Cerebral ischemia aggravates cognitive impairment in a rat model of Alzheimer's disease

Aim: 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. Main methods: AD was modeled by injection of aggregated A beta(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. A beta deposition, neuronal loss and phosphorylated tau expression in hippocampus were examined by Congo red staining, Nissl's staining and immunohistochemistry, respectively. Reactive astrocytes, IL-1 beta and TNF-alpha expressions were measured by immunohistochemistry, in situ hybridization and reverse transcription-polymerase chain reaction. Key findings: Compared with rats treated with either A beta or endothelin alone, rats treated with both A beta and endothelin showed more aggravated cognitive impairment and more A beta deposits, neuron loss, phosphorylated tau expression, reactive astrocytes, IL-1 beta and TNF-alpha expressions in hippocampus. Significance: Hippocampal ischemia aggravates cognitive impairment of AD rats by increasing A beta 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. (C) 2011 Elsevier Inc. All rights reserved.