The role of creatine supplementation and mTORC1 signaling in ameliorating cognitive deficiency in a neuroinflammatory rat model

Abstract

Mild cognitive impairment (MCI) was defined as a boundary area between cognitive function of natural aging and dementia. Early studies have suggested that MCI could be a therapeutic window for prevention of dementia, given the irreversible nature involved in the pathology of dementia. One promising intervention may appear to be beneficial for MCI is creatine (Cr), which has been proven to be effective for ameliorating cognitive deficiency in general. However, it is unclear whether Cr supplementation could ameliorate cognitive deficiency in MCI. Moreover, the neuro-molecular evidence regarding the positive neurocognitive effects of Cr supplementation is currently lacking, hindering the clinical application. In order to better understand the neurocognitive and neuro-molecular effects underlying the Cr supplementation in the context MCI, I established a neuroinflammatory female Wistar rat model, which resembles the pathology of MCI in humans. Chronic (6-week) supplementation of Cr significantly ameliorated cognitive deficits in rats receiving intracerebroventricular injections of lipopolysaccharides (LPS) that induces neuroinflammation. Molecular analysis revealed that Cr supplementation robustly increased mTORC1 signaling and its downstream synaptic proteins, PSD-95 and synapsin, in dentate gyrus but not in medial prefrontal cortex. Immunohistochemistry analysis revealed upregulation of mTORC1 in NeuN+ neurons. Importantly, selective inhibition of mTORC1 signaling through rapamycin attenuated the protective effects of chronic Cr supplementation in ameliorating cognitive deficits. Lastly, acute Cr treatment (12 and 24-hour) was sufficient to activate mTORC1 signaling within PC12 cells. In conclusion, the present study provides a novel insight to this field and offers a promising therapeutic treatment for cognitive deficiency.