Vascular Cognitive Impairment Caused by Cerebral Small Vessel Disease Is Associated with the TLR4 in the Hippocampus

Abstract

Background: Cerebral small vessel disease (CSVD) can lead to leukodystrophy and cognitive impairment. 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.

Objective: To explore the roles and mechanisms of TLR4 in the development of VCI.

Methods: Male spontaneous hypertension rats (SHR) and Wistar Kyoto rats (WKY) 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. Cerebral white matter damage was evaluated using a 3.0T magnetic resonance imaging (MRI) every 12 weeks. After 35 weeks, all rats were decapitated, and the expression of TLR4 in the hippocampus was determined using western blot. The number of positive cells of TLR4, active astrocyte and microglia in hippocampus were measured using immunohistochemistry and immunofluorescence.

Results: Compared with WKY, the BP of SHR was maintained at a high level. Spatial learning and memory declined. IL-1β and TNF-α levels were elevated. Cranial coronal scanning with T2-weighted MRI showed high signal intensity in corpus callosum and external capsule of SHR. Furthermore, in SHR, the expression of TLR4, GFAP, and Iba1 in the hippocampus were increased.

Conclusion: Hypertension can cause small vascular damage and partial white matter degeneration in the brain. SHR showed cognitive impairment with increasing age. High expression of TLR4 and glial cell response in hippocampus is one of the key mechanisms of this disease.

Keywords: Cerebral small vessel disease; glial cell; neuroinflammation; spontaneous hypertension rats; toll-like receptor 4; vascular cognitive impairment.