Effect of creatine supplementation on cognitive performance and apoptosis in a rat model of amyloid-beta-induced Alzheimer's disease

Document Type: Original Article


1 Department of Cellular- Molecular Nutrition, School of Nutrition Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

3 Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

4 Anatomy and Cell Biology Department, School of Medicine, Shahid Beheshti University of Medical Sciences


Objective(s): Neuroprotective effect of creatine (Cr) against β-amyloid (Aβ) is reported in an in vitro study. This study investigated the effect of Cr supplementation on β-amyloid toxicity in vivo.
Materials and Methods: Thirty two, male Wistar rats were divided into 4 groups. During ten weeks of study, control group went through no surgical or dietary intervention. At the 4th week of study Sham group had a hippocampal normal saline injection, while Aβ and AβCr groups had an β-amyloid  injection in the hippocampus. AβCr group were fed by Cr diet during the study. After 10 weeks, Morris water maze (MWM) test was administered to measure learning ability and memory retrieval. Animals were sacrificed for TUNEL anti apoptotic assay and staining of amyloid plaques by Thioflavin-T.
Results: There was a significant retention deficit among AβCr and Aβ group while the escape latency and the distance traveled to the platform were significantly higher in AβCr group compared to Aβ group. AβCr group had same percent of TUNEL positive neurons compared to Aβ group.
Conclusion: Cr supplementation before and after β-amyloid injection into the CA1 area of hippocampus deteriorates the learning and memory impairment of rats and it does not protect neuronal apoptosis caused by β-amyloid.


1. Allen PJ, D'Anci KE, Kanarek RB, Renshaw PF. Chronic creatine supplementation alters depression-like behavior in rodents in a sex-dependent manner. Neuropsychopharmacology 2009; 35:534-546.

2. Tarnopolsky MA. Caffeine and creatine use in sport. Ann Nutr Metab 2010; 57:1-8.

3. Poortmans JR, Francaux M. Adverse effects of creatine supplementation: fact or fiction? Sports Med 2000; 30:155-170.

4. Watanabe A, Kato N, Kato T. Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neurosci Res 2002; 42:279-285.

5. Dechent P, Pouwels PJW, Wilken B, Hanefeld F, Frahm J. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol Regul Integr Comp Physiol 1999; 277:R698-R704.

6. Dedeoglu A, Kubilus JK, Yang L, Ferrante KL, Hersch SM, Beal MF, et al. Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice. J Neurochem 2003; 85:1359-1367.

7. Pan JW, Takahashi K. Cerebral energetic effects of creatine supplementation in humans. Am J Physiol Regul Integr Comp Physiol 2007; 292:R1745-R1750.

8. Hadjicharalambous M, Kilduff L, Pitsiladis Y. Brain serotonin and dopamine modulators, perceptual responses and endurance performance during exercise in the heat following creatine supplementation. J Int Soc Sports Nutr 2008; 5:14.

9. McMorris T, Mielcarz G, Harris RC, Swain JP, Howard A. Creatine supplementation and cognitive performance in elderly individuals. Neuropsychology, development, and cognition Section B. Aging Neuropsychol Cogn 2007; 14:517-528.

10. Rae C, Digney AL, McEwan SR, Bates TC. Oral creatine  monohydrate supplementation improves brain performance: a double–blind, placebo–controlled, cross–over trial. Proc Biol Sci 2003; 270:2147-2150.

11. Rawson ES, Lieberman HR, Walsh TM, Zuber SM, Harhart JM, Matthews TC. Creatine supplementation does not improve cognitive function in young adults. Physiol Behav 2008; 95:130-134.

12. Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, et al. Neuroprotective effects of creatine in a transgenic mouse model of huntington's disease. J Neurosci 2000; 20:4389-4397.

13. Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R, et al. Neuroprotective Effects of creatine and cyclocreatine in animal models of huntington’s disease. J Neurosci 1998; 18:156-163.

14. Pluta R. Unresolved questions concerning etiology of Alzheimer’s disease: Hypometabolism. Nutr 2011; 27:1-2.

15. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci 1986; 83:4913-4917.

16. Ihara Y, Nukina N, Miura R, Ogawara M. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J Biochem 1986; 99:1807-1810.

17. Mohamed A, Posse de Chaves E. Aβ Internalization by Neurons and Glia. Int J Alzheimers Dis 2011; 2011:17.

18. Terry RD, Katzman R. Senile dementia of the Alzheimer type. Ann Neurol 1983; 14:497-506.

19. Brewer GJ, Wallimann TW. Protective effect of the energy precursor creatine against toxicity of glutamate and β-amyloid in rat hippocampal neurons. J Neurochem 2000; 74:1968-1978.

20. Gallant M, Rak M, Szeghalmi A, Del Bigio M, Westaway D, Yang J, et al. Focally elevated creatine detected in amyloid precursor protein (APP) transgenic mice and alzheimer disease brain tissue. J Biol Chem 2006; 281: 39576 - end of article.

21. Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev 2000; 80:1107-1213.

22. Chambon C, Wegener N, Gravius A, Danysz W. Behavioural and cellular effects of exogenous amyloid-β peptides in rodents. Behav Brain Res 2011; 225:623-641.

23. Tamagno E, Bardini P, Guglielmotto M, Danni O, Tabaton M. The various aggregation states of β-amyloid 1–42 mediate different effects on oxidative stress, neurodegeneration, and BACE-1 expression. Free Radic Biol Med 2006; 41:202-212.

24. Aksenov M, Aksenova M, Butterfield DA, Markesbery WR. Oxidative modification of creatine kinase BB in Alzheimer's disease brain. J Neurochem 2000; 74:2520-2527.

25. Hensley K, Carney J, Mattson M, Aksenova M, Harris M, Wu J, et al. A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci 1994; 91:3270-3274.

26. Yatin SM, Aksenov M, Butterfield DA. The antioxidant vitamin E modulates amyloid β-peptide-induced creatine kinase activity inhibition and increased protein oxidation: implications for the free radical hypothesis of alzheimer's disease. Neurochem Res 1999; 24:427-435.