Impact Of Curcumin On The App/ps1 Double Transgenic Mouse Brain Energy Metabolism

ObjectiveAlzheimer's disease (AD) is the most common type of dementia. Aging and family history are two major risk factors of AD. AD is clinically characterized with progressive and irreversible memory and other cognitive function imparement together with behavioral changes, resulting in dementia and death. The distinctive neuropathological lesions of AD include extensive neuronal and synaptic loss, extracellular senile plaques and intracellular neurofibrillary tangles. In recent years, studies have shown that abnormal cerebral glucose metabolism can be detected in preclinical stage of AD patients, thereby the relationship between energy dysmetabolism and AD pathogenesis has become one of the spotlights of AD research.The current study aims to elucidate the potential neuroprotective mechanism of curcumin from the perspective of cerebral energy metabolism and provide scientific evidence to design efficacious, safe and convenient interventions for early prevention and treatment of AD by observing the effect of curcumin on spacial learning and memory ability, cerebral glucose metabolism and expression of hippocampal GLUT1, GLUT 3 and IRS2.Material and Methods1. APP/PS1 double transgenic mice (APP/PS1 dtg mice) of 3 months were randomized into APP/PS1 dtg, Rosiglitazone (RSG) group and curcumin-treated groups of high, medium and low doses. Genetic background and age-matched C57/BL6J mice were used as normal control group. Mice were treated through intragastric administration once daily for 3 months.2. The spatial learning and memory together with memory retention ability were assessed by Morris water maze to evaluate the therapeutic effects of curcumin on cognitive function.3. Cerebral glucose metabolism was detected using functional imaging technique-microPET to address the effect of curcumin on cerebral energy metabolism of APP/PS1 dtg mice. 4. The expression of GLUT1,GLUT3 and IRS2 in the hippocampus of APP/PS 1 dtg mice was examined using immunohistochemistry and Western blot methods to evaluate the therapeutic effects of curcumin on the expression of cerebral energy metabolism-related proteins5. Statistical analysis:Data are presented as means±SD. Differences among groups were determined by one-way ANOVA. P<0.05 was considered significant.Results1. The effects of curcumin on ethology, spacial learning and memory ability of APP/PS 1 dtg mice In probe trial of Morris water maze, compared with the normal control, the frequency of platform site transversing and swimming time in target quadrant of APP/PS1 dtg mice were significantly decreased (P<0.01). Compared with APP/PS1 dtg mice, the transversing frequency of APP/PS1+RSG mice and APP/PS1+curcumin-H mice were significantly augmented (P<0.05), the transversing frequency of APP/PS1+curcumin-M group was markedly augmented (P<0.01). Compared with APP/PS1+RSG mice, the transversing frequency of APP/PS1+curcumin-H and APP/PS1+curcumin-L was significantly decreased (P<0.05) whereas APP/PS1+curcumin-M group showed no difference (P>0.05). The swimming time in target quadrant of APP/PS1+RSG group and APP/PS1+curcumin-M group was significantly extended (P<0.05) in comparison with APP/PS1 dtg mice. The swimming time in target quadrant of APP/PS1+curcumin-L group was significantly shortened compared with APP/PS1+RSG group (P<0.05) whereas neither of APP/PS1+curcumin-H and APP/PS1+curcumin-M groups showed significant difference (P>0.05).The swimming trajectory of CON demonstrated searching strategy of tendency pattern. APP/PS1+VEH displayed peripheral pattern. APP/PS1+RSG showed random pattern. All curcumin-treated group exhibited random pattern with APP/PS1+curcumin-M group spending more time in target quadrant or nearby than both APP/PS1+curcumin-L group and APP/PS1+curcumin-H group. 2. The effects of curcumin on cerebral glucose metabolism of APP/PS1 dtg mice using microPET technique microPET imaging showed that the average radioactivity of 18F-FDG ofAPP/PS1+curcumin-M group and CON group were higher than APP/PS1 dtg group.The average uptake rate of cerebral 18F-FDG of APP/PS1+curcumin-M group and CON group were higher than APP/PS1 dtg group.3. Effects of curcumin on the expression of GLUT1 in the hippocampus of APP/PS1 dtg miceResults of immunohistochemistry:Compared with CON group mice, GLUT1 positive cells of hippocampus CA1 area of APP/PS 1 dtg mice were markedly decreased (P<0.01). Compared with APP/PS 1 dtg mice, GLUT1 positive cells of hippocampus CA1 area of APP/PS1+RSG group were markedly increased(P<0.01), APP/PS 1-i-curcumin-H and APP/PS1+curcumin-M group were significantly increased (P<0.05). GLUT1 positive cells of APP/PS H-curcumin-H group were significantly reduced in comparison with APP/PS1+RSG group (P<0.05), APP/PS1+curcumin-L group reduced more (P<0.01) while no statistical difference was found with APP/PS1+curcumin-M group.The results of the average gray value were consistent with the results of immunohistochemistry.The results of Western blot: The results of the expression of GLUT1 corresponded to the above results.4. The effects of curcumin on the expression of GLUT3 in the hippocampus of APP/PS1 dtg miceResults of immunohistochemistry:Compared with CON group mice, GLUT3 positive cells of hippocampus CA1 area of APP/PS 1 dtg mice were markedly decreased (P<0.01). Compared with APP/PS 1 dtg mice, GLUT3 positive cells of hippocampus CA1 area of APP/PS1+RSG group and APP/PS1+curcumin-M were markedly increased(P<0.01), that of APP/PS1+curcumin-H group were significantly increased (P<0.05). GLUT1 positive cells of APP/PS1+curcumin-H and APP/PS1+curcumin-L groups were significantly reduced compared with APP/PS1+RSG group, APP/PS1+curcumin-M group showed no statistical significance. The results of the average gray value of GLUT3 were consistent with the results of immunohistochemistry. The results of the average gray value of GLUT3 were consistent with the results of immunohistochemistry.The results of Western blot:The result of the expression of each protein corresponded to the above results.5. The effects of curcumin on the expression of IRS2 in the hippocampus of APP/PS 1 dtg miceResults of immunohistochemistry:Compared with CON group mice, IRS2 positive cells of hippocampal CA1 area of APP/PS1 dtg mice and APP/PS1+curcumin-L group were markedly decreased (P<0.01), APP/PS1+curcumin-H group and APP/PS1+curcumin-M groups were significantly decreased (P<0.05). Compared with APP/PS 1 dtg mice. IRS2 positive cells of hippocampus CA1 area of APP/PS1+RSG group and APP/PS1+curcumin-M were significantly increased (P<0.05). The IRS2 positive cells of APP/PS1+curcumin-H group was significantly decreased (P<0.05) in comparison with APP/PS1+RSG group, APP/PS1+curcumin-L group was decreased more (P<0.01) There was no statistical significance between APP/PS 1+curcumin-M group and APP/PS1+RSG group. The results of the average gray value of IRS2 were consistent with the results of immunohistochemistry.ConclusionThe potential neuroprotective role of curcumin is accomplished by improving cerebral glucose metabolism and affecting the hippocampal expression of energy metabolism-related proteins such as GLUT1,GLUT3 and IRS2.