Objective: It is increasingly recognized that vascular cognitive impairment may be a new complication of the disease in both type 1 and type 2 diabetes. We have shown that diabetic Goto-Kakizaki rats present with cognitive deficits and vascular dysfunction, especially impaired relaxation that can be ameliorated by Toll-like receptor-2 (TLR2) inhibition. Since brain function heavily depends on constant perfusion, and decreased cerebral blood flow (CBF) precedes development of inflammation and cognitive deficits, we hypothesized that TLR2 knockout would confer a protection from diabetes mediated cognitive decline.
Methods and Results: Wild-type (WT) and TLR2 knockout (KO) control and diabetic mice were used. Diabetes was induced by streptozotocin (STZ) injection. 14 weeks after, cerebral perfusion was measured by MRI and cognitive function was assessed by a battery of tests including Y-maze and fear conditioning. There was no difference in cerebral perfusion in WT and TLR2 KO mice (CBF ml/100gxmin:141.1± 5.374 vs. 156.3± 6.727, p >0.05). Diabetic WT mice exhibited an increase in perfusion vs. WT control (185.3± 9.018*, p<0.05), while diabetic TLR2 KO mice did not increase significantly vs. TLR KO control (159.0± 3.038). In Y maze, % novel arm entries were not different amongst all groups. In fear conditioning, WT, WT STZ, and TLR2 KO STZ mice did not differ from each other significantly (% freezing time: WT: 25.5± 6.1, WT STZ: 31.3± 4.9, TLR2 KO STZ: 35.1±7.9). TLR2 mice had significantly decreased freezing % compared to other groups (12.2± 2.7, p<0.05).
Conclusions: Diabetes induced by STZ mediates an increase in whole brain perfusion in WT mice, an effect that is not observed in TLR2 mice. The lack of difference in percent novel arm entries is likely a result of the relative increase in exploratory behavior in the STZ groups. TLR2 KO mice were protected from the development of fear and anxiety as indicated by the low %freezing time during fear conditioning tests. This could be due to alterations in perfusion. These findings suggest that TLR2 is involved in the development of diabetic cerebrovascular disease and potentially in vascular cognitive impairment.