Vascular Cognitive Impairment Caused By Cerebral Small Vessel Disease Is Associated With The TLR4 In The Hippocampus

Background: Cerebral small vessel disease(CSVD)is one of the most predominant neurodegenerative diseases and is a main complication of hypertension.The inflammatory response mediated by Toll-like receptor 4(TLR4)is involved in the pathological process of CSVD,but the roles of TLR4 in vascular cognitive impairment(VCI)following CSVD are not clear.Spontaneous hypertension rats(SHR)were used as the CSVD model to explore the roles and mechanisms of TLR4 in the development of VCI.Methods: A total of 15 male SHR(experimental group)and 10 male Wistar Kyoto rats(WKY,control group)rats were monitored for blood pressure(BP).The spatial learning and memory were assessed every 6 weeks using Morris water maze(MWM).Blood samples from femoral artery were collected and serum was isolated every 12 weeks.Enzymelinked immunosorbent assay(ELISA)was used to detect the expression of IL-1? and TNF-? in serum of rats in each group.Cerebral white matter damage was evaluated using a 3.0T MRI every 12 weeks.At the end of 35 weeks,all rats were sacrificed and the expression of TLR4 in hippocampus were tested using western blotting.The mRNA expression of IL-1? and TNF-? in hippocampus were tested using Reverse transcription–polymerase chain reaction(RT-PCR).Cerebral vascular injury was observed by crystal violet staining and hematoxylin eosin staining.The number of positive cells of TLR4,active astrocyte and microgila in CA1 regions of hippocampus were measured using immunohistochemistry and immunofluorescence.Results: Compared with WKY,the blood pressure of SHR was maintained at a high level,spatial learning and memory decreased,and serum IL-1? and TNF-?elevated.Cranial coronal scanning with T2-weighted magnetic resonance imaging(MRI)showed high signal intensity in corpus callosum and capsula externa of SHR rats.Histological examination showed that the cerebral small blood vessel walls thickened in SHR,the expression of TLR4 in the hippocampus was increased,and the number of positive cells of TLR4,GFAP,and Iba1 in the hippocampal CA1 region.Conclusion: Hypertension can cause small vascular damage and partial white matter degeneration in the brain.SHR showed different degrees of cognitive impairment with increasing age.High expression of TLR4 and glial cell response in hippocampus is one of the key mechanisms of this disease.