Proprotein convertase subtilisin/kexin type 9 inhibitor exerts greater efficacy than atorvastatin on ameliorating cognitive impairment in high‐fat diet–induced obesity

Abstract

AbstractBackgroundLong‐term consumption of a high‐fat diet (HFD) caused not only obesity with dyslipidemia but also caused brain pathologies which resulted in cognitive impairment. Atorvastatin, a recommended first‐line lipid‐lowering drug, had beneficial effects on metabolic control and mitigated brain pathologies in several models. However, the long‐term use of statin had many side effects which may result in discontinuation of statins for therapeutic treatment. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved as an effectively therapeutic drug for lowering cholesterol level. PCSK9 inhibitor decreases low‐density lipoprotein receptor (LDLR) degradation, and consequently lowers of LDL levels in the circulation. However, there were only few studies that reported the effect of PCSK9 inhibitor on brain functions. In addition, the comparative effects of atorvastatin and PCSK9 inhibitor on brain functions and cognitive function in HFD‐induced obesity have not been elucidated. We hypothesize that PCSK9 inhibitor has greater effect than atorvastatin on improving brain function and cognitive function in HFD‐induced obesity.MethodTwenty Female Wistar rats were fed with either a normal diet (ND) or HFD for 15 weeks. At week 13, ND rats were given normal saline, and HFD rats were divided into two subgroups to receive either normal saline, atorvastatin (40 mg/kg/day) or PCSK9 inhibitor (4 mg/kg/day) for 3 weeks. At the end of experimental protocol, metabolic parameters, brain function, and cognitive function were determined.ResultHFD‐fed rats developed obesity, dyslipidemia and insulin resistance. An increase in PCSK9 level, LDLR degradation, oxidative stress, blood brain barrier breakdown, microglial hyperactivation, synaptic dysplasticity, apoptosis, Alzheimer’s‐related proteins production in hippocampus, and cognitive decline were observed in HFD‐fed rats. Atorvastatin and PCSK9 inhibitor equally attenuated Alzheimer’s‐related proteins production and apoptosis in hippocampus of HFD‐fed rats. Interestingly, PCSK9 inhibitor had greater efficacy than atorvastatin on the amelioration of hippocampal oxidative stress level, blood brain barrier breakdown, microglial hyperactivation, synaptic dysplasticity and cognitive decline in HFD‐fed rats. Furthermore, PCSK9 inhibitor, but not atorvastatin, decreased the hippocampal PCSK9 and increased LDLR expression in HFD‐fed rats (p<0.05, Figure 1).ConclusionPCSK9 inhibitor exerted greater efficacy than atorvastatin in improving metabolic and brain function in HFD‐induced obesity.