IGF-1 LR3 txhajyog siv rau subcutaneously los yog intramuscularly, feem ntau yog siv los txhawb cov leeg kev loj hlob, ua kom cov ntaub so ntswg kho, txhim kho metabolic muaj nuj nqi, thiab tiv thaiv -aging. Nws cov txheej txheem ntawm kev ua haujlwm zoo ib yam li ntuj IGF-1, tab sis nws cov txiaj ntsig ntev dua muab nws qhov tshwj xeeb zoo hauv kev tshawb fawb thiab kev tawm dag zog. Nws qhib qhov chaw PI3K / Akt / mTOR kev taw qhia txoj hauv kev los ntawm kev khi rau IGF-1 receptor (IGF1R) ntawm lub xov tooj ntawm tes. Txoj hauv kev no yog lub hauv paus kev tswj hwm kev sib koom tes rau kev loj hlob ntawm tes, kev loj hlob, thiab cov metabolism hauv, txhawb kev hloov pauv ntawm cov piam thaj mus rau hauv cov cell membrane thiab txhim kho cov piam thaj thiab kev siv; Ib txhij inhibiting gluconeogenesis thiab txo cov ntshav qab zib. Nws tseem ncaj qha txhawb kev sib txuas ntawm cov protein, inhibits protein ntau, thiab txhawb cov leeg hlwb hypertrophy thiab proliferation. Los ntawm upregulating Cyclin D1 thiab downregulating Cyclin p21, cell division thiab regeneration yog ceev.
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IGF 1 LR3 COA
Lub paradox ntawm IGF-1 LR3 nyob rau hauv A plaque remodeling thiab kev txawj ntse txhim kho nyob rau hauv Alzheimer tus kab mob
Alzheimer's disease (AD) yog cov kab mob neurodegenerative uas tshwm sim ntau tshaj plaws, uas tshwm sim los ntawm senile plaques tsim los ntawm deposition ntawm beta amyloid protein (A), neurofibrillary tangles (NFTs) tsim los ntawm ntau phosphorylation ntawm Tau protein ntau, thiab neuronal poob. Nyob rau hauv xyoo tas los no, lub luag haujlwm ntawm insulin-zoo li kev loj hlob zoo (IGF) system nyob rau hauv pathophysiology ntawm Alzheimer's tus kab mob tau txais kev saib xyuas ntxiv. Ntawm lawv,IGF 1 LR3 Txhaj, raws li kev hloov pauv molecular IGF-1 analog, tau dhau los ua lub ntsiab lus kub hauv kev tshawb fawb txog kev kho AD vim nws lub neej ntev ib nrab thiab txhim kho kev ua haujlwm lom neeg.
A plaque remodeling: pov thawj thiab mechanism
Ib qho ntawm cov teebmeem tseem ceeb tshaj plaws ntawmIGF 1 LR3 Txhajhauv kev kho AD yog nws txoj haujlwm tswj hwm hauv A pathology, tshwj xeeb hauv kev txhawb nqa A plaque remodeling thiab tshem tawm. Tshooj lus no yuav tshawb nrhiav kom ntxaws txog cov pov thawj kev sim thiab cov txheej txheem molecular uas IGF-1 LR3 cuam tshuam rau A metabolism.
Kev tshawb fawb tau pom tias IGF-1 LR3 kev kho mob tuaj yeem hloov kho qhov muaj pes tsawg leeg thiab cov qauv ntawm A plaques. Engel et al. pom tias 5XFAD nas kho nrog intranasal LR3-IGF-1 rau 7 lub hlis tau pom qhov txo qis hauv fibrous plaques thiab nce inert plaques hauv lawv thaj chaw cortical. Kev hloov pauv ntawm hom plaque no yog qhov tseem ceeb heev, vim tias cov plaques fibrous feem ntau cuam tshuam nrog kev muaj zog neurotoxicity thiab cov lus teb inflammatory, thaum cov plaques inert kuj yog benign.
Qhov tseem ceeb tshaj, kev kho LR3 yog nrog los ntawm kev txo qis molecular hnyav A oligomers. A oligomers tam sim no suav hais tias yog cov tshuaj neurotoxic tseem ceeb hauv AD, nrog kev muaj zog toxicity dua li fibrous A thiab ze ze rau kev ua haujlwm tsis zoo ntawm synaptic thiab kev paub tsis meej. Yog li ntawd, txo A oligomers yuav yog ib qho ntawm cov txiaj ntsig tseem ceeb ntawm IGF-1 LR3 txoj kev kho.
Ib tug clearance mechanism
Cov txheej txheem los ntawm IGF-1 LR3 txhawb nqa Kev tshem tawm muaj ntau txoj hauv kev, suav nrog kev txhim kho cell phagocytosis, txhawb nqa cov enzyme degradation, thiab txhim kho vascular clearance:
Glial cell -kev kho mob phagocytosis
Kev tshawb fawb tau pom tias IGF-1 LR3 tuaj yeem txhim kho lub peev xwm phagocytic ntawm microglia thiab astrocytes ntawm A. Cov kev sim hauv vitro tau pom tias kev kho LR3-IGF-1 tuaj yeem txhim kho qhov nce ntawm A 1-42 peptide los ntawm BV-2 microglia, uas cuam tshuam nrog kev txhim kho ntawm cov noob txoj hauv kev cuam tshuam nrog kev hloov kho actin thiab endocytosis. Lub caij no, cov kev tshawb fawb tau pom tias qhov tsis muaj scaffold protein Rack1 nyob rau hauv microglia nce IGF-1 qib, uas nyob rau hauv lem txhim kho lub phagocytic muaj peev xwm ntawm astrocytes los ntawm IGF-1-IGF-1R signaling thiab txo tus deposition.
Enzyme degradation txoj kev
IGF-1 kev taw qhia tuaj yeem txhawb nqa kev qhia ntawm ntau yam A - degrading enzymes, suav nrog insulin-dependent enzyme (IDE), enkephalinase (NEP), thiab matrix metalloproteinases (MMPs). Cov enzymes no tuaj yeem degrade A mus rau hauv cov khoom me me, tsis muaj tshuaj lom, yog li txo A deposition.
Vascular clearance thiab ntshav - hlwb barrier muaj nuj nqi
IGF-1 ntseeg tau tias yuav txhim kho cov ntshav- lub hlwb thaiv kev ua haujlwm thiab txhawb nqa kev tshem tawm ntawm A los ntawm cov kua nruab nrab mus rau cov ntshav peripheral. Cov txheej txheem no suav nrog kev tswj hwm kev qhia ntawm A transporters xws li qis- ntom lipoprotein receptor txuam nrog protein 1 (LRP-1) thiab P-glycoprotein. Txawm li cas los xij, cov kev tshawb fawb tau pom tias qhov siab peripheral IGF-1 tsis tau lees paub tias muaj kev cuam tshuam rau A clearance nyob rau hauv tag nrho cov qauv, qhia tias lub luag hauj lwm ntawm IGF-1 nyob rau hauv ib tug vascular clearance tej zaum yuav nyob ntawm seb lub physiological ib puag ncig thiab kev tswj hwm txoj kev.
Kev tswj ntawm neuroinflamation
Kev tso tawm ntawm A feem ntau ua rau cov tshuaj tiv thaiv neuroinflammatory, ua kom microglia thiab astrocytes tso tawm pro- cytokines inflammatory, exacerbating neuronal puas. IGF-1 LR3 nthuav tawm cov kev tswj hwm ntawm neuroinflammation, tejzaum nws los ntawm inhibiting NF - κ B signaling txoj kev thiab txo cov tsim tawm ntawm pro-inflammatory cytokines xws li TNF - , IL-1 , thiab IL-6 kom alleviate inflammatory teb.
Kev tswj cov nyhuv thiab pov thawj ntawm IGF-1 LR3 ntawm A pathology
| Regulatory Mechanism | Kev sim ua pov thawj | Qauv System |
| Transformation ntawm plaque morphology | Fibrous plaques txo qis, inert plaques nce | 5 XFAD transgenic nas |
| Kev txo qis ntawm A oligomers | Txo cov qib qis molecular hnyav A oligomers | 5 XFAD transgenic nas |
| Phagocytosis ntawm microglia | Txhim kho qhov uptake ntawm A 1-42 peptide | BV-2 microglia |
| Phagocytosis ntawm astrocytes | Txhim kho phagocytic kev ua haujlwm kho mob los ntawm IGF-1 | Thawj astrocytes |
| Neuroinflammatory kev cai | Txo kev tso tawm ntawm pro-inflammatory cytokines | Ntau tus qauv AD |
Cov teebmeem tshwj xeeb hauv cheeb tsam
Interestingly, qhov cuam tshuam ntawm IGF-1 LR3 ntawm A pathology nthuav tawm lub hlwb thaj tsam tshwj xeeb. Kev tshawb fawb tau pom tias kev kho LR3 feem ntau pom kev txhim kho hauv A plaques hauv cerebral cortex, thaum cov nyhuv tsis tseem ceeb hauv hippocampus. Qhov sib txawv hauv cheeb tsam no tuaj yeem cuam tshuam txog qhov sib txawv ntawm IGF-1R qhia theem, glial cell ceev, lossis A deposition yam ntxwv nyob rau hauv ntau lub paj hlwb.
Qhov tsis muaj kev txhim kho hauv A pathology hauv hippocampus, thaj chaw tseem ceeb ntawm lub hlwb rau kev kawm thiab kev nco, tuaj yeem piav qhia qee yam vim li cas IGF-1 LR3 kev kho mob tsis tsim cov txiaj ntsig tseem ceeb thaum kev txhim kho tag nrho A load. Qhov kev tshawb pom no qhia tau hais tias kev kho mob AD ua tiav yuav xav tau kom muaj kev txhim kho pathological txaus hauv lub cim xeeb tseem ceeb hauv cheeb tsam hauv lub hlwb.
Kev sim ua pov thawj
Ntau qhov kev tshawb fawb tau lees paub qhov tsis muaj kev paub txog kev txhim kho hauvIGF 1 LR3 Txhajkev kho mob. Engel et al. kho 5XFAD nas nrog intranasal LR3-IGF-1 rau 7 lub hlis thiab ntsuam xyuas lawv cov kev txawj ntse los ntawm ntau yam kev ntsuam xyuas tus cwj pwm, suav nrog Morris dej maze thiab cov khoom tshiab paub. Lawv pom tias txawm hais tias cortical A pathology tau txhim kho, kev kho mob tsis tau hloov cov tsos mob ntawm kev txawj ntse. Ib yam li ntawd, hauv kev sim tshuaj tib neeg, kev nce siab ntev ntawm cov ntshav IGF-1 qib tsis tau pom cov txiaj ntsig zoo rau cov neeg mob AD hauv ib xyoos kev loj hlob hormone secretagogue sim. Qhov kev tsis sib haum xeeb no tsis yog tshwj xeeb rau IGF-1 LR3, thiab cov xwm txheej zoo sib xws tau pom nyob rau hauv lwm cov kev kho mob A tsom, xws li qee cov tshuaj tiv thaiv kab mob uas tuaj yeem tshem tawm A ntawm lub hlwb tab sis muaj cov txiaj ntsig kev txawj ntse. Qhov no qhia tau hais tias tej zaum yuav muaj qhov sib txawv tseem ceeb hauv kev nkag siab tam sim no ntawm cov txheej txheem pathological ntawm AD.
Muaj peev xwm piav qhia ntawm Paradox
Pathological complexity thiab irreversibility
AD yog ib qho kab mob ntau yam kab mob uas suav nrog tsis yog A deposition nkaus xwb, tab sis kuj muaj ntau yam kab mob xws li Tau protein lesions, neuroinflammation, synaptic dysfunction, thiab neuronal poob. Nyob rau theem kawg ntawm tus kab mob, cov kev hloov pauv pathological no tuaj yeem mus txog qhov tsis tuaj yeem rov qab los, thiab txawm tias A deposition raug tshem tawm, lwm cov txheej txheem pathological tseem yuav ua rau muaj kab mob loj zuj zus thiab kev paub tsis meej.
Tshwj xeeb tshaj yog neuronal poob, uas yog lub hauv paus tseem ceeb rau kev paub tsis meej hauv cov neeg mob AD. Thaum pib ntawm IGF-1 LR3 kev kho mob, qhov tseem ceeb neuronal poob yuav tshwm sim, thiab kev tshem tawm yooj yim ntawm A tsis tuaj yeem rov qab cov neurons ploj thiab kev sib txuas ntawm neural network.
Lub Sijhawm Kho Mob Qhov Teeb Meem
Ntau thiab ntau cov pov thawj qhia tau hais tias Txoj kev kho lub hom phiaj yuav muaj lub sijhawm kho mob tseem ceeb. Nyob rau theem pib ntawm tus kab mob, kev cuam tshuam yuav ua tau zoo dua thaum A pathology twb muaj lawm tab sis lwm cov txheej txheem hauv qab no tseem tsis tau nthuav tawm tag nrho. Nyob rau theem kawg ntawm tus kab mob, thaum lub pathological cascade cov tshuaj tiv thaiv tau pib tag nrho, kev tshem tawm yooj yim ntawm A yuav tsis txaus los hloov cov kab mob kev loj hlob.Hauv feem ntau cov kev tshawb fawb preclinical, IGF-1 LR3 kev kho mob pib tom qab A deposition tau tsim, uas tej zaum yuav plam lub qhov rais kho kom zoo. Kev tshawb fawb yav tom ntej yuav tsum tshawb xyuas qhov ua tau zoo ntawm kev cuam tshuam ntawm cov theem ua ntej ntawm tus kab mob.
Neural circuits thiab synaptic plasticity disorders
Lub sij hawm ntev raug rau A oligomers tuaj yeem ua rau muaj kev hloov pauv tsis tu ncua hauv synaptic plasticity thiab kev ua haujlwm tsis zoo ntawm cov neural circuits, txawm tias A tau raug tshem tawm, cov kev hloov pauv no tseem tuaj yeem tshwm sim. A oligomers paub tias cuam tshuam ntev -lub sij hawm potentiation (LTP), txhawb kev ntev -lub sij hawm kev nyuaj siab (LTD), thiab cuam tshuam rau neurotransmitter receptor tsheb thiab stability.Ntxiv, cov kev tshawb fawb tau pom tias txawm hais tias IGF-1 LR3 txoj kev kho tuaj yeem txo qis molecular hnyav A oligomers, nws yuav muaj kev txwv tsis pub muaj kev cuam tshuam rau lwm yam tshuaj lom A * (s. 56 los yog siab dua molecular hnyav oligomers), uas tej zaum yuav ua rau tsis muaj zog synaptic.
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