Creatine Supplementation Upregulates mTORC1 Signaling and Markers of Synaptic Plasticity in the Dentate Gyrus While Ameliorating LPS-Induced Cognitive Impairment in Female Rats.

Xuansong Mao,Frank W Booth,Taylor J Kelty,Nathan R Kerr,Thomas E Childs,Michael D Roberts

doi:10.3390/nu13082758

Abstract

Mild cognitive impairment (MCI) designates the boundary area between cognitive function in natural aging and dementia, and this is viewed as a therapeutic window to prevent the occurrence of dementia. The current study investigated the neurocognitive effects of oral creatine (Cr) supplementation in young female Wistar rats that received intracerebroventricular injections of lipopolysaccharide (LPS) to mimic MCI. Neuromolecular changes within the dentate gyrus were analyzed following behavioral testing. We also investigated both neurocognitive and neuromolecular changes following Cr supplementation in the absence of LPS in young female Wistar rats to further investigate mechanisms. Interestingly, based on trial 2 of Barnes maze test, Cr supplementation ameliorated spatial learning and memory deficit induced by LPS, shown by decreased latency time and errors to reach the escape box (p < 0.0001, n = 12). Cr supplementation also attenuated recognition memory deficit induced by LPS, shown by increased amount of time taken to explore the new object (p = 0.002, n = 12) during novel object recognition testing. Within the dentate gyrus, Cr supplementation in LPS injected rats upregulated mTORC1 signaling (p = 0.026 for mTOR phosphorylation, p = 0.002 for p70S6K phosphorylation, n = 8) as well as the synapsin (p = 0.008) and PSD-95 synaptic proteins (p = 0.015), in comparisons to LPS injected rats. However, Cr supplementation failed to further enhance spatial memory and recognition memory in the absence of LPS. In conclusion, Cr ameliorates LPS-induced cognitive impairment in a rodent MCI model. Mechanistically, these phenotypic effects may, in part, be mitigated via an upregulation of mTORC1 signaling, and an enhancement in synaptogenesis in the dentate gyrus. While preliminary, these findings may inform future research investigating neurocognitive effects of Cr for MCI patients.

Highlights

Dementia is a comprehensive descriptor for various combinations of symptoms, which include deficits in memory, problem solving, thinking skills, or language [1]
We examined the dentate gyrus for Mammalian target of rapamycin complex 1 (mTORC1) signaling markers as well as select synaptic proteins (Figure 4)
In line with our finding of increased mTORC1 signaling, we found upregulation of synapsin and PSD-95 proteins expression with Cr supplementation

Summary

Introduction

Dementia is a comprehensive descriptor for various combinations of symptoms, which include deficits in memory, problem solving, thinking skills, or language [1]. Results from the Rush Memory and Aging Projects showed 42% of the MCI patients developed dementia after a median of ~3 yrs with 38% of patients reverting back to normal at the same time [3], studies have shown that the AD pathology is irreversible in nature once it occurs [4,5]. This implies the clinical significance of using MCI as an early therapeutic window for populations who are vulnerable to AD. Therapeutic interventions for mitigating the progression of MCI are currently lacking

Methods

Results

Conclusion