Tau Mediates Kev Paub Txog Kev Ruaj Ntseg Hauv Alzheimer's Disease Patients Los Ntawm Kev Ua Haujlwm CGAS-IFN Txoj Kev hauv Microglia
Apr 25, 2023
Alzheimer's disease (AD), uas feem ntau tshwm sim ntawm qhov pib dementia lig, muaj lub sijhawm ntev asymptomatic thaum lub sijhawm amyloid-beta plaques thiab tau aggregates tau nce zuj zus, nws thiaj li nkag mus rau lub sijhawm cov tsos mob nrog kev paub tsis meej thiab lwm yam tsos mob. Txawm hais tias tus txheej txheem ntawm kev hloov pauv no tsis paub, nws zoo ib yam nrog kev hloov pauv hauv lub cev tiv thaiv kab mob, cov hlab ntsha, thiab cov metabolism. Ib leeg nucleotide polymorphisms nyob rau hauv lub cev tiv thaiv kab mob yog txuam nrog rau kev raug rau sporadic lig-pib pib AD, tawm tswv yim tias tsis zoo innate lub cev tiv thaiv kab mob ua rau kev txawj ntse poob.
Nyem rau cistanche tubulosa capsules rau Alzheimer's kab mob
Txoj kev tiv thaiv kab mob tiv thaiv kab mob yog upregulated hauv AD thiab tswj cov kab mob microglial teb, suav nrog kev tiv thaiv kab mob / kev tawm tsam, thiab synapse pruning hauv kev laus, thiab cov kab mob neurodegenerative. Cyclic GMP-AMP synthetase (cGAS) yog ib qho tshuaj tiv thaiv kab mob DNA tseem ceeb uas khi ob txoj hlua DNA (dsDNA) thiab ua rau kev tsim cov cyclic GMP-AMP (cGAMP), yog li ua kom lub zog ntawm interferon noob (STING). STING nrhiav TANK-binding kinase 1 (TBK1) thiab txhawb nqa TBK1 autophosphorylation kom qhib hom -1 interferon (IFN-I) qhia.
Cov kev tshawb fawb tau pom tias txoj hauv kev cGAS-STING ua rau muaj kev cuam tshuam IFN-I ua kom muaj ntau yam kab mob neurodegenerative, suav nrog Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), thiab Huntington's disease (HD). cGAS-STING activation exacerbates amyloid-pathology hauv 5xFAD nas. Txawm hais tias tau qhib txoj hauv kev cGAS-STING thiab nce NF-κB signaling nyob rau hauv microglia hauv vitro, yuav ua li cas cGAS ua kom lub hlwb ua rau muaj kev paub txog kev poob qis tseem tsis paub.
Thaum Lub Plaub Hlis 24, 2023, Li Gan pab neeg ntawm Weill Cornell Medicine (co-sau li Joe C. Udeochu1, Sadaf Amin, thiab Yige Huang) tau luam tawm tsab xov xwm Tau ua kom microglial cGAS-IFN txo MEF2C-mediated cognitive resilience hauv Nature Neuroscience. Hauv txoj kev tshawb no, cov kws sau ntawv tshawb fawb txog kev ua kom lub cGAS-STING-IFN qhia txoj hauv kev hauv microglia los ntawm nas nrog P301S tau pathology thiab los ntawm tib neeg cov neeg mob AD.
Siv cov kev coj cwj pwm, electrophysiological, thiab ib leeg-nuclear (sn) RNA-sequencing mus kom ze, peb qhia tau hais tias Cgas knockdown muaj zog tiv thaiv cov teebmeem cuam tshuam nrog synaptic thiab kev txawj ntse tsis txaus ntxias los ntawm MEF2C transcriptional network, MEF2C yog ib tug noob txuam nrog kev txawj ntse resilience. Ib leeg-cell nuclear (sn) RNA-sequencing tsom xam ntawm AD cov neeg mob kuj qhia dysregulation ntawm IFN-I noob hauv microglia thiab MEF2C transcriptional network hauv neurons.
Txoj kev cGAS-STING ua haujlwm li cas hauv microglia? Raws li ib tug sensor ntawm cytosolic DNA, cGAS tej zaum yuav qhib tau los ntawm mitochondrial los yog nuclear DNA to. Cov kws tshawb nrhiav pom tias tom qab tau yog phagocytized, nws muaj nyob hauv mitochondria thiab lysosomes, thiab tau fibers tuaj yeem ua rau kev tso tawm ntawm mtDNA rau hauv cytoplasm. Los ntawm depleting mtDNA, cov lus teb tau-induced interferon yog attenuated nyob rau hauv ib koob tshuaj raws li mtDNA concentration.
Los ntawm Morris dej tshawb nrhiav, cov kws tshawb nrhiav pom tias Cgas knockout tau txhim kho qhov kev kawm thiab kev nco txog ntawm P301S nas. Tau-induced defects nyob rau hauv hippocampal synaptic plasticity yog txuam nrog kev nco tsis txuam nrog tau pathology. Kev ntsuas lub sij hawm ntev (LTP) tshwm sim los ntawm Theta burst stimulation (TBS) nyob rau hauv hippocampus qhia lig LTP deficiency nyob rau hauv P301S nas, uas tau cawm los ntawm knockout ntawm Cgas noob. Kev ntsuas ntxiv PSD-95, ib qho cim ntawm excitatory postsynaptic terminals nyob rau hauv CA1 cheeb tsam ntawm hippocampus, cov kws tshawb fawb pom tias knockdown ntawm Cgas gene ameliorated tau pathology-induced PSD -95 txo qis hauv CA1 pyramidal neurons.
Siv snRNA-seq, peb pom tias kev tiv thaiv tau muab los ntawm cGAS inactivation yog txuam nrog kev txhawb nqa kev sib txuas lus ntawm kev paub txog kev txawj ntse gene MEF2C. MEF2C yog ib qho kev pheej hmoo AD, thiab kev hloov pauv hauv MEF2C qhov chaw muaj feem cuam tshuam nrog qhov sib txawv ntawm tib neeg kev txawj ntse. Hauv kev tshuaj ntsuam snRNA-seq, MEF2C yog ib qho ntawm cov genetic upregulated tshaj plaws nyob rau hauv txawv gene qhia (DEG) tom qab Cgas knockdown. Ob lub roj knockout thiab cGAS pharmacological inhibitor TDI-6570 induced MEF2C lub hom phiaj noob qhia nyob rau hauv tau nas neurons, tawm tswv yim tias upregulated MEF2C underlies lub kev txawj ntse tiv thaiv mechanism.
Ntawm MEF2C lub hom phiaj cov noob, Cgas knockdown tau hloov pauv cov noob sib txuas koom nrog hauv axon kev taw qhia, dendrite outgrowth, synapse txij nkawm, calcium signaling / homeostasis, thiab neuronal excitability nyob rau hauv ob qho tib si excitatory thiab inhibitory hippocampal neurons. Siv cov STING agonist DMXAA, peb pom tau hais tias ua kom lub STING-IFN axis downregulates kev qhia ntawm Mef2c thiab nws lub hom phiaj noob nyob rau hauv neurons los ntawm interferon-alpha / beta receptor 1 (IFNAR1).
Hauv kev xaus, txoj kev tshawb fawb no txuas cov lus teb rau cov tshuaj tiv thaiv kab mob siab rau cGAS-IFN kom txo tau MEF2C-txog kev paub txog kev txawj ntse, lees paub tias cov tshuaj tiv thaiv kab mob hauv lub cev tsis zoo ua rau muaj kev cuam tshuam ntau ntxiv rau kev paub tsis meej. Hauv kab mob, cGAS overactivation txhawb nqa microglial IFN-I cov lus teb, txo cov kev ua haujlwm neuronal MEF2C transcriptional, thiab ua rau poob ntawm kev txawj ntse resilience. cGAS knockdown attenuates microglial IFN-I cov lus teb thiab txhim kho neuronal MEF2C transcriptional tes hauj lwm thiab kev txawj ntse resilience txuam nrog tau pathology. Inhibition ntawm cGAS nrog TDI-6570 txhim kho MEF2C lub hom phiaj cov noob thiab rov qab kho cov synaptic kev ncaj ncees thiab kev nco, txhawb kev kho lub peev xwm ntawm lub hom phiaj ntawm cGAS-MEF2C axis los txhim kho kev txawj ntse tiv thaiv AD-txog dementia.
Dab tsi yog qhov mechanism ntawm Cistancheanti-Alzheimer tus kab mob nyhuv
Muaj qee qhov kev tshawb fawb tawm tshiab qhia tias Cistanche tuaj yeem tiv thaiv Alzheimer's kab mob los ntawm nws lub peev xwm los ua kom lub hlwb tau txais txiaj ntsig neurotrophic (BDNF), txo oxidative kev nyuaj siab, thiab txhawb kev tiv thaiv neuroprotection.
Ib txoj kev tshawb fawb luam tawm nyob rau hauv Phau Ntawv Xov Xwm ntawm Ethnopharmacology pom tias kev kho mob nrog Cistanche tubulosa extracts txhim kho kev nco thiab kev txawj ntse hauv cov nas nrog Alzheimer's kab mob zoo li cov tsos mob los ntawm kev nce qib ntawm BDNF hauv hippocampus, lub paj hlwb qhov tseem ceeb rau kev kawm thiab kev nco. BDNF yog ib qho protein uas txhawb kev loj hlob, muaj sia nyob, thiab kev sib txawv ntawm cov neurons thiab paub tias yuav poob rau cov tib neeg uas muaj kab mob Alzheimer.
Lwm cov kev tshawb fawb tau qhia tias Cistanche tuaj yeem tiv thaiv lub hlwb tiv thaiv kev puas tsuaj los ntawm oxidative kev nyuaj siab los ntawm kev tshem tawm cov dawb radicals thiab txhawb kev tiv thaiv antioxidant. Nws kuj tseem tuaj yeem muaj cov teebmeem neuroprotective los ntawm kev tswj kev mob, inhibiting apoptosis (programmed cell tuag), thiab txhim kho mitochondrial muaj nuj nqi.
