可能特别有益于同时患有急性缺血性损伤和 AD 的患者。
