Ikev taw qhia
Raws li cov kab mob neurodegenerative uas tau lees paub ntau tshaj plaws, tsis muaj kev kho mob zoo rau Alzheimer's disease. Thaum Lub Rau Hli 3, ib tsab xov xwm luam tawm ntawm Nature Neuroscience tau tshaj tawm tias qhov ua rau Alzheimer's disease (AD) yog lysosomal acidification tsis meej, uas yog qhov feem ntau yuav ze rau qhov tseeb. Txawm li cas los xij, qhov no tsis yog qhov deb me me los ntawm kev txhim kho zaum kawg ntawm cov tshuaj rau Alzheimer's disease.
Cov yam ntxwv ntawm kev hloov pauv neuropathological hauv AD hlwb suav nrog, a Amyloid plaques tsim los ntawm protein deposition, neurofibrillary tangles (intracellular aggregates muaj li ntawm hyperphosphorylated tau proteins), synaptic poob thiab atrophy, xaiv depletion ntawm neurotransmitter systems (xws li acetylcholine) thiab Lewy lub cev (ob peb kis), uas ua rau muaj kev tsis sib haum xeeb ntawm cov ntaub ntawv. pauv ntawm neurons thiab txawm tias kev tuag ntawm neurons, thiab thaum kawg ua rau ad. Yog li ntawd, tam sim no kev xav ntawm kev txhim kho tshuaj feem ntau yog tsom rau kev tshem tawm Amyloid protein (ib Protein), tswj tau cov protein, thiab mob (acetylcholinesterase inhibitor), tab sis nyob rau hauv xyoo tas los no, kuj tseem muaj qee cov txheej txheem tshiab thiab kev kho mob ntawm AD, xws li o txoj kev xav, qia cell kho thiab kho noob. Alzheimer's kab mob neuropathology suav nrog ntau amyloid proteins- (A ) Extracellular amyloid plaques ntawm oligomers thiab intraneuronal tangles muaj phosphorylated tau. Microglia thiab astrocytes tau qhib, ua rau muaj kev sib kis ntawm neuroinflamation thiab neuropathology. A Protein cascade hypothesis a Protein yog lub ntsiab protein tivthaiv ntawm diffuse thiab neuroinflammatory plaques, uas yog los ntawm proteolysis ntawm amyloid precursor protein (APP). App yog hom 1 integrated transmembrane protein nrog a C-terminal ib feem ntawm yog embedded nyob rau hauv lub cell membrane. Tsim ib Protein yuav tsum muaj ob theem sib law liag protein hydrolysis, uas yog thawj zaug txiav txim los ntawm - secretory enzyme nyob rau hauv a N-terminal cheeb tsam ntawm qhov sib lawv liag cleaves app, tsim me ntsis soluble N-terminals (apps ） Thiab amyloid C-terminal fragment (C99), - Lub cleavage ntawm C99 los ntawm secretase tso tawm 50 residues ntawm C-terminal ntawm app, hu ua app intracellular domain (AICD) thiab a .
Nyob rau hauv tus txheej txheem ntawm nws decomposition, lysosomes nyob rau hauv hlwb siv rau feem ntau ntawm cov hauj lwm. Lysosomal acidification teeb meem ua rau cellular yuam kev nyob rau hauv zus tau tej cov a Cov protein tsis tuaj yeem decomposed ib txwm, thiab tom qab ntawd txhawb cov lysosome, ua rau cov cell tawg thiab Cov protein yog tso tawm sab nraum lub cell thiab ntxiv cov ntaub ntawv plaque.
A Proteins tuaj yeem ua rau muaj cov teeb liab cascades. Cov kev tshawb fawb tau pom tias lawv tuaj yeem txo cov synaptic plasticity (cov yam ntxwv ntawm kev hloov kho synaptic kev sib txuas lub zog (neurotransmitter tso tawm, rhiab hom cell txais synapse, thiab lwm yam) los yog txo cov synaptic ceev los ntawm txoj kev hauv qab no. 1. Nws khi rau cellular prion protein (PrPC) , activates Fyn kinase, thiab tom qab ntawd tig rau lub sij hawm ntev inhibition ntawm synapses (LTD) los ntawm NMDA hom glutamate receptor (NMDAR) txoj kev. nyob rau hauv impaired synaptic plasticity thiab txo synaptic ntom. 3. A Kev sib sau ntawm tau protein tuaj yeem ua rau tsis ncaj ncees rau kev sib sau thiab nthuav tawm ntawm tau cov protein nyob hauv cov cheeb tsam hauv hlwb. 4,A Protein tuaj yeem inhibit acetylcholine receptor (AChR), induce Ltd, thiab ua rau inhibition ntawm synaptic kis. Cov xwm txheej tam sim no ntawm kev tshawb fawb tshuaj thiab kev txhim kho siv cov tshuaj tiv thaiv monoclonal los khi extracellular a Protein monomer / soluble aggregate (txoj kev tseem ceeb tshaj plaws nyob rau tam sim no) los tiv thaiv nws cov polymerization lossis txhawb nqa cov teeb liab hauv qab. Cov tshuaj sawv cev yog aducanumab ntawm Baijian, donanemab ntawm Lilly thiab crenezumab ntawm Roche. Tab sis raws li a Teeb liab cascade txoj kev xav, hauv a Kev tsim cov protein ntau thiab cov txheej txheem degradation muaj lub sijhawm rau kev tshawb fawb txog tshuaj thiab kev loj hlob. Tam sim no, qee qhov kev tshawb fawb tshuaj thiab kev txhim kho yog tsom rau app los tsim ib qho Protein txheej txheem - Secretase thiab tsim nws cov inhibitor (beta secretase inhibitor / bace), xws li mh-84 ntawm Frankfurt University thiab mbi-10 ntawm MSD. Txawm li cas los xij, cov no tam sim no nyob rau theem kev tshawb fawb ua ntej, thiab tseem muaj txoj hauv kev ntev mus ua ntej dhau los ua tshuaj patent. Tseem muaj lwm yam kev tshawb fawb qhia, xws li a Aggregation inhibitor (trimeric acid, sharinositol, pbt2) a Antigen (AN{0}}, vanutide, ad02, cad-106) anti-A Polyclonal antibody (immunoglobulin) - Secretase inhibitors (begacestat, semagacestat thiab avagacestat) - Secretory enzyme regulator (tarenflurbil) - Site amyloid precursor protein lyase (bace) inhibitors (ly2811376, ly2886721, azd3839, verubecestat, atabecestat, thiab lanabecestat). Thaiv nws txoj hauv kev downstream kuj tseem siv tau los ua ib lub tswv yim tshiab rau kev txhim kho AD tshuaj. Piv txwv li, ib tsab xov xwm luam tawm ntawm kev tshawb fawb nyob rau lub Rau Hli 1 xyoo no tau qhia tias mglu5rs 'silent (SAM) allosteric modulator (bms-984923, Bristol Myers Squibb) tuaj yeem thim rov qab synaptic poob hauv Alzheimer's nas. Kuj tseem muaj cov tshuaj NMDA tsim rau txoj hauv kev NMDAR. Txawm hais tias cov tshuaj no muaj txiaj ntsig zoo rau kev txhim kho neurocognition, nws yooj yim rau kev nyuaj siab. Tau protein hypothesis tau yog ib qho ntawm cov microtubule txuam nrog cov proteins (daim ntawv qhia) uas tswj cov kab mob neuronal microtubules, feem ntau hauv axons (piv nrog somatic dendritic MAP2). Cov ntaub ntawv kis tau tus mob ntawm cov neurons nyob ntawm microtubules raws li lub orbit, thiab tau protein ua ke nrog microtubules kom nws ruaj khov. Thaum qhov chaw tseem ceeb ntawm tau yog phosphorylated (tsuas yog ser262 lossis ser214), tau raug tso tawm los ntawm cov microtubules khi, ua rau microtubule rupture thiab tau aggregation rau hauv khub helices (PHF). Tau hyperphosphorylation thiab neurofibrillary tangles yog cov khoom tseem ceeb ntawm AD pathology thiab ntseeg tau tias yog tshwm sim los ntawm cov dej ntws ntawm tib neeg lub hlwb. Synaptic pathology tau tsav, thiab nrog a Synergism rau ntxiv synaptic poob.
Qhov chaw phosphorylation tseem ceeb tau muaj cov tshuaj acidic N-terminal domain, ib qho yooj yim thiab proline nplua nuj intermediate domain, ib qho yooj yim sau uas muaj peb lossis plaub qhov rov ua dua, thiab C-terminal domain. Nws tuaj yeem ua phosphorylated ntawm ntau qhov chaw, qee qhov tswj hwm nws cov microtubule khi cov khoom. Ob peb ser pro lossis thr Pro motifs uas tshwm sim nyob rau hauv ob cheeb tsam ntawm ob sab ntawm qhov rov ua dua ib ntus tsuas muaj qhov cuam tshuam nruab nrab ntawm tau microtubule kev sib cuam tshuam, tab sis tuaj yeem siv los ua cov cuab yeej kuaj mob rau kev tshaj tawm xws li tau phosphorylation. Nws kuj yog lub hom phiaj ntawm proline qhia kinases, xws li glycogen synthase kinase 3, cyclin dependent kinase Cdk5 lossis MAP kinase. Lwm qhov chaw muaj xws li protein kinase A (xws li ser214), microtubule affinity regulated kinase (kos, ntawm kxgs motif, nrog rau ser262, ser356), los yog lub hom phiaj ntawm Ca 2 plus / calmodulin dependent protein kinase (ser416). Tshawb nrhiav thiab tsim cov tswv yim ntawm tau protein
Ntau qhov chaw phosphorylation txawv txav yog nyob ntawm ser pro lossis thr Pro motifs, yog li ntau yam tshuaj tiv thaiv tsim rau ad tau hnov mob nrog cov chaw phosphorylation. Tsis ntev los no, cov kev tshawb fawb ntawm genome-wide tau qhia tias kev sib sau ntawm neuroinflammation yog ib qho kev pheej hmoo ntawm caj ces uas cuam tshuam qhov pib thiab kev loj hlob ntawm AD. Hauv kev tshawb fawb tib neeg, ntau dua 25 hom kab mob caj ces cuam tshuam nrog kev pheej hmoo ntawm AD, feem ntau yog qhia hauv microglia thiab cuam tshuam rau neuroinflamation. Neuroinflamation tuaj yeem txhawb nqa a Protein ntau lawm thiab induced tau phosphorylation. Neuroinflamation thiab nws txoj hauv kev downstream a Microglia nyob ib ncig ntawm cov quav hniav yog qhib rau lub xeev pro-inflammatory thiab secrete interleukin (IL) -1 . IB -1 Txhawb kev soluble amyloid precursor protein (Sapp) hauv cov neurons Generation of, Sapp Los ntawm activating nuclear factor kappa B (NF-κ B) Pro-il-1 hauv cov teeb liab transduction microglia Tiam ntawm. Tib lub sijhawm, a Ua kom NLRP3 inflammatory lub cev, tsim tau activated caspase-1 los ntawm inactivated procaspase-1, thiab ua rau microglia ntxiv secrete IL-1 . Lub voj voog no ua rau cov xwm txheej neuroinflammatory mob ntev thiab induces hyperphosphorylation ntawm tau thiab txo cov synaptic proteins nyob rau hauv neurons los ntawm activating p38 mitogen activated protein kinase (p38 MAPK) txoj kev. Tus neeg sawv cev pro-inflammatory yam regulating neuroinflammation ntawm microglia nyob rau hauv Alzheimer's kab mob (AD) hypothesized los ntawm neuropathology kev tshawb fawb yog cov kev cai yam tseem ceeb muaj feem xyuam rau cov neuroinflammatory mechanism ntawm AD, nrog rau cov pob txha hlwb hlwb -2 (TREM2) transmembrane protein (txo ntawm nws hydrolytic cleavage yuav aggravate neuroinflammation thiab yog ib tug regulator ntawm lub paj hlwb microglia kev ua ub no), leucine repeat sequence (NLR) nplua nuj nyob rau hauv nucleotide binding domain thiab pyrin domain 3 (NLRP3), Apoptosis ntsig txog dot xws li protein (ASC), CD33 thiab CD22 muaj caspase recruitment. domain (ASC). Calcium homeostasis regulator nyob rau hauv lub hlwb, microglia yog hom tshuaj tiv thaiv kab mob ntau tshaj plaws, suav txog ntau dua 80 feem pua ntawm tag nrho cov kab mob tiv thaiv kab mob. Calcium homeostasis yog ze ze rau kev ua kom microglia, a Ua kom cov calcium nyob rau hauv lub cell, uas nyob rau hauv lem ua rau lub activation ntawm NLRP3 inflammatory lub cev nyob rau hauv microglia. Lub luag haujlwm ntawm calcium homeostasis regulator tsev neeg cov proteins (calhm, CALHM1, calhm2 thiab calhm3) tau nyiam ntau thiab ntau dua hauv kev tshawb fawb AD. Hauv calhm2 knockout nas, a Sedimentation thiab neuroinflamation tau txo qis, thiab kev tshaj tawm txog kev paub txog kev puas hlwb tau txo qis. Gene therapy apoE4 tam sim no tau txheeb xyuas tias cov noob muaj feem xyuam rau kev tshaj tawm yog ApoE noob hloov, tshwj xeeb tshaj yog cov noob apoE4. Lub luag haujlwm ntawm cov noob no tuaj yeem raug xa mus rau kev ua tiav! Cell luam tawm ib tsab xov xwm hais txog lub tswv yim ntawm apoE4 ua rau Alzheimer's kab mob. Tam sim no, tseem muaj qee qhov kev sim tshuaj ntsuam xyuas cov noob no. Peroxisome proliferator activated receptor Coactivator -1 （PGC-1 ） PGC-1 Feem ntau koom nrog kev cai - Kev tsim cov APP cleaving enzyme 1 (BACE-1), uas yog lub luag haujlwm rau a Kev tsim tawm ntawm. Ib qho cuam tshuam rau hpgc-1 Cov kev sim tshuaj ntsuam xyuas ntawm APP23 transgenic nas tau pom tias lub cim xeeb ntawm cov nas tau txhim kho thiab cov amyloid deposits raug txo. Tsis tas li ntawd, vim muaj kev nthuav qhia ntau ntxiv ntawm NGF thiab lub hlwb-derived neurotrophic yam, crispr / cas9ad kuj muaj cov nyhuv neuroprotective. Crispr/cas9ad muaj lub hauv paus caj ces ntawm kev cuam tshuam rau app, PSEN1 thiab psen2 noob hloov pauv. Nws kuj tseem cuam tshuam rau kev qhia ntawm apoE4 alleles. Cov noob loci no tuaj yeem siv los ua cov hom phiaj kho mob. Tam sim no, muaj qee qhov kev tshawb fawb txog kev kho mob siv CRISPR, raws li hauv qab no:
Cov ntsiab lus
Ntau thiab ntau cov pov thawj qhia tau hais tias ad yog kab mob heterogeneous tshwm sim los ntawm ntau yam pathophysiological mechanisms dhau dogma. Piv txwv li, txog li ib feem peb ntawm cov neeg mob uas kuaj mob nrog ad tsis muaj ib tug Kev sib sau ua ke, thiab ntau tus neeg mob tau kuaj pom nrog kev tshaj tawm hauv postmortem biopsy tsis pom kev puas hlwb. Cov kev xav tam sim no ntseeg tias Alzheimer's kab mob yuav muaj ntau yam kab mob xws li mob qog noj ntshav, yog li kev txheeb xyuas cov kab mob molecular ntawm ad kom paub qhov txawv subtypes tej zaum yuav yog tus yuam sij los tsim cov tshuaj zoo dua, thiab yav tom ntej, cov tshuaj kho mob Alzheimer's kab mob sib txawv. yuav tawg.