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

• Published in: Nutrients 2020-11, Vol.12 (11), p.3589
• Main Authors: Snow, Wanda M, Cadonic, Chris, Cortes-Perez, Claudia, Adlimoghaddam, Aida, Roy Chowdhury, Subir K, Thomson, Ella, Anozie, Adama, Bernstein, Michael J, Gough, Kathleen, Fernyhough, Paul, Suh, Miyoung, Albensi, Benedict C
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - physiopathology; Alzheimer Disease - prevention & control; Alzheimer's disease; Amyloid; Animal cognition; Animals; Behavior, Animal - drug effects; Behavior, Animal - physiology; Brain; Ca2+/calmodulin-dependent protein kinase II; Chromium; Cognition; Creatine; Creatine - pharmacology; Cyclic AMP response element-binding protein; Data search; Diet; Dietary Supplements; Disease Models, Animal; Female; Females; Food; Gender differences; Hippocampus - drug effects; Hippocampus - physiopathology; Kinases; Latency; Male; Males; Memory; Mice; Mitochondria; Neurons; Neuropathology; NF-κB protein; Oxygen consumption; Pathology; Phosphorylation; Postsynaptic density proteins; Proteins; Respiration; Search methods; Sex Factors; Spatial Memory - drug effects; Spatial Memory - physiology; Western blotting
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu12113589

The creatine (Cr) energy system has been implicated in Alzheimer's disease (AD), including reductions in brain phosphoCr and Cr kinase, yet no studies have examined the neurobehavioral effects of Cr supplementation in AD, including the 3xTg mouse model. This studied investigated the effects of Cr supplementation on spatial cognition, plasticity- and disease-related protein levels, and mitochondrial function in the 3xTg hippocampus. Here, 3xTg mice were fed a control or Cr-supplemented (3% Cr ( )) diet for 8-9 weeks and tested in the Morris water maze. Mitochondrial oxygen consumption (Seahorse) and protein levels (Western blots) were measured in the hippocampus in subsets of mice. Overall, 3xTg females exhibited impaired memory as compared to males. In females, Cr supplementation decreased escape latency and was associated with increased spatial search strategy use. In males, Cr supplementation decreased the use of spatial search strategies. Pilot data indicated mitochondrial enhancements with Cr supplementation in both sexes. In females, Cr supplementation increased CREB phosphorylation and levels of IκB (NF-κB suppressor), CaMKII, PSD-95, and high-molecular-weight amyloid β (Aβ) species, whereas Aβ trimers were reduced. These data suggest a beneficial preventative effect of Cr supplementation in females and warrant caution against Cr supplementation in males in the AD-like brain.