Anti-hypertensive agents do not prevent blood-brain barrier dysfunction and cognitive deficits in dietary-induced obese mice

Abstract

BACKGROUND: While vascular risk factors including Western-styled diet and obesity are reported to induce cognitive decline and increase dementia risk, recent reports consistently suggest that compromised integrity of cerebrovascular blood-brain barrier (BBB) may play an important role in neurodegeneration and cognitive deficits. A number of studies report that elevated blood pressure increases the permeability of BBB. METHODS: In this study, we investigated the effects of anti-hypertensive agents, candesartan or ursodeoxycholic acid (UDCA), on BBB dysfunction and cognitive decline in wild-type mice maintained on high fat and fructose (HFF) diet for 24 weeks. RESULTS: In HFF-fed mice, significantly increased body weight with elevated blood pressure, plasma insulin and glucose compared to mice fed with low-fat control chow was observed. Concomitantly, significant disruption of BBB and cognitive decline were evident in the HFF-fed obese mice. Hypertension was completely prevented by the co-provision of candesartan or UDCA in mice maintained on HFF diet, while only candesartan significantly reduced the body weight compared to HFF-fed mice. Nevertheless, BBB dysfunction and cognitive decline remained unaffected by candesartan or UDCA. CONCLUSIONS: These data conclusively indicate that modulation of blood pressure and/or body weight may not be directly associated with BBB dysfunction and cognitive deficits in Western diet-induced obese mice, and hence anti-hypertensive agents may not be effective in preventing BBB disruption and cognitive decline. The findings may provide important mechanistical insights to obesity-associated cognitive decline and its therapy.