Macroautophagy Thiab Mitophagy nyob rau hauv Neurodegenerative Disorders: Tsom Rau Kev Kho Mob Ntu 4

Tsis tas li ntawd, dhau li ntawm mitophagy, mHTT cuam tshuam kev lag luam mitochondrial, txij li HTT aggregates tuaj yeem ua rau lub cev tsis muaj zog ntawm cov kab mob hauv nruab nrog cev, whereasdiffuse mHTT kuj tuaj yeem cuam tshuam nrog kev lag luam adapter proteins, cuam tshuam rau mitochondrialand autophagosomal dynamics [314].

Cov kev tshawb fawb tsis ntev los no tau pom tias cov protein tseem ceeb heev rau peb lub cim xeeb. Protein yog ib qho tseem ceeb uas ua rau lub cev cov hlwb. Nws tsis tuaj yeem pab peb ntxiv dag zog rau peb cov leeg thiab txhim kho peb cov kev tiv thaiv, tab sis cov tshuaj no muaj txiaj ntsig zoo rau peb lub cim xeeb.

Protein muaj cov amino acids tseem ceeb, uas yog cov amino acids uas peb lub cev tsis tuaj yeem tsim los ntawm nws tus kheej thiab yuav tsum tau ntxiv los ntawm cov khoom noj. Cov amino acids no tuaj yeem pab txhawb kev loj hlob ntawm cov neurons, yog li txhim kho kev ua haujlwm ntawm lub paj hlwb. Kev loj hlob muaj zog thiab kev ua haujlwm ntawm lub paj hlwb ncaj qha cuam tshuam rau peb lub peev xwm xav.

Tsis tas li ntawd, peb lub hlwb tsis tsuas yog xav tau carbohydrates los muab lub zog tab sis kuj xav tau cov protein kom tswj cov metabolism hauv ib txwm. Kev noj cov protein ntxiv tas mus li tuaj yeem pab peb tswj lub hlwb cov metabolism hauv ib txwm, yog li txhawb kev ua haujlwm ntawm lub cim xeeb. Qhov no yog vim li cas qee qhov kev tshawb fawb tau pom tias muaj kev sib raug zoo ntawm kev noj cov protein txaus thiab kev nco zoo dua.

Tau kawg, tsis yog tag nrho cov proteins yog tib yam. Txhawm rau txhim kho kev nco, peb yuav tsum xaiv cov khoom noj uas muaj cov protein zoo. Piv txwv li, cov khoom noj uas muaj cov protein zoo xws li nqaij, ntses, qe, taum, mis nyuj, thiab lwm yam yog cov khoom noj uas peb tuaj yeem xav txog noj.

Hauv ntej, cov protein tseem ceeb heev rau kev noj qab haus huv ntawm peb lub cev thiab lub hlwb. Peb yuav tsum tswj hwm qhov tsim nyog ntawm cov protein kom tsawg thiab xaiv cov khoom noj muaj protein ntau kom peb thiaj li muaj peev xwm tswj tau qhov kev nco zoo, thiab muaj peev xwm xav tau, thiab tswj peb txoj kev noj qab haus huv zoo dua. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim tias nws tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob, uas tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov khoom noj txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub ntxiv los txhim kho kev nco

Qhov kev xav tau ntawm mHTT-induced mitochondrial dysfunction yog qhov txo qis hauv ATP ntau lawm, txwv tsis pub ATP-raws li kev ua ub no ntawm proteostasis network [315].

Dhau li ntawm kev txwv ATP, mitochondrial tsis ua haujlwm tuaj yeem ua rau cov autophagic tivthaiv ntawm proteostasis los ntawm lwm cov txheej txheem. Piv txwv li, mitochondrial dysfunction yuav cuam tshuam ER-mitochondrial chaw sib cuag, uas cuam tshuam rau kev tsim autophagosome [316].

Ib yam li ntawd, mitochondrial dysfunction muaj feem cuam tshuam rau qhov txawv txav ntawm mitochondria-lysosome reciprocal regulation [316] thiab impaired lysosomalfunction [317], uas yuav cuam tshuam qhov ua tiav ntawm autophagy.

4. Cov tswv yim kho mob

4.1. Targeting Macroautophagy thiab Mitophagy hauv AD

Cov kev kho AD tam sim no feem ntau ncua cov tsos mob yam tsis tau tsom rau cov txheej txheem pathogenic. Lub xub ntiag ntawm misfolded proteins thiab kev puas tsuaj ntawm autophagy yog ob qho tseem ceeb ua rau AD; Yog li, autophagy yog ib txoj hauv kev kho tau rau AD.

Txawm hais tias nws yog qhov xav tias qhov induction ntawm autophagy tej zaum yuav yog ib qho kev cog lus kho mob, kev cuam tshuam ntawm ob peb kauj ruam ntawm autophagic flux tau piav qhia hauv ADcomplicates qhov kev xav no. Ntxiv mus, yuav tsum tau ceev faj thaum kawm txog cov nyhuv ntawm autophagy-targeting tshuaj nyob rau hauv ntau theem ntawm tus kab mob.

Ib qho ua tau los ua kom autophagy yog los ntawm kev hloov pauv ntawm kev tswj hwm kev taw qhia txoj hauv kev mus rau autophagy induction. Txoj kev mTORC1 yog qhov tsim tau zoo ntawm cov neeg ua haujlwm hauv kev tswj hwm autophagy thiab yog dysregulated hauv AD, tsim kom muaj lub hom phiaj kho mob. Rapamycin yog ib qho tshuaj uas tau pom zoo los ntawm FDA uas inhibits mTORC1 kev ua, ua rau autophagy activation.

Kev kho mob mus sij hawm ntev nrograpamycin cawm tau kev paub tsis txaus ntseeg hauv ntau tus qauv nas ntawm AD [318]. Cov txiaj ntsig tau txais txiaj ntsig los ntawm rapamycin suav nrog txo qis A deposition thiab txo phosphorylation thiab tsub zuj zuj ntawm misfolded tau rau hauv NFTs [319,320].

SMER28, ib qho enhancerof rapamycin, nce autophagy los ntawm ATG5- txoj kev nyob thiab txo A peptide tsub zuj zuj [321]. Qhov tseem ceeb, kev txhim kho rapamycin-mediated tau pom thaum kho tau pib ua ntej cov tsos mob pib [322]. Raws li txoj cai, autophagyinduction nrog rapamycin tsis ua haujlwm zoo hauv kev paub txog kev paub yog A plaques thiab tangles twb muaj lawm [322].

Nyob rau theem kawg ntawm tus kab mob, cov kab mob lysosomal cuam tshuam tsis zoo, thiab kev kho mob rapamycin tseem tuaj yeem ua rau cov kab mob hnyav dua.Txawm hais tias tag nrho cov pov thawj preclinical qhia tias kev hloov pauv ntawm mTORC1 nrog rapamycinis yog ib qho kev cog lus kho mob nyob rau theem pib ntawm AD, tsis muaj kev sim tshuaj. mus txog rau tam sim no [323].

Nws yog ib qho tseem ceeb kom nco ntsoov tias mTOR yog lub hauv paus hauv paus ntawm intracellularsignaling, nrog rau cov kev cai ntawm cov noob txhais lus thiab cell homeostasis. Nws yog qhov tsim nyog xav tias qhov kev txwv ntev ntev ntawm mTOR yuav muaj kev mob tshwm sim, yog li nws tseem ceeb heev los tsim cov tshiab autophagy modulators. Lwm qhov kev cog lus zoo yog qhov kev hloov pauv ntawm autophagy-txog cov proteins uas cuam tshuam hauv AD.

Piv txwv li, ib qho kev tshawb fawb pom tias kev txhaj tshuaj ntawm lentivirus encoding beclin-1 nyob rau hauv hippocampus thiab frontal cortexof APP-transgenic nas induced autophagy thiab txo intracellular thiab extracellularA deposition [113].

Ntxiv mus, nce p62 qhia nyob rau hauv APP / PS1 nas qauv ua rau autophagy activation los ntawm mTOR-kev ywj pheej txoj hauv kev, ua rau txo qis ntawm A pathology thiab amelioration ntawm kev txawj ntse tsis txaus [324]. Cov tswv yim raws caj ces tomodulate autophagy tuaj yeem tsim kho qhov tseeb dua hauv AD cov ntsiab lus, tab sis qhov ua kom zoo dua ntawm txhua cov kauj ruam autophagic thiab cov proteins cuam tshuam hauv AD yog qhov yuav tsum tau ua ua ntej cov tswv yim kho mob siv.

Carbamazepine (CBZ) yog ib qho tshuaj tiv thaiv kab mob vwm uas pom tau tias muaj txiaj ntsig zoo hauv kev tswj hwm tus cwj pwm agitative hauv cov neeg mob AD [325]. CBZ tau pom tias inhibitmTORC1 kev ua haujlwm, yog li txhim kho autophagy thiab txo qis amyloid lub nra thiab A 42levels hauv cov qauv AD transgenic [326]. Txawm li cas los xij, nws qhov kev cuam tshuam thib ob nrog rau lwm cov tshuaj ua rau nws tsis tshua nyiam ntawm cov tshuaj tiv thaiv kab mob uas siv rau hauv cov ntsiab lus ntawm AD.

Memantine yog ib qho antagonist ntawm N-methyl-D-aspartate (NMDA) receptor thiab ib qho ntawm ob peb cov tshuaj FDA pom zoo rau cov tsos mob ntawm kev mob nruab nrab mus rau AD.

Qee cov kev tshawb fawb pom tau tias nws ua tau zoo hauv kev ua kom lub cev muaj zog, lub hlwb amyloidosis, thiab kev nco poob [327]. Ib txoj kev tshawb nrhiav pom tias memantine tuaj yeem ua rau nws txoj haujlwm los ntawm inhibiting autophagy los ntawm mTORC1 lossis Beclin-1 qhia hauv AD [328].

Contrariwise, memantine tau raug txheeb xyuas tias yog ib qho autophagy enhancer nyob rau hauv ib tug loj kev tshuaj ntsuam txoj kev tshawb no kom characterizes clinically pom zoo molecules rau hnub nyoog-txog kev mob thiab neurodegeneration [329].

Kev sib xyaw ua ke ntawm memantine nrog cholinesterase inhibitors tau siv nyob rau hauv nruab nrab mus rau qhov hnyav AD thiab pom tias muaj kev txhim kho hauv kev paub [330], tab sis xav tau kev tshawb fawb ntxiv los qhia meej txog cov txheej txheem ntawm kev txiav txim ntawm memantine raws li autophagy modulatorin AD.

Metformin yog cov tshuaj tiv thaiv kab mob ntshav qab zib uas ua rau AMPK los ntawm kev nce qib AMP thiab tau siv rau hauv cov neeg mob ntshav qab zib hom II los tiv thaiv kev dementia thiab Alzheimer-likephenotypes cuam tshuam nrog hyperinsulinemia [331]. Kev siv metformin ua monotherapy rau AD yog qhov tsis sib xws.

AMPK activation suppresses mTOR kev ua thiab inducesautophagy, yog li exacerbating autophagosome tsub zuj zuj thiab kuj A tiam los ntawm - thiab -secretase [332,333]. Metformin tau pom tias ua rau mob hnyav dua A pathology dhau los ntawm A tiam los ntawm kev hloov pauv kev tswj hwm ntawm BACE1 thiab A secretion inneuronal cell qauv [332].

Kev ua haujlwm tau zoo heev tau pom tias metformin tuaj yeem nce microglial phagocytosis thiab lysosomal acidification, txhim kho extracellular A clearance thiab tiv thaiv cov plaque tsim [334], uas tuaj yeem them nyiaj rau A generationand secretion hauv neuronal hlwb.

Lwm cov kev tshawb fawb pom tias metformin txo qis hyperphosphorylation ntawm tau los ntawm AMPK-kev ywj pheej mechanism [335]. Kev tshawb fawb ntxiv tau pom tias metformin nce qib ntawm cov kab mob tsis sib haum tau txawm tias muaj txiaj ntsig zoo ntawm lub xeev hyperphosphorylation ntawm tau [336]. Tag nrho cov kev tshawb fawb tau ua kom deb li deb los qhia txog cov txiaj ntsig ntawm metformin hauv AD tau tsim cov txiaj ntsig tsis sib haum [337].

Cov kev tsis sib xws no yog qhov tshwm sim ntawm qhov tshwm sim ntawm cov nyhuv ntawm metformin ondistinct biological pathways (saib xyuas kom meej hauv [338]) thiab kev tshawb fawb ntxiv yog yuav tsum tau hais txog seb metformin yuav tsum tau siv los ua AD kho tshuaj tiv thaiv autophagy.

Kev siv natural bioactive compounds muab rho tawm los ntawm cov zaub mov los hloov cov txheej txheem biological tau nyob rau hauv lub tsom teeb rau ob peb xyoos dhau los. Ib qho ntawm qhov zoo tshaj plaws-tus cwj pwm targetsis AMPK, ob qho tib si hauv neurodegenerative thiab metabolic ntshawv siab. Resveratrol, polyphenolfound nyob rau hauv cov txiv hmab txiv ntoo liab thiab ib qho kev lees paub SIRT1 activator, tau pom los txhawb AMPK inneurons [339].

Tsis tas li ntawd, resveratrol txo qis A qib thiab tso tawm los ntawm AMPKmediated inhibition ntawm mTOR kev ua thiab nce lysosomal degradation hauv mouseprimary neurons [340]. Ntxiv mus, kev noj zaub mov ntxiv nrog resveratrol txo qis amyloid plaque tsim thiab cawm nco tsis tau hauv cov qauv AD transgenic AD [341].

Resveratrol tuaj yeem cuam tshuam ncaj qha rau SIRT1 thiab txhawb nqa kev tshem tawm ntawm cov protein uas txawv txav los ntawm mTOR-dependent thiab ywj siab mechanisms [342]. Hauv 52- lub limtiam theem II kev sim tshuaj, resveratrol tau hais lus rau cov neeg mob AD uas muaj mob me me-rau-moderatedementia thiab tau kuaj pom nyob rau hauv qis nanomolar concentrations hauv CSF ntawm cov neeg mob no, txhais tau tias qhov sib xyaw no tuaj yeem hla BBB tab sis nrog tsis muaj bioavailability. .

Kuj ceeb tias, A 40 qib tau muaj nyob rau hauv CSF thiab cov ntshav ntawm cov placebo-tswj pab pawg ntawm qis dua piv rau cov pab pawg kho resveratrol nyob rau theem kawg ntawm txoj kev tshawb no [343], txhawb kev hla ntawm BBB thiab lub hauv paus cuam tshuam rau lub hlwb.

Txawm li cas los xij, qhov txiaj ntsig zoo ntawm resveratrol ntawm AD biomarkers xws li CSF thiab plasma A 42 lossis p-tau tsis tau kuaj pom hauv qhov kev sim ntsuas no, tej zaum yog vim cov qauv me me.

Txawm li cas los xij, resveratrol tej zaum yuav muaj txiaj ntsig zoo rau AD los ntawm kev ua kom autophagy los ntawm SIRT1 thiab mTOR-mediated signaling pathways. Quercetin yog flavonol feem ntau pom muaj nyob rau hauv dub thiab ntsuabtea uas tuaj yeem qhib AMPK. Cov kev tshawb fawb tsis ntev los no tau pom tias kev tswj hwm quercetin txo qis qhov tso tawm thiab tau hyperphosphorylation thiab ameliorated kev paub txog kev ua haujlwm hauv triple transgenic AD nas qauv [344].

Ntxiv mus, kev kho mob mus sij hawm ntev nrog quercetin tau pom tias muaj kev tiv thaiv hauv neurodegeneration yog siv ua ntej qhov tshwm sim ntawm AD histopathological alterations nyob rau hauv tib tus qauv [344]. Qhov ua tau ntawm kev hloov pauv ntawm autophagy los ntawm resveratrol lossis quercetin hauv AD txhawb kev tshawb fawb ntxiv astherapeutic cov tswv yim.Modulation ntawm GSK3 kev ua haujlwm kuj tseem tuaj yeem tsim cov tswv yim kho tshiab rau AD [345].

GSK3 tswj cov qib phosphorylation ntawm tau thiab PSEN thiab tuaj yeem hloov kho lysosomal acidification thiab txo A ntau lawm [346]. Curiously, nws tau npaj siab tias qhov txiaj ntsig zoo ntawm GSK3 inhibition tshwm sim los ntawm kev rov ua haujlwm ntawm mTOR thiab kev tawm tsam ntawm autophagy, uas, dhau los, ua kom muaj kev txawj ntse hauv 5xFAD nas qauv.

Lwm cov kev tshawb fawb tau sib cav txog kev tiv thaiv ntawm mTOR kev hloov kho hauv AD; activation ofmTOR txhim kho kev paub tsis txaus ntseeg thiab tau cuam tshuam nrog kev txo qis hauv A -associatedevents [347,348].

Lithium, lub siab stabilizer siv rau cov kab mob bipolar, tau raug kuaj raws li cov tshuaj apotential kho rau AD [349,350]. Lithium tswj ntau cov txheej txheem biochemical, ntawm lawv qhov inhibition ntawm GSK3 thiab kev hloov pauv ntawm phosphatidylinositidecascade [351]. Kev noj cov lithium los ntawm mutant tau transgenic nas ncua kev tsim cov neurofibrillary tangles [352] thiab txo A pathology hauv Drosophila AD qauv [353].

Ntxiv mus, lithium yog ib tug zoo regulator ntawm autophagy ob leeg los ntawm ib tug mTOR-dependent txoj kev [354] thiab depletion ntawm intracellular free inositol thiab 1,4,5-inositol trisphosphate (IP3) [355], tejzaum nws los ntawm inhibition ntawm IP3 receptor signaling cascade, ib qho txawv txav-autophagy-modulatory mechanism [356].

Kev sim tshuaj ntsuam xyuas tam sim no txuas ntxiv los ntsuas qhov cuam tshuam ntawm lithium ntawm qhov pib ntawm dementia hauv cov neeg laus thiab nws qhov cuam tshuam nrog ADprogression (Clinical trial: NCT03185208).

Kev kho mob mus sij hawm ntev nrog nicotinamide txo qis qhov sib txuam ntawm A thiab hyperphosphorylated tau nyob rau hauv cortex thiab hippocampus ntawm 3xTg-AD qauv nas nrog attenuation ntawm kev txawj ntse poob [357].

Qhov no tau nrog kev txhim kho ntawm lysosomal acidification, autophagic-lysosomal muaj nuj nqi, thiab txo qis ntawm LC3-II, uas qhia txog kev txhim kho ntawm autolysosomal degradation. Tsis tas li ntawd, lwm txoj kev tshawb fawb nrog tus qauv 3xTg-ADmice tau qhia tias kev tswj hwm nicotinamide tuaj yeem hloov kho SIRT1 kev ua haujlwm thiab lysosomal proton gradient, yog li txhawb nqa autolysosome acidification [358].

Txawm hais tias nws pom muaj txiaj ntsig zoo, nicotinamide tau pom tias muaj kev zam zoo tab sis txwv tsis pub muaj txiaj ntsig kev paub txog kev txhim kho hauv theem II kev sim tshuaj nrog cov neeg mob AD tom qab 24 lub lis piam kho mob (Kev sim tshuaj ntsuam xyuas: NCT00580931) [359].

Txawm li cas los xij, lwm qhov kev sim tshuaj tau pom zoo los ntsuas nicotinamide cov txiaj ntsig ntawm tau qib hauv CSF ntawm cov neeg mob AD thaum 48 lub lis piam (Kev sim tshuaj kho mob: NCT03061474), tab sis tsis muaj cov txiaj ntsig tau tshaj tawm txog tam sim no. Txawm tias muaj txiaj ntsig zoo, nicotinamide uas tau tso tawm los ntawm adeninecotinuclear (nicotinamide). NAD +, ib qho nucleotide xav tau rau kev ua sirtuins) thaum lub sij hawm deacylationreaction ntawm sirtuins tau pom tias ua raws li qhov tsis sib tw inhibitor [360] thiab yog li tuaj yeem cuam tshuam cov teebmeem neuroprotective los ntawm cov chav kawm III lysine deacetylases.

Vim tias cov kauj ruam lig ntawm autophagic flux kuj raug cuam tshuam hauv AD, nws yog qhov ua tau tias kev kho lub hom phiaj ntawm cov kauj ruam thaum ntxov yuav tsis txaus los ua kom tag nrho cov txheej txheem rov qab thiab txo cov protein sib xyaw.

Yog li, lub hom phiaj nthuav dav rau kev tsim tshuaj yeeb yog TFEB, uas hloov kho autophagosome thiab lysosome biogenesis thiab tseem yog tus tswj hwm ntawm autophagy [149]. Nws tau pom tias overexpression ntawm TFEB txo ​​A tsub zuj zuj thiab muaj phospho-tau nyob rau hauv tangles thiab ameliorated cognitiveand synaptic deficits nyob rau hauv ob qho tib si rTg4510 thiab APP/PS1 nas qauv ntawm AD [361].

Lwm qhov kev tshawb fawb pom tias kev txhaj tshuaj ntawm TFEB rau hauv hippocampus ntawm APP / PS1 transgenic nas los ntawm tus kab mob adeno-txuas nrog rau kev txhawb nqa nws txoj kev hloov mus rau hauv cov nucleus thiab txhim kho kev ua haujlwm lysosomal thiab autophagy, uas txo qis A qib thiab amyloid plaques [155].

Tsis tas li ntawd, kev ua haujlwm ntawm astroglial TFEB ua rau kev tshem tawm ntawm cov cellular tau dhau los ntawm kev puas tsuaj, ua rau txo qis ntawm tau kis [362], uas txhawb nqa cov nyhuv neuroprotective ntawm TFEB kev hloov pauv hauv AD tau pathology. Therapeutics targeting TFEB activation yuav tsum xav txog kev zam ntawm kev cuam tshuam nrog mTOR kev ua ub no thiab cov cim qhia txog txoj hauv kev.

Kev tshawb nrhiav tshiab TFEB-targeting molecules tau nce nyob rau hauv ob peb xyoos dhau los los ntawm attenuating A tiam thiab amyloid plaque deposition nyob rau hauv AD.Vim hais tias neuronal mitophagy yog compromised nyob rau hauv AD, kev nrhiav pom ntawm mitophagyinducers tshiab yog ib txoj kev cog lus kho mob los txhawb kev tshem tawm ntawm puas mitochondria. thiab cuam tshuam cov cim qhia ntawm tus kab mob [363].

Modulation ofautophagy, tshwj xeeb tshaj yog cov kauj ruam lig, yuav tsum txhim kho mitophagy hauv AD. Piv txwv li, metformin txhawb nqa mitophagy los ntawm kev rov ua kom mTOR-dependent activation ntawm autophagy thiab Parkin-mediated mechanism [364].

Lwm txoj kev tshawb fawb pom tau hais tias kev hloov pauv ntawm autophagy nrog Nilotinib txhawb kev nce qib ntawm cov kab mob hauv lub cev ntawm Parkin uas cuam tshuam nrog Beclin1, txo A tsub zuj zuj [365]. Txawm li cas los xij, tseem tsis tau paub yog tias qhov kev hloov pauv ntawm Parkin qib los ntawm Nilotinib kuj txhawb nqa mitophagy hauv AD.

Kev hloov pauv ntawm NAD + / sirtuins txoj hauv kev yog lub hom phiaj kho mob uas xav tias yuav txhim kho mitophagy hauv AD. Kev tshuaj ntsuam xyuas tshuaj tsis ntev los no tau pom tias kev sib xyaw ntawm NAD + precursors nrog mitophagy inducers, urolithin A thiab actinonin, rov qab kho mitophagy thiab ameliorated kev txawj ntse los ntawm kev txo cov phospho-tau thiab A deposition hauv AD transgenic nematodes thiab nas qauv [163].

Supplementationwith NAD + precursors attenuated A thiab tau pathological hallmarks nyob rau hauv AD qauv inpart ntawm lub activation ntawm mitophagy [163].tag nrho, cov ntaub ntawv tsis sib haum xeeb qhia tau hais tias induction ntawm autophagy raws li ib tug generalized kho rau AD yog questionable. Stimulation ntawm autophagy tsis yog ib txwm beneficialand tej zaum yuav txawm exacerbate A pathology, ua rau siab A ntau lawm thiab secretion.

Autophagy yog tswj hwm los ntawm kev sib txuas lus sib txuas ntawm cov kab hluav taws xob sab saud uas tseem tswj hwm lwm cov txheej txheem ntawm tes. Cov nyhuv autophagy-inducing ntawm txhua yam tshuaj tsom rau ib qho ntawm cov kev cai qhia txoj hauv kev lossis cov proteins feem ntau yuav cuam tshuam rau lwm yam kev taw qhia nrog cov txiaj ntsig los yog qhov cuam tshuam. Tsis tas li ntawd, qee qhov kev kho mob autophagy-targeting ncaj qha hloov A tiam.

Qhov sib txawv ntawm cov qauv AD kuj tseem tuaj yeem cuam tshuam cov lus xaus txog autophagymodulation thiab / lossis A - thiab tau-txog cov kab mob thiab ua rau kev txhim kho ntawm kev txawj ntse tsis txaus.

Tsis tas li ntawd, qhov tsis muaj tus qauv txheej txheem los ntsuas autophagyin vivo kuj cuam tshuam qhov kev soj ntsuam kev soj ntsuam ntawm kev kho mob ntawm cov tshuaj uas ua rau autophagy hauv cov neeg mob.Nyob rau hauv xaus, kho kev loj hlob aiming autophagy yuav tsum coj mus rau hauv tus account lub multifactorial ua rau AD.

Yog li, kev tsim qauv tsim nyog ntawm AD cov tshuaj kho mob lossis kev txheeb xyuas cov tswv yim kho mob ua ke yuav tsum xav txog kev tsom mus rau ob qho tib si autophagyand APP ua lossis A tiam thiab tau pathology.

Qhov tseeb autophagy tsis xws luag, thaum twg yuav siv autophagy-modulating kev kho mob thaum lub sij hawm tus kab mob mus zuj zus, thiab lub sij hawm ntawm kev kho mob yuav tsum tau txiav txim siab thaum tsim tshiab kho cov tswv yim rau AD (Daim duab 4).

Daim duab 4. Txheej txheem cej luam ntawm kev hloov kev cai ntawm autophagy thiab mitophagy mechanisms nyob rau hauv AD-lub luag hauj lwm ntawm cov tshuaj tiv thaiv. Kev ua autophagy thiab cov proteins uas muaj feem cuam tshuam tau txo qis hauv AD. mTORC1 tau pom tias yuav nce ntxiv hauv AD, thaum nws cov inhibitors (xa mus rau hauv lub thawv liab doog) tau pom tias muaj cov txiaj ntsig zoo hauv cov qauv AD sib txawv, feem ntau ntawm lawv los ntawm kev txo qis mTORC1 qib.

Concordantly, AMPK inducer tus neeg sawv cev (xa mus rau hauv lub thawv liab liab) kuj tau pom tias muaj txiaj ntsig zoo hauv AD qauv. Ntau tus qauv AD tau pom tias muaj kev nce ntxiv ntawm autophagosome thiab txo cov lysosomal muaj nuj nqi, uas ua rau A thiab Tau oligomer tsub zuj zuj.

Ntxiv mus, inducers ntawm lysosomal muaj nuj nqi (xa mus rau hauv lub thawv xim av dashed) tau pom tias yuav txhim kho AD nta hauv cov qauv AD sib txawv. Hais txog augmented puas mitochondria, ADmodels tau pom tias txo qis kev ua haujlwm ntawm mitophagy, thaum cov neeg ua haujlwm inducer (xa mus rau hauv lub thawv blackdashed) kuj tau pom tias nce mitophagy hauv AD qauv.

Tsis tas li ntawd, qib PINK1 tau pom tias yuav txo qis hauv AD qauv, thaum cov neeg ua haujlwm inducer (xa mus rau hauv lub thawv daj daj) tau pom tias yuav nce cov qib uas muaj txiaj ntsig zoo.

4.2. Targeting Macroautophagy thiab Mitophagy hauv PD

Cov pov thawj loj hlob los ntawm PD cov qauv qhia tau hais tias cov tshuab autophagic cuam tshuam rau hauv PD, yog li macroautophagy tshwm sim raws li cov hom phiaj kho mob los txhawb kev tshem tawm cov tshuaj lom neeg.

Piv txwv li, kev tswj hwm ntawm rapamycinis txaus los tiv thaiv dopaminergic neurons los ntawm degenerating hauv nas raug rau MPTP-induced parkinsonism [366]. Kev tiv thaiv cov nyhuv ntawm rapamycin yog txuam nrog nce autophagy, txij li cov nas raug rau MPTP nrog kev kho mob rapamycin ua ntej tsis muaj qhov pom tau ntawm cov kab mob autophagosomes lig, tsis zoo li cov pab pawg uas raug rau MPTP.

Hauv lwm tus qauv ntawm PD, siv 6-OHDA-kho nas, rapamycin kuj tseem ua haujlwm zoo hauv kev kho lub cev muaj zog nrog txo qis aSyn deposition [367]. Ib yam li ntawd, Cov neeg ua haujlwm thiab cov neeg ua haujlwm tau pom zoo ua kom pom tau tias cov tshuaj intra-cerebral infusions ntawm rapamycinin cortical txheej ntawm nas overexpressing WT aSyn txo cov kev tsis sib haum xeeb pom nyob rau hauv cov txheej txheem autophagic, xws li LC3 thiab cathepsin D qhia, nrog rau augmentedclearance ntawm aSyn.

Ib txoj kev tshawb fawb siv metformin los txhim kho AMPK1-dependent autophagy qhia tau tias cov tshuaj no muaj peev xwm cawm lub cev tsis muaj zog thiab cov kab mob proinflammatory ntawm MPTP-kho nas, los ntawm kev ua haujlwm ntawm autophagy thiab kev cawm ntawm autophagic flux [369].

Txawm hais tias cov kev tshawb fawb no qhia txog qhov tseem ceeb ntawm autophagy rau clearaSyn deposits thiab txwv tsis pub cov txheej txheem neurodegenerative, kev tswj hwm ntawm autophagyproduces ntau yam tsis zoo, uas cuam tshuam rau kev kho mob ntawm ntau tus qauv [370].

Beclin-1, piv txwv li, yog qhov tseem ceeb hauv thawj kauj ruam ntawm kev tsim autophagosome thiab yog li ua lub luag haujlwm tseem ceeb hauv kev tswj hwm autophagy. Ua tau zoo, Beclin-1 lentiviral txhaj rau hauv nas overexpressing aSyn cawm qhov cuam tshuam tsis zoo ntawm aSyn pathology nyob rau hauv lub corticallayer ntawm lub hlwb los ntawm ameliorating tus naj npawb ntawm LC3- vesicles zoo thiab yog li ua rau kom tshem tawm ntawm aSyn aggregates tam sim no nyob rau hauv cov nas. [371].

Nyob rau hauv consonance nrog txoj kev tshawb no, kev ua kom Beclin-1-dependent autophagy nrog isorhynchophyllineinduced degradation ntawm aSyn oligomers nyob rau hauv dopaminergic neurons constitutively overexpressing A53T aSyn mutant daim ntawv [372]. Mitophagy yuav muaj txiaj ntsig zoo txij li Beclin-1 kev ua haujlwm txhawb nqa kev hloov pauv ntawm Parkin mus rau OMM rau qhov pib ntawm mitophagy [373].

Raws li tau piav qhia ua ntej hauv qhov kev tshuaj xyuas no, kev tshem tawm ntawm kev puas tsuaj mitochondria los ntawm mitophagy yog qhov tseem ceeb heev rau kev ua haujlwm ntawm lub paj hlwb. Tseeb, ib qho kev nce lub cev ntawm cov pov thawj qhia tau hais tias tus nqi kho mob ntawm kev tshem tawm mitochondria puas nyob rau hauv ntau cov qauv PD [374].

Pharmacological activation ntawm PINK1 los ntawm kev kho mob ntawm dopaminergic SH-SY5Y hlwb nrog ib tug neo-substrate, kinetin triphosphate, tsub kom cov phosphorylation ntawm nws substrates thiab txhawb nqa sai recruitment ntawm Parkin rau mitochondria, uas ua rau ib tug amelioration ntawm cov kev ntxhov siab vim los ntawm oxidative kev nyuaj siab. [375].

Tsis tas li ntawd, ib qho kev kawm nthuav dav siv Drosophila melanogaster qhia tau hais tias, byoverexpressing PINK1, kev tshem tawm ntawm puas mitochondria txhim kho los ntawm kev ua kom zoo dua ntawm mitochondrial axonal motility [376].

Raws li txoj hauv kev no, overexpression ntawm Parkin tau txais txiaj ntsig hauv MPTP tus qauv nas. Transgenic nas overexpressingParkin tsis tshua muaj kev cuam tshuam rau MPTP-induced dopaminergic neurodegeneration thiab tam sim no qis qis ntawm aSyn oligomers hauv striatal homogenates [377].

Ib yam li ntawd, yoov uas tau tswj hwm nrog SR3677 ROCK inhibitor uas txhawb nqa kev txhim kho mitophagy los ntawm Parkin ua kom pom tau tias txo qis kev coj tus cwj pwm tom qab paraquat thuam.

ROCK tau ua haujlwm tas li nyob rau hauv ntau tus qauv neurodegenerative thiab tseem suav tias yog autophagy modulator [378]. Remarkably, puas mitochondria raug tsav forlysosomal degradation raws li kev kho mob SR3677 [379].

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