Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.
Life Sci. 2011 Jul 18;89(3-4):86-92. doi: 10.1016/j.lfs.2011.04.024. Epub 2011 May 18.
Autopsy evidence suggests that the presence of both Alzheimer(')s disease (AD) and cerebral infarction pathology is associated with more severe cognitive impairment than that produced by AD pathology alone. This study aims to investigate the effect of cerebral ischemia on cognitive function in rats with AD constructed by hippocampal injection and to determine its underlying mechanism, which is proposed to be of significance to the treatment of AD.
AD was modeled by injection of aggregated Aβ(1-40), either alone or followed by hippocampal endothelin-1 injection to mimic cerebral ischemia in hippocampus, into the right dentate gyrus (DG) of rats. The Morris water maze was used to evaluate cognitive function. Aβ deposition, neuronal loss and phosphorylated tau expression in hippocampus were examined by Congo red staining, Nissl's staining and immunohistochemistry, respectively. Reactive astrocytes, IL-1β and TNF-α expressions were measured by immunohistochemistry, in situ hybridization and reverse transcription-polymerase chain reaction.
Compared with rats treated with either Aβ or endothelin alone, rats treated with both Aβ and endothelin showed more aggravated cognitive impairment and more Aβ deposits, neuron loss, phosphorylated tau expression, reactive astrocytes, IL-1β and TNF-α expressions in hippocampus.
Hippocampal ischemia aggravates cognitive impairment of AD rats by increasing Aβ deposits, neuron loss and tau phosphorylation in hippocampus. The enhanced inflammatory response may be responsible for cerebral ischemia-induced aggravation of cognitive impairment in AD rats. Based on these findings, prevention and treatment of cerebral ischemia may improve clinical symptoms of AD and suppress the progression of AD.
尸检证据表明，阿尔茨海默病（AD）和脑梗死病理共存与单纯 AD 病理引起的认知障碍更为严重。本研究旨在探讨脑缺血对海马注射构建 AD 大鼠认知功能的影响，并确定其潜在机制，这对于 AD 的治疗具有重要意义。
通过向大鼠右侧齿状回（DG）注射聚集的 Aβ（1-40），或在海马内注射内皮素-1 模拟脑缺血，单独或联合构建 AD 模型。采用 Morris 水迷宫评估认知功能。通过刚果红染色、尼氏染色和免疫组织化学分别检测海马 Aβ 沉积、神经元丢失和磷酸化 tau 表达。通过免疫组织化学、原位杂交和逆转录-聚合酶链反应测量反应性星形胶质细胞、IL-1β 和 TNF-α 的表达。
与单独给予 Aβ 或内皮素的大鼠相比，同时给予 Aβ 和内皮素的大鼠认知功能障碍更为严重，海马 Aβ 沉积、神经元丢失、磷酸化 tau 表达、反应性星形胶质细胞、IL-1β 和 TNF-α 表达增加。
海马缺血通过增加海马 Aβ 沉积、神经元丢失和 tau 磷酸化加重 AD 大鼠的认知障碍。增强的炎症反应可能是脑缺血引起 AD 大鼠认知障碍加重的原因。基于这些发现，预防和治疗脑缺血可能改善 AD 的临床症状并抑制 AD 的进展。
