Downregulated Expression Of Monocarboxylate Transporters Is Involved In Long-term Memory Deficits In An APP/PS1Transgenic Mouse Of Alzheimer’s Disease

BackgroundAlzheimer’s disease (AD) is a chronic neurodegenerative disease. Aprominent symptom in AD patients is the inability to consolidate long-termmemory (LTM), which results in progressive memory deterioration in elderpeople. Memory deficits disrupt patients’ lives and pose substantial psychicand economic burden on their families as well as on society. Therefore, thesevere memory dysfunction in AD requires therapies that can effectivelylead to recovery of memory function.Physically, the brain exhibits high energy metabolism to meet theenergy needs of numerous neuronal activities, particularly the formation ofLTM. Numerous studies have shown that hypometabolism in the brain mayprecede and contribute to a pathologic cascade that results in memorydeficits in AD.The monocarboxylate transporter (MCTs) family consists of14transmembrane protein members that are involved in lactate transport, whichis crucial for the neuron-glia metabolic coupling between neuronal activityand metabolism. In the central nervous system (CNS), MCT1and MCT4,which are expressed in astrocytes, are involved in lactate release into theextracellular space; MCT2is present in neurons and is responsible for lactate uptake. Previous studies emphasize that LTM is associated withMCTs-mediated neuron-glia metabolic coupling in the brain.ObjectiveTo investigate the relationship between monocarboxylate transporters(MCT1, MCT2, MCT4) and LTM deficit in an APP/PS1transgenic mousemodel of AD. The outcome of the present study will provide an experimentalevidence for exploring the mechanism of LTM impairment in AD.MethodsThe present study was consists of two parts. Part Ⅰ, the mice were usedto determine the correlation between LTM function and MCTs expression inthe brain. Part Ⅱ, curcumin was given to APP/PS1mice, and its effects onMCTs expression and LTM function were determined.Part Ⅰ,4.5-month-old APP/PS1double transgenic mice andage-matched nontransgenic wile-type (WT) C57BL/6J mice with the samegenetic background were conducted in this part. The male mice were dividedinto the WT mice group (n=6) and APP/PS1mice group (n=6). Morris watermaze test were performed to detect spatial learning and memory function ofthe mice; Immunochemical staining and double immunofluorescence wereused to examine the expression of the Senile Plaque (SP), MCT1, MCT2,MCT4and memory-related proteins, activity-regulated cytoskeletal protein(Arc), phosphorylated Cofilin and phosphorylated cAMP responseelement-binding protein (pCREB) in the brain of the mice; Western blotwere used to detect the protein levels of MCT1, MCT2, MCT4andmemory-related proteins in the brain of the mice.Part Ⅱ, the APP/PS1mice were assigned into the PBS-treated micegroup (n=6) and curcumin-treated mice group (n=6). Curcumin and the same amount of PBS were intraperitoneally administered at a dose of50mg/kg/day. The treatment lasted for four weeks. Morris water maze testwere performed to detect spatial learning and memory function of the mice;Western blot were used to detect the protein levels of MCT1, MCT2, MCT4,memory-related proteins and insulin-like growth factor (IGF-1) in the brainof the mice.ResultsPart Ⅰ,(1) Morris water maze tests: in the hidden platform test, theaverage escape path length and escape latency in4.5-month-old APP/PS1mice were significantly longer than those of WT mice (P＜0.05); in thespatial probe test, compared with WT mice, the APP/PS1mice exhibited lessplatform-passing times and the time spent in the target quadrant (P＜0.05).(2) Morphological tests:①Immunochemical staining showed that none ofsenile plaques was found in the WT mice cerebral cortex and hippocampus.Numerous amyloid plaques stained with Aβ antibody were presented incerebral cortex and hippocampus of4.5-month-old APP/PS1mice. Thenumber of SP in the APP/PS1mice were significantly increased (P＜0.05);②Immunochemical staining and double immunofluorescence showed thatMCT1-, MCT2-and MCT4-positive cells were distributed in the cerebralcortex and hippocampus in the mice. At the cellular level, MCT1wasexpressed in astrocytes, MCT2and MCT4was expressed in neurons;Compared with the WT mice, the expressions of MCT1, MCT2and MCT4in APP/PS1mice were significantly decreased (P＜0.05);③Immunochemical staining and double immunofluorescence showed thatArc-, pCofilin-and pCREB-positive cells were distributed in the cerebral cortex and hippocampus in the mice, and Arc-, pCofilin-andpCREB-positive cells were expressed in neurons. Compared with the WTmice, the expressions of Arc, pCofilin and pCREB in APP/PS1mice weresignificantly decreased (P＜0.05).(3) Protein level tests: Western blottingshowed that MCT1, MCT2and MCT4levels in APP/PS1mouse brainsignificantly decreased compared with those of WT mice (P＜0.05);meanwhile, the expression of Arc, pCofilin and pCREB decreased in theAPP/PS1mice than those of WT mice (P＜0.05).Part Ⅱ,(1) Morris water maze tests: in the hidden platform test, theaverage escape path length and escape latency in curcumin-treated APP/PS1mice were significantly decreased than those of PBS-treated APP/PS1mice(P＜0.05); in the spatial probe test, compared with PBS-treated APP/PS1mice, the curcumin-treated APP/PS1mice exhibited more platform-passingtimes and the time spent in the target quadrant (P＜0.05);(2) Protein leveltests:①Western blotting showed that MCT1, MCT2and MCT4levels incurcumin-treated APP/PS1mouse brain significantly increased comparedwith those of PBS-treated APP/PS1mice (P＜0.05);②T he expression ofArc, pCofilin and pCREB increased in the curcumin-treated APP/PS1micethan the PBS-treated APP/PS1mice (P＜0.05);③The protein level of IGF-1,which activates the expression of MCT1and MCT2, increased incurcumin-treated APP/PS1mice compared with that in PBS-treatedAPP/PS1mice (P＜0.05).Conclusions1. The down-regulated MCT1, MCT2and MCT4in the APP/PS1mice might impair the energy metabolism between astrocytes and neurons,which contributed to impaired expression of memory-related proteinsand subsequently LTM deficits.2. Curcumin can ameliorate memory deficits in the APP/PS1mice,possibly because it promotes MCTs expression and thus enhancesneuron-glia metabolic coupling and the expression of memory-relatedproteins in APP/PS1mouse brain.