Effects of creatine supplementation on learning, memory ...mjiri.iums.ac.ir/article-1-3247-en.pdf · sion of dementia, and neuron loss related to Alzheimer disease(3, 11, 12, 15)

Original Articlehttp://mjiri.iums.ac.ir Medical Journal of the Islamic Republic of Iran (MJIRI)

Iran University of Medical Sciences

____________________________________________________________________________________________________________________1. MSc graduated, Department of Cellular- Molecular Nutrition, School of Nutrition Sciences and Dietetics, Tehran University of Medical Sci-ences, Tehran, Iran. [email protected]. Professor, Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, [email protected]. Professor, Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran, Iran. [email protected]. PhD student, Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. [email protected]. (Corresponding author) Assistant Professor, Department of Cellular, Molecular Nutrition, School of Nutrition Sciences and Dietetics, Teh-ran University of Medical Sciences, Tehran, Iran. [email protected]

Effects of creatine supplementation on learning, memoryretrieval, and apoptosis in an experimental animal model of

Alzheimer disease

Malek AliMohammadi1, Mohammadreza Eshraghian2

Mohammad-Reza Zarindast3, Abbas Aliaghaei4, Hamideh Pishva*5

Received: 27 July 2014 Accepted: 7 January 2015 Published: 4 October 2015

AbstractBackground: Alzheimer disease is the main cause of dementia in middle-aged and elderly people.

Considering the improving effects of creatine supplementation on cognitive performance, this studyaimed to determine the effects of creatine supplementation on learning, memory, and apoptosis in anexperimental model of Alzheimer’s disease.

Methods: Thirty-two male Wistar rats each weighing 250±50 grams were divided into four groups.The AdCr+ (Aβ injection, creatine supplementation) and AdCr- groups (Aβ injection, no creatinesupplementation) were injected bilaterally with amyloid beta (Aβ) (0.2µg in each CA1 area), and thesham group was injected with normal saline in the same area. After the injection, the AdCr+ groupreceived a diet of 2% creatine for six weeks. The control group underwent no surgical or dietary in-tervention. After six weeks the Morris Water Maze (MWM) test was administered, to measure learn-ing and memory retrieval. After sacrificing the animals, TUNEL staining for an anti-apoptosis assaywas performed for the sham, AdCr+, and AdCr- groups. All groups were compared by independent t-test using SPSS software.

Results: Results of MWM show that rats in sham and control groups performed better than those inthe AdCr- and AdCr+ groups. Compared to sham group, AdCr+ and AdCr- groups had moreTUNEL positive neurons count. Results indicated no differences between the AdCr+ and AdCr-groups in learning, memory retrieval, and percentage of TUNEL positive neurons.

Conclusion: After Aβ injection, creatine supplementation had no effect on learning, memory re-trieval, or neuron apoptosis in male Wistar rats.

Keywords: Creatine supplementation, Amyloid beta, Alzheimer disease, Memory, Learning, Apop-tosis.

Cite this article as: AliMohammadi M, Eshraghian M, Zarindast M.R, Aliaghaei A, Pishva H. Effects of creatine supplementation onlearning, memory retrieval, and apoptosis in an experimental animal model of Alzheimer disease. Med J Islam Repub Iran 2015 (4 October).Vol. 29:273.

IntroductionAlzheimer disease is the main cause of

dementia in middle-aged and elderly peo-ple (1). Impaired short-term memory andenvironmental disorientation are earlyhallmarks of the disease (2). There aremedications to treat this disease but efforts

to control Alzheimer have been disappoint-ing so far. Social and medical supports,however, are useful for increasing thequality of life for patients (1).

Studies have shown that brain function isimproved when the fuel supplies for neu-rons, are increased. Considering the crucial

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http://mjiri.iums.ac.ir/article-1-3247-en.html

Alzheimer and creatine and memory

2 Med J Islam Repub Iran 2015 (4 October). Vol. 29:273.http://mjiri.iums.ac.ir

role of creatine in neuron energy homeo-stasis, it seems that creatine could improvebrain function by improving the energystatus of neurons (3). One study showedthat mental training increased creatine lev-els in neurons (4). Increased creatine levelsin the brain following creatine supplemen-tation have also been reported in humansand other rodents (5-9). Acute oral creatinesupplementation has been shown to reducemental fatigue and to decrease task-responsive oxygen demand to activated ar-eas on performance of a serial calculationtask (10). Five grams per day of creatinesupplementation in healthy subjects ap-pears to enhance performance on validatedtests related to intelligence and workingmemory. Although a dose of 0.03 gr/kgcreatine supplementation in young adultshad no effect on short-term memory, 20gr/day of creatine supplementation for aweek in healthy elderly was effective inimproving short-term memory and spatialmemory (3, 11, 12).The effects of creatine supplementation

on short-term memory in people sufferingfrom Alzheimer disease has not yet beenstudied; however, there is some evidencethat neuronal creatine kinase activity de-clines in neurons under the toxic effects ofamyloid beta (13) and another studyshowed that creatine content of brain de-creases during conversion from Mild Cog-nitive Impairment (MCI) to Manifest De-mentia (MD) (14). One in vitro studyshowed the neuroprotective effects of crea-tine against amyloid beta, while some otherstudies have found creatine deposits in theneurons of humans with Alzheimer diseaseand in the neurons of transgenic mice mod-els of Alzheimer (15-17).

Studies on healthy individuals that haveshown the positive effects of creatine sup-plementation on short-term memory andspatial memory along with studies that havereported the neuroprotective effects of crea-tine give rise to a curiosity about how crea-tine supplementation can help people suf-fering from memory impairment, progres-sion of dementia, and neuron loss related to

Alzheimer disease (3, 11, 12, 15). Sinceinflammation is reportedly caused by crea-tine deposition in the neurons of both ani-mal models of Alzheimer’s disease andpeople afflicted with it, a big risk is at-tached to prescribing creatine in a clinicaltrial (16); thus, the current study investi-gates the effects of creatine supplementa-tion on spatial memory and neuronal apop-tosis in an experimental model of Alz-heimer disease.

MethodsAnimalsAdult male Wistar rats (200-250g) were

obtained from the Pastor Institute (Tehran,Iran).

They were caged at a constant tempera-ture of 21 ±1°C with controlled 12h/12hlight-dark cycles, and ad libitum access tofood and water. The rats were given oneweek to habituate to the facilities, and thenexperimental procedures were begun. Theguidelines of the Committee of Care in theUse of Experimental Animals were fol-lowed, and study procedures were approvedby the Ethics Committee of Tehran Univer-sity of Medical Sciences. Efforts weremade to minimize animal suffering and re-duce the number of animals used.

Study designThe animals were divided into four

groups (n=8 per group): control, sham,AdCr-, and AdCr+. Animals in the sham,AdCr-, and AdCr+ groups underwent ste-reotaxic surgery. Those in the AdCr- andAdCr+ groups were given a bilateral amy-loid beta injection (4 µl) in the CA1 hippo-campus (0.5µg/µl), while the sham groupwas given a normal saline injection in thesame area of the brain. After surgery, theAdCr+ group received creatine monohy-drate powder mixed in their CHO (2%creatine/diet) while the other groups con-tinued receiving normal CHO. The controlgroup had no surgical or dietary interven-tion during the study period. After sixweeks of dietary intervention, behavioraltests carried on and also histological tests

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M. AliMohammadi, et al.

3Med J Islam Repub Iran 2015 (4 October). Vol. 29:273. http://mjiri.iums.ac.ir

performed after sacrificing the animals.

SurgeryHuman β-amyoid 1-42 (Sigma-Aldrich

USA) was solved in 0.1M phosphate buffersaline (PBS; PH=7.4) and then aliquotedand stored at -70°C until use. Every aliquotwas incubated at room temperature for 48hours before injection. The animals wereanesthetized with intraperitoneal ketamine(100mg/kg) and Xylazine (10 mg/kg) andthen injected bilaterally under stereotaxicconditions with Aβ or normal saline intothe CA1 hippocampus (AP=3.9mm,LR=2.2mm, D=2.7mm). Injections wereperformed at a rate of 0.5µl/min using aHamilton syringe attached to the stereotaxapparatus. Four micro-liters of Aβ(0.5µg/µl) solution injected in every hippo-campus, and the needle was kept in placefor one minute after injection before beingslowly retracted.

SupplementationTwo percent creatine (Sigma-Aldrich

USA) was mixed into the normal CHO us-ing an electric mill. After adding some wa-ter and cutting the paste, the creatine andCHO mixture were dried in a 30-45 minuteexposure to a continuous warm air stream.After injection, animals in the AdCr+ grouphad free access to this creatine-CHO mix-ture for six weeks.

Morris Water MazeThe Morris water maze (MWM) proce-

dure was performed 6 weeks after the Aβinjection.

ApparatusThe water maze consisted of a pool (155

cm in diameter) filled with water (21±1◦C)to a level 10 cm from the edge of the tank.A transparent Plexiglas platform (10cm di-ameter) was located 1.5 cm below the sur-face in the eastern quadrant of the tank(target quadrant). Climbing onto the plat-form was the only means of escape fromthe water. The walls surrounding the poolwere decorated with distinct extra maze

spatial cues which were kept in fixed posi-tions during the entire experiment to allowthe animals to find the hidden platform.The animals’ movements were recorded bya CCD camera (Panasonic Inc., Japan)hanging from the ceiling above the MWMapparatus, and locomotion tracking wasmeasured using Ethovision software (ver-sion XT7, the Netherlands), a video track-ing system for automated analysis of ani-mal behavior.

HabituationTwenty-four hours before starting the

hidden platform training, rats were given60 seconds to swim in the tank without theplatform in order to adapt to their environ-ment.

ProcedureThe reference spatial learning and

memory tests were performed based on theprocedure previously conducted in our la-boratory with some modifications for train-ing; the platform was submerged in theeastern quadrant of the pool. Its place re-mained unchanged throughout training, butanimals were released into the water (whilefacing the tank wall) from different loca-tions chosen randomly from the south,north, west, northwest and southwest be-tween the trials. Rats received one trainingsession per day for 3 consecutive days.Each session consisted of four trials with 1-min inter-trial intervals. The animals wereallowed to swim for 60 sec to localize theplatform’s position in the tank. Rats thatdid not find the platform within 60 sec weredirected to it and allowed to rest on it for 10sec. Twenty-four hours after the third ses-sion, the spatial probe test was given. In it,the platform was removed, and rats wereallowed to swim for 60 sec before theywere removed. Animals were released intothe water at a location near the platform.Behavior was recorded with a video track-ing system. Escape latencies, time spent intarget quadrant, and swim speed were rec-orded for subsequent analysis.

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Preparation for histological testsThe rats were anesthetized and their

brains were fixed through a transcardialfixation surgery (normal saline and 4% par-aformaldehyde solution) within 24 hoursafter the spatial probe test. After that, thebrains were kept in a 4% paraformaldehydesolution. In preparation for the histologicalstaining, the rat brains were embedded withparaffin, cut into consecutive 5 µm trans-verse sections by a microtome, and placedon the poly-D-lysine-coated glass slides.Alternate sections were stained with hema-toxylin and eosin (H&E) to observe generalmorphologic alterations, and neighboringsections were used for thioflavin t andTUNEL staining.

ThioflavinIn order to detect Aβ plaques in brain sec-

tions thioflavin-t (Sigma-Aldrich USA) wasused for staining. Brain sections were de-paraffinized in xylene, rehydrated, coveredwith thioflavin-t solution (0.5% thioflavin-tin 0.1N HCl), and incubated at room tem-perature and away from light for 10 min.Slides were immersed in distilled watertwice before being observed through a fluo-rescent microscope.

TUNELIn order to detect apoptotic neurons in

brain sections the TUNEL staining protocolwas performed by use of Kit (TUNELApoptosis Detection Kit, Millipour, andUK). Brain sections were deparaffinized inxylene, rehydrated, immersed in PBS, andthen incubated at 37°C for 30 min. Of PBS,sections were covered with diluted proteinkinase and incubated at 37°C for 20 min.To halt protein kinase activity, sectionswere washed in PBS solution (4×2minutes). Every brain section was coveredwith 50µl TdT buffer for 10 min. The TdTbuffer was removed using a sampler, andthen each section was covered with 50µlTdT mixture solution (90% TdT buffer, 5%dUTP-biotin, 5% TdT) and incubated for60 min at 37°C. Slides were washed for 5min by immersing them in TB buffer at

room temperature and then immersed inPBS (4×2 min). After the washing process,sections were covered with 50µl of block-ing solution and incubated for 20 min atroom temperature. After removing theblocking buffer with a sampler, 50µl Avi-din-FTC mixture (1 part Avidin FTC, 9parts blocking solution) was used for everysection, and slides were incubated at 37°Cfor 30 min away from light. To obtain themean percentage of apoptotic neurons inthe hippocampus area, the number ofTUNEL positive cells were counted inthree adjacent 40X microscopic fields.

Statistical analysisThe data were presented as mean±SD us-

ing SPSS v.16. Mean escape time, distancetraveled to the platform, time spent in targetquadrant, swimming speed, and percentageof apoptotic cells were analyzed using theindependent samples t-test, to comparesham and control groups, sham and AdCr-

groups and also AdCr- and AdCr+.

ResultsThioflavinThioflavin staining was performed to con-

firm the induction of Alzheimer’s in ani-mals. Beta amyoid (Aβ) plaques were ob-served in the brain sections derived fromanimals in the AdCr+ and AdCr- groups, butnot in the brain sections of those from thesham group or the control group (Fig. 1).

Learning and memory retrievalRats in the AdCr- group had a higher

mean escape time than rats in the sham(p<0.001) and control groups (p=0.001),but no significant difference was shownbetween the AdCr+ and AdCr- groups(p=0.102) (Table 1 & Fig. 2) .These datashowed the learning impairment in AdCr+

and AdCr- groups and that creatine supple-mentation had no effect on the learningability of rats after Aβ injection. These re-sults were confirmed by comparison of themean distance that rats traveled to find theplatform in training trials (Table 1 & Fig.3).

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Rats in the AdCr- group spent less time inthe target quadrant than rats in the shamand control groups (p=0.017). There was nosignificant difference between rats in theAdCr+ and AdCr- groups (p=0.235), whichindicates that after Aβ injection creatinesupplementation had no effect on the abilityto retrieve memories (Table 1).

ApoptosisThe TUNEL staining protocol was per-

formed to detect apoptotic neurons in brainsections (Fig. 4). As is obvious in Fig. 4 thebrain sections of rats in the AdCr+ andAdCr- groups contained more TUNEL pos-itive neurons than those of the sham group.

The mean percentage of TUNEL positiveneurons in the study group (minus thecontrol group) is presented in Table 1. Thepercentage of TUNEL positive neuronsfound in the brain sections of rats in theAdCr+ and AdCr- groups was significantlyhigher than those found in the sham group(p=0.010, p=0.001), but no significantdifference was shown in the percentage ofTUNEL positive neurons of the AdCr+ andAdCr- groups (P=0.322), which means thatafter Aβ injection creatine supplementationdid not affect the apoptotic effect of Aβ inneurons.

DiscussionThe results of our study showed that

memory impairments and apoptosis induc-tion caused by a single injection of Aβcould not be affected by six weeks of crea-tine supplementation started right after theinjection while there are evidence that sug-gest improving effects of creatine supple-mentation on learning, memory and mentalperformance (3, 10, 11). The reason that wecould not see any improving effects ofcreatine supplementation on learning andmemory may be due to a possible downregulation of creatine kinase activity causedby Aβ injection.

Fig. 1. Thioflavin-T staining of amyloid beta plaques.Arrows show the amyloid beta plaques in the brainsection derived from an Alzheimer’s induced (Ad).No amyloid beta plaque is visible in brain section ofthe rat from sham group (sham). Obiective × 10

Table 1. Descriptive statistics of escape time (in 3 days of trainnig), distance travel (in 3 days of trainnig), time spent(in target quadrant in probe test) and percentage of TUNEL positive neurons in brain section of rats,in different groups

TUNELd

(Mean±SD)Time spent(Cm)c

(Mean±SD)Distance Travel(Cm)b

(Mean±SD)Escape timea

(Mean±SD)Group

-33.57±2.58374.0±19.7617.2±1.19Control4.83±1.3235.91±0.91425.8±20.4820.9±0.99Sham

24.00±4.4531.99±0.78645.1±35.1227.9±0.53AdCr-21.25±3.4730.37±2.00650.0±24.6529.5±1.07AdCr+

a. Sham & Control, Independent sample t-test (p=0.098), Sham & AdCr-, Independent sample t-test (p=0.001), AdCr- & AdCr+,Independent sample t-test (P=0.102)b. Sham & Control, Independent sample t-test (p=0.119), Sham & AdCr-, Independent sample t-test (p=0.002), AdCr- & AdCr+,Independent sample t-test (P=0.455)c. Sham & Control, Independent sample t-test (p=0.222), Sham & AdCr-, Independent sample t-test (p=0.017), AdCr- & AdCr+,Independent sample t-test (P=0.235)d. Sham & AdCr-, Independent sample t-test (=0.001), AdCr- & AdCr+, Independent sample t-test (p=0.322)

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A reduction in creatine kinase activitycaused by Aβ has been reported in Alz-heimer’s disease and in experimental andcell culture model studies (16, 18). Onestudy reported 86% reduction in creatinekinase activity (19). This decrease is im-portant in the pathogenesis of Alzheimer’sdisease, and it is claimed to be the maincause of cognition impairment in elderlyindividuals and in Alzheimer’s disease(18). Thus the metabolism of creatine inbrain is quite different in situations likeAlzheimer’s disease and elderly. McMorriset al reported possitive effects of creatinesupplementation in healthy elderlyindivituals (11) suggesting the creatinesupplementation could have improving ef-fects in Alzheimer’s disease as well. None-theless our result showed no improvementin learning or memory retrieval among ratsin the AdCr+ group (compared with rats in

the AdCr- group), however creatine kinaseactivity was not measured, and this is onelimitation of this study. Based on the resultsof previous studies, the researchers as-sumed that the reduction in creatine kinaseactivity was too severe to attenuate thecognitive side effects by supplying moresubstrate for the enzyme through creatinesupplementation (18, 19). It is also possiblethat the role of decreased creatine kinaseactivity in cognitive impairment in the el-derly and people with Alzheimer’s diseaseis somewhat exaggerated. Furtherer studiesare warranted to investigate effects of crea-tine supplementation on mental functions indifferent experimental models of Alz-heimer’s disease and to clarify the mecha-nisms by measuring the creatine kinase ac-tivity during a similar study.

Present study also showed no differencein mean percentages of TUNEL positive

Fig. 2. Mean escape time in every single

Fig. 3. Mean distance traveled to the platform in every single training

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neurons among rats in the AdCr+ and AdCr-

groups which is in line with our behavioraltests. This results indicated that after Aβinjection, creatine supplementation did notshow any neuroprotective effects againstAβ toxicity. Country to the results ofBrewer‘s study which showed neuroprotec-tive effects of creatine against Aβ in vitro(15) due to slow rate of increase in braincreatine following oral creatine supplemen-tation (18). On the other hand, knowingthat supplementation started after Aβ injec-

tion, the increase in the brain creatine sup-ply was probably too slow to show the neu-roprotective effects of creatine against Aβtoxicity. Further research is needed to eval-uate the neuroprotective effects of creatinesupplementation when it starts before theAβ injection.

ConclusionAfter Aβ injection creatine supplementa-

tion had no effect on learning, memory re-trieval, or neuron apoptosis in male Wistarrats. More studies are needed in the field.

AcknowledgementsThe authors extend their sincere thanks to

Professor Fereshteh Motamedi for her help-ful cooperation in this study. We would liketo thank the Research Council of TehranUniversity of Medical Sciences for theirfinancial support (18530).

Conflict of interestThe authors have no conflict of interest.

References1. Akhondzadeh S, Noroozian M, Mohammadi M,

Ohadinia S, Jamshidi AH, Khani M. Melissaofficinalis extract in the treatment of patients withmild to moderate Alzheimer’s disease: a doubleblind, randomised, placebo controlled trial. Journalof Neurology, Neurosurgery & Psychiatry 2003 July1, 2003;74(7):863-6.

2. Cherrier MM, Matsumoto AM, Amory JK,Asthana S, Bremner W, Peskind ER, et al.Testosterone improves spatial memory in men withAlzheimer disease and mild cognitive impairment.Neurology 2005;64(12):2063-8.

3. Rae C, Digney AL, McEwan SR, Bates TC.Oral creatine monohydrate supplementationimproves brain performance: a double–blind,placebo–controlled, cross–over trial. Proceedings ofthe Royal Society of London Series B: BiologicalSciences 2003;270(1529):2147-50.

4. Valenzuela MJ, Jones M, Caroline Rae WW,Graham S, Shnier R, Sachdev P. Memory trainingalters hippocampal neurochemistry in healthyelderly. NeuroReport. 2003;14(10):1333-7.

5. Dechent P, Pouwels PJW, Wilken B, HanefeldF, Frahm J. Increase of total creatine in human brainafter oral supplementation of creatine-monohydrate.American Journal of Physiology-Regulatory,Integrative and Comparative Physiology 1999;

Fig. 4. TUNEL staining. Arrows show the TUNELpositive neurons in brain section picture. Alzheimerinduced rats (AdCr- & AdCr+, groups) have moreTUNEL positive neurons compare to rats in shamgroup. Objective × 40

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mjir

i.ium

s.ac

.ir a

t 8:2

5 IR

DT

on

Thu

rsda

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ugus

t 29t

h 20

19




277(3): 698-704.6. Dedeoglu A, Kubilus JK, Yang L, Ferrante KL,

Hersch SM, Beal MF, et al. Creatine therapyprovides neuroprotection after onset of clinicalsymptoms in Huntington's disease transgenic mice. JNeurochem 2003;85(6):1359-67.

7. Ferrante RJ, Andreassen OA, Jenkins BG,Dedeoglu A, Kuemmerle S, Kubilus JK, et al.Neuroprotective Effects of Creatine in a TransgenicMouse Model of Huntington's Disease. The Journalof Neuroscience 2000;20(12):4389-97.

8. Matthews RT, Yang L, Jenkins BG, FerranteRJ, Rosen BR, Kaddurah-Daouk R, et al.Neuroprotective Effects of Creatine andCyclocreatine in Animal Models of Huntington’sDisease. The Journal of Neuroscience 1998;18(1):156-63.

9. Pan JW, Takahashi K. Cerebral energeticeffects of creatine supplementation in humans.American Journal of Physiology - Regulatory,Integrative and Comparative Physiology 2007;292(4):R1745-R50.

10. Watanabe A, Kato N, Kato T. Effects ofcreatine on mental fatigue and cerebral hemoglobinoxygenation. Neuroscience Research 2002; 42(4):279-85.

11. McMorris T, Mielcarz G, Harris RC, SwainJP, Howard A. Creatine supplementation andcognitive performance in elderly individuals.Neuropsychology, development, and cognitionSection B, Aging, Neuropsychology and Cognition2007;14(5):517-28.

12. Rawson ES, Lieberman HR, Walsh TM, ZuberSM, Harhart JM, Matthews TC. Creatinesupplementation does not improve cognitivefunction in young adults. Physiology &Behavior 2008;95(1-2):130-4.

13. Aksenov M, Aksenova M, Butterfield DA,Markesbery WR. Oxidative modification of creatinekinase BB in Alzheimer's disease brain. Journal ofneurochemistry 2000;74(6):2520-7.

14. Kuzyk A, Kastyak M, Agrawal V, Gallant M,Sivakumar G, Rak M, et al. Association amongamyloid plaque, lipid, and creatine in hippocampusof TgCRND8 mouse model for Alzheimer disease.Journal of Biological Chemistry 2010;285(41):31202-7.

15. Brewer GJ, Wallimann TW. Protective Effectof the Energy Precursor Creatine Against Toxicityof Glutamate and β-Amyloid in Rat HippocampalNeurons. Journal of neurochemistry 2000; 74(5):1968-78.

16. Gallant M, Rak M, Szeghalmi A, Del Bigio M,Westaway D, Yang J, et al. Focally ElevatedCreatine Detected in Amyloid Precursor Protein(APP) Transgenic Mice and Alzheimer DiseaseBrain Tissue. Journal Name: Journal of BiologicalChemistry 2006;281(1): 39576.

17. Pilatus U, Lais C, de Rochmont AdM,Kratzsch T, Frölich L, Maurer K, et al. Conversionto dementia in mild cognitive impairment isassociated with decline of N-actylaspartate andcreatine as revealed by magnetic resonancespectroscopy. Psychiatry Research: Neuroimaging2009;173(1):1-7.

18. Wyss M, Kaddurah-Daouk R. Creatine andCreatinine Metabolism. Physiological Reviews2000;80(3):1107-213.

19. David S, Shoemaker M, Haley BE. Abnormalproperties of creatine kinase in Alzheimer's diseasebrain: Correlation of reduced enzyme activity andactive site photolabeling with aberrant cytosol-membrane partitioning. Molecular Brain Research1998;54(2):276-87.

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Effects of creatine supplementation on learning, memory ...mjiri.iums.ac.ir/article-1-3247-en.pdf · sion of dementia, and neuron loss related to Alzheimer disease(3, 11, 12, 15)