| Background and Objective:White matter lesions(WML)have a high prevalence in the middle-aged and elderly population.A large number of clinical studies have shown that WML can cause cognitive dysfunction and significantly increase the risk of cognitive impairment and dementia.With the aging of the global social population,the health effects of cognitive disorders on the population have become increas ingly prominent.Cognitive impairment caused by WML has gradually become a research hotspot.However,the pathogenesis has not yet been fully elucidated.?-amyloid(A?)is one of the main pathological hallmark proteins in Alzheimer's disease.A number of recent clinical studies have shown that changes in CSF or plasma A? are closely related to WML.However,due to the limitations of clinical studies,it is impossible to directly observe the abnormal deposition of A? in WML brain.Hypertension is an important risk factor for WML,which has been widely recognized.The hypertensive rat model has also been increas ingly used in the study of WML.Therefore,we established a model of hypertensive cerebral white matter damage in stroke-prone renovascular hypertensive rats,and initially observed cognitive dysfunction and abnormal deposition of A? in the brain of hypertens ive WML rats in order to predict hypertensive WML and its prevention of cognitive disorders provide a new way of thinking.Method:1.Male Sprague-Dawley rats were used to prepare stroke-prone renovascular hypertens ive rats models by double kidney double clamps method.The rats were randomly divided into control group,sham operation group,and hypertens ion model group.Each group was divided into five subgroups: preoperative,postoperative 4 weeks,postoperative 8 weeks,postoperative 12 weeks,and postoperative 16 weeks,according to the time of the operation.The blood pressures at different time points in each group of rats were measured,and lateral comparisons between different time points in the group and longitudinal comparisons between different groups at the same time point were performed.2.The Morris water maze test was used to evaluate cognitive,behavioral changes such as motor,learning,and visual memory in the sham-operated and hypertensive model groups.3.HE staining was used to observe the neuronal cell number changes in the prefrontal cortex,temporal lobe,hippocampus,and corpus callosum of rats in the sham-operated group and the hypertensive model group.LFB staining was used to observe myelin sheath changes in the lateral ventricles and corpus callosum.Immunohistochemical staining was used to observe the astrocytes number changes in the hippocampus and corpus callosum.4.Immunohistochemical staining was used to observe the accumulation of A? in the brain of sham-operated and hypertensive rats.Enzyme-linked immunosorbent assay was used to detect the concentration of A? 1-42 in the hippocampus.Western Blot was used to detect the expression levels of APP and BACE1 proteins which related to the production of A? in hippocampus and corpus callosum.Result:1.The blood pressure measurement of rats showed that compared with the sham group at the same time point,the blood pressure in the model group was significantly increased(P<0.01).Among the subgroups in the model group,the blood pressure was higher at the 4th,8th,and 12 th weeks after the operation in the model group(P<0.01),but no significant change in blood pressure between the 16 th and 12 th week after operation(P>0.05).There was no significant difference in blood pressure between the control group and the sham group(P>0.05).2.The Morris water maze test showed that in the adaptive training,compared with postoperative 16 weeks between the two groups,the swimming distance of the hypertension model group rats was significantly shorter(P<0.01).In the place navigation test,escape latency of the hypertension model group at postoperative 12 and 16 weeks was significantly longer than that of the sham operation group(P<0.01).In the spatial probe test,the number of rats crossing the original platform position at postoperative 12 and 16 weeks in the hypertension model group was significantly reduced(P<0.01).3.HE and myelin staining showed that compared with the sham group at 12 and 16 weeks after operation,the number of granulosa cells in the CA1 area of the hippocampus in the hypertensive model group decreased,and the glial cell proliferation in the corpus callosum area(P<0.01).The thickness of the corpus callosum was reduced(P<0.05),the myelin sheath around the lateral ventricle was lost,and the white matter structure was loose and disordered.4.Immunohistochemical staining showed that compared with the sham group,astrocyte proliferation in the hippocampus of the hypertensive model group at 12 and 16 weeks postoperatively(P<0.01).Astrocytes in the corpus callosum were also significantly proliferatedat postoperative 8 weeks,12 weeks and 16 weeks(P<0.01).The number of anti-MOAB-2 positive cells in the cortex of the hypertensive model group was significantly increased at postoperative 8weeks,12 weeks and 16 weeks(P<0.01),while no anti-MOAB-2 positive cells were found in the hippocampus and corpus callosum of hypertensive rats.5.Enzyme-linked immunosorbent assay showed there was no significant difference in the A? 1-42 content of hippocampus between the hypertensive model group and the sham group(P>0.05).6.Western blot showed that the expression of APP and BACE1 in the hippocampus and corpus callosum of rats in the hypertens ion model group had no significant difference compared with the sham group(P>0.05).Conclusion:1.Hypertens ive WML rats suffer from cognitive impairment such as exercise,learning,and visual spatial memory.2.The expression of A? increases in the cortex of hypertensive WML rats,and it increases gradually with the increase of blood pressure and the development of white matter lesions. |
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