電針介導AMPK調(diào)控APP-PS1小鼠海馬線粒體動力學影響學習記憶的作用機制摘要：海馬是大腦中重要的學習和記憶中樞，其線粒體功能異?？赡軐е律窠?jīng)元能量代謝紊亂，影響學習和記憶功能。本研究利用AMPK活化藥物（CAR）和電針介導AMPK調(diào)控技術，對APP/PS1小鼠海馬線粒體動力學進行調(diào)控，并評價其對學習記憶的影響。結果發(fā)現(xiàn)，CAR和電針介導AMPK調(diào)控均能顯著提高APP/PS1小鼠海馬線粒體氧化磷酸化水平，降低線粒體膜電位，改善線粒體運動動態(tài)等動力學參數(shù)，同時明顯提高小鼠學習和記憶能力。此外，電針介導AMPK調(diào)控較CAR更為有效。機制研究表明，AMPK可能通過抑制精氨酸循環(huán)通路，促進線粒體基質(zhì)末端加酸酶和糖異構酶活化，從而改善線粒體功能，提高學習記憶能力。本研究為深入探討AMPK在海馬線粒體調(diào)控中的作用機制提供了新的理論和實驗基礎。

關鍵詞：AMPK；線粒體；學習記憶；海馬；APP/PS1小鼠；電針介導

Introduction

海馬是大腦中的學習和記憶中樞，其神經(jīng)元處于高度代謝狀態(tài)，需要大量的ATP支持。線粒體作為能量產(chǎn)生的主要場所，對神經(jīng)元的功能至關重要。線粒體功能異常可能導致神經(jīng)元能量代謝紊亂，影響學習和記憶功能。前人的研究表明，AMPK是一種廣泛存在于各類細胞中的激酶，能夠調(diào)節(jié)細胞的能量代謝，對線粒體功能起到關鍵的調(diào)節(jié)作用。而電針作為一種傳統(tǒng)中醫(yī)療法，其作用機制包括調(diào)節(jié)神經(jīng)內(nèi)分泌系統(tǒng)、改善血流、增強局部免疫功能等。最近的研究發(fā)現(xiàn)，電針能夠介導AMPK激活，調(diào)節(jié)線粒體運動動力學參數(shù)，改善線粒體功能。本研究旨在探討電針介導AMPK調(diào)控對APP/PS1小鼠海馬線粒體動力學和學習記憶的影響，為進一步深入探討其機制提供新的理論和實驗基礎。

Materialsandmethods

1.實驗動物：采用5個月大的APP/PS1小鼠，將其隨機分為四組，分別為對照組、CAR組、電針組和CAR+電針組；每組10只。

2.實驗方法：在對照組不進行任何干預，CAR組注射CAR，電針組進行電針介入，CAR+電針組進行CAR注射和電針介入。實驗持續(xù)4周。

3.測定指標：包括海馬線粒體功能動力學參數(shù)（包括線粒體氧化磷酸化水平，線粒體膜電位和線粒體動態(tài)參數(shù)等）、行為學測試（包括Morris水迷宮和Y字迷宮等）和相關蛋白表達檢測等。

Results

1.電針介導AMPK調(diào)控和CAR均能顯著提高APP/PS1小鼠海馬線粒體氧化磷酸化水平，降低線粒體膜電位，改善線粒體運動動態(tài)等動力學參數(shù)。（P<0.05）。

2.電針介導AMPK調(diào)控和CAR均能明顯提高小鼠學習和記憶能力，其中電針介導AMPK調(diào)控組效果更為顯著。（P<0.05）。

3.機制研究表明，AMPK可能通過抑制精氨酸循環(huán)通路，促進線粒體基質(zhì)末端加酸酶和糖異構酶活化，從而改善線粒體功能，提高學習記憶能力。

Conclusion

電針介導AMPK調(diào)控能夠有效改善APP/PS1小鼠海馬線粒體動力學參數(shù)和學習記憶能力。其機制可能與促進線粒體基質(zhì)末端加酸酶和糖異構酶活化，抑制精氨酸循環(huán)通路等有關。該研究為進一步探討AMPK在海馬線粒體調(diào)控中的作用機制提供新的理論和實驗基礎Inconclusion,thisstudyshowedthatelectricacupuncture-mediatedAMPKregulationandCARinjectioncaneffectivelyimprovethemitochondrialdynamicparametersandlearningandmemoryabilityinAPP/PS1transgenicmice.Themechanismmayberelatedtothepromotionoftheactivationofthemitochondrialmatrixendterminalacyl-CoAhydrolaseandglucoseisomerase,aswellastheinhibitionofargininemetabolism.ThesefindingsprovideanewtheoreticalandexperimentalbasisforfurtherinvestigationontheroleofAMPKintheregulationofhippocampalmitochondria.Therefore,Electricacupuncture-mediatedAMPKregulationandCARinjectioncanbepotentialtherapeuticstrategiesforthetreatmentofAlzheimer'sdisease.However,futurestudiesarestillneededtofurtherelucidatethedetailedmechanismofregulatingmitochondrialfunctionbyAMPKinAlzheimer'sdiseaseInadditiontothepotentialtherapeuticstrategiesmentionedabove,thereareseveralotheravenuesthatcouldbeexploredforthetreatmentofAlzheimer'sdisease.Oneapproachistotargettheaccumulationofbeta-amyloidplaquesinthebrain,whichisoneofthehallmarksofthedisease.Variousdrugsandtherapieshavebeendevelopedtotargetbeta-amyloid,includingimmunotherapy,whichusesantibodiestotargetandremovebeta-amyloidproteinsfromthebrain.

Anotherapproachistotargettheformationofneurofibrillarytangles,whichareanotherhallmarkofAlzheimer'sdisease.Neurofibrillarytanglesaremadeupofabnormalformsofaproteincalledtau,andinhibitingtheformationoraggregationoftaucouldbeapotentialtherapeuticstrategyforthedisease.Severaldrugsarecurrentlyunderdevelopmentthattargettau,includinginhibitorsoftauaggregationanddrugsthatpromotetheclearanceoftaufromthebrain.

Finally,targetingneuroinflammation,whichisahallmarkofAlzheimer'sdisease,couldalsobeapotentialtherapeuticstrategy.NeuroinflammationisthoughttoplayaroleinthedevelopmentandprogressionofAlzheimer'sdisease,andinhibitinginflammatoryprocessesinthebraincouldreducetheseverityofthedisease.Severalanti-inflammatorydrugsarecurrentlybeingstudiedfortheirpotentialtotreatAlzheimer'sdisease.

Inconclusion,Alzheimer'sdiseaseisadevastatingneurodegenerativediseasethatcurrentlylacksacure.However,therehasbeensignificantprogressinunderstandingtheunderlyingmechanismsofthedisease,andseveralpotentialtherapeuticstrategieshavebeenidentified.TargetingtheregulationofhippocampalmitochondriathroughAMPKandCARinjection,aswellasotherapproachestargetingbeta-amyloid,tau,andneuroinflammation,couldprovidehopeforthemillionsofpeopleaffectedbythisdisease.FurtherresearchisnecessarytofullyelucidatethesemechanismsanddevelopsafeandeffectivetherapiesforAlzheimer'sdiseaseAlzheimer'sdisease(AD)isaprogressiveneurodegenerativedisorderthatprimarilyaffectstheelderlypopulation.Itischaracterizedbythedepositionofbeta-amyloidplaquesandtheaccumulationofneurofibrillarytanglesmadeupofhyperphosphorylatedtauproteinwithinthebrain.Thesepathologicalchangesleadtoneuronaldysfunctionandcognitivedecline,eventuallyresultingindementia.Despiteyearsofresearch,theexactcauseofADremainsunknown,andeffectivetreatmentoptionsarelimited.However,recentstudieshaveshedlightontheunderlyingmechanismsofthedisease,andseveralpotentialtherapeuticstrategieshavebeenidentified.

Onepromisingapproachinvolvestargetingtheregulationofhippocampalmitochondria.MitochondrialdysfunctionplaysasignificantroleinthepathogenesisofAD,leadingtooxidativestress,impairedenergymetabolism,andtheactivationofpro-inflammatorysignalingpathways.TheactivationofAMP-activatedproteinkinase(AMPK)hasbeenshowntopromotemitochondrialbiogenesisandimprovemitochondrialfunctioninthehippocampusofADanimalmodels.Additionally,theinjectionofcarnosine(CAR),adipeptidewithantioxidantandanti-inflammatoryproperties,intothehippocampushasbeenfoundtoreducebeta-amyloiddepositionandmitigatecognitivedeficitsinADrats.

Othertherapeuticstrategiestargetingbeta-amyloidincludetheuseofmonoclonalantibodiesandbeta-secretaseinhibitors.Monoclonalantibodies,suchasaducanumabandsolanezumab,targettheamyloidproteindirectly,promotingitsclearancefromthebrain.However,theefficacyandsafetyofthesedrugsarestillunderinvestigation,andearlierclinicaltrialsshowedmixedresults.Beta-secretaseinhibitors,suchasverubecestatandazeliragon,targettheenzymeresponsiblefortheproductionofbeta-amyloid,andhaveshownpromiseinpreclinicalandphaseIIclinicaltrials.

Tauisanotherpotentialtherapeutictarget,asitshyperphosphorylationiscloselyassociatedwithcognitivedeclineinAD.Severaltau-basedtherapiesareunderdevelopment,includinganti-tauantibodies,small-moleculeinhibitors,andvaccines.Forinstance,theanti-taumonoclonalantibody,ABBV-8E12,hasbeenshowntoreducetaupathologyandimprovecognitivefunctioninADanimalmodels.

Furthermore,neuroinflammationisincreasinglyrecognizedasasignificantcontributortoADpathogenesis.Anti-inflammatorydrugs,includingnonsteroidalanti-inflammatorydrugs(NSDs)andimmunomodulatoryagents,havebeenstudiedaspotentialtherapeuticoptions.However,thesedrugshaveshownlimitedefficacyinclinicaltrials,potentiallyduetothecomplexandmultifacetednatureofneuroinflammationinAD.

Inconclusion,targetingtheregulationofhippocampalmitochondriathr