Chronic dietary creatine enhances hippocampal-dependent spatial memory, bioenergetics, and levels of plasticity-related proteins associated with NF-κB

Abstract

The brain has a high demand for energy, of which creatine (Cr) is an important regulator. Studies document neurocognitive benefits of oral Cr in mammals, yet little is known regarding their physiological basis. This study investigated the effects of Cr supplementation (3%, w/w) on hippocampal function in male C57BL/6 mice, including spatial learning and memory in the Morris water maze and oxygen consumption rates from isolated mitochondria in real time. Levels of transcription factors and related proteins (CREB, Egr1, and IκB to indicate NF-κB activity), proteins implicated in cognition (CaMKII, PSD-95, and Egr2), and mitochondrial proteins (electron transport chain Complex I, mitochondrial fission protein Drp1) were probed with Western blotting. Dietary Cr decreased escape latency/time to locate the platform ( < 0.05) and increased the time spent in the target quadrant ( < 0.01) in the Morris water maze. This was accompanied by increased coupled respiration ( < 0.05) in isolated hippocampal mitochondria. Protein levels of CaMKII, PSD-95, and Complex 1 were increased in Cr-fed mice, whereas IκB was decreased. These data demonstrate that dietary supplementation with Cr can improve learning, memory, and mitochondrial function and have important implications for the treatment of diseases affecting memory and energy homeostasis.

What Is Nuclear Factor Kappa B (NF-κB) Doing in and to the Mitochondrion?

“…These findings also have important implications for AD treatment as demonstrated by recent studies by Snow et al (2018) and as shown in other related studies (Djordjevic et al, 2017; Adlimoghaddam et al, 2019) that suggest targeting NF-κB signaling in the mitochondria may have therapeutic value. For example, in Snow et al’s study, creatine – a known modulator of mitochondrial function (Tarnopolsky and Beal, 2001), was shown to increase and positively alter protein levels of CaMKII, PSD-95, and Complex 1 subunits in creatine fed mice, whereas the NF-κB inhibitory IκB subunit was decreased.…”

Sex-Specific Effects of Chronic Creatine Supplementation on Hippocampal-Mediated Spatial Cognition in the 3xTg Mouse Model of Alzheimer’s Disease

“…In vitro, the neuroprotective effects of Cr appear to be mediated by NF-κB-dependent pathways, as treatment of cultured neurons with Cr reduced levels of IκB, the NF-κB tethering protein, consistent with enhanced activation of NF-κB with Cr [ 18 ]. Consistent with such data, our previous work with Cr supplementation in C57BL/6 mouse model [ 19 ] demonstrated a similar reduction in hippocampal IκB protein levels, consistent with increased activation of NF-κB, as well as elevations in calcium-calmodulin-dependent protein kinase II (CaMKII), a protein shown to be required for long-term memory formation [ 20 ] and for which isoforms serve as both activators [ 21 ] and downstream targets of NF-κB [ 22 ]. Further, hippocampal levels of postsynaptic density protein 95 (PSD-95), a synaptic protein implicated in learning and memory that is also under the transcription regulation of neuronal NF-κB [ 23 ], were increased in Cr-supplemented mice.…”

“…Further, hippocampal levels of postsynaptic density protein 95 (PSD-95), a synaptic protein implicated in learning and memory that is also under the transcription regulation of neuronal NF-κB [ 23 ], were increased in Cr-supplemented mice. Importantly, these molecular alterations were accompanied by enhanced hippocampal-associated learning, memory, and mitochondrial function [ 19 ]. Moreover, a subunit of complex I of the electron transport chain, which is intricately involved in mitochondrial function, was elevated with oral Cr [ 19 ].…”

Effects of supplemental creatine and guanidinoacetic acid on spatial memory and the brain of weaned Yucatan miniature pigs

“…Furthermore, creatine may support cognitive function during stress in human [53] and animal studies [20,21]. However, it is not clear whether this increased support was due to enhanced anaerobic demands in brain, as chronically supplemented mice had enhanced in vitro oxidative phosphorylation in hippocampal mitochondria [9]. Further studies might investigate the ontogeny of brain creatine metabolism in vivo in the more translational pig model.…”

“…Indeed, studies in rats show improved efficiency with spatial working memory during chronic stress following a single creatine dose [8]. Whereas mice chronically supplemented with creatine elicited better performance on a variety of memory tasks and had improved mitochondrial energetics [9]. Many have argued that creatine has neuroprotective effects that may be beneficial after mild brain trauma [10], or in neurodegenerative disease [11].…”