GTP Energy Dependence Of Endocytosis Thiab Autophagy nyob rau hauv Lub Laus Lub hlwb thiab Alzheimer's Disease

Abstract

Txaus siab rau kev laus thiabAlzheimer tus kab mob(AD) - cuam tshuam txog kev puas tsuaj hauv autophagy hauv lub hlwb tsa cov lus nug tseem ceeb txog kev tswj hwm thiab kev kho mob. Txij li ntau cov kauj ruam hauv endocytosis thiab autophagy nyob ntawm GTPases, kev ntsuas tshiab ntawm cellular GTP yuav tsum tau ua.soj ntsuam kev tswj lub zog hauv kev laus thiab AD. Kev txhim kho tsis ntev los no ntawm ratiometric GTP sensors (GEVALS) thiab kev tshawb pom tias GTP qib tsis sib xws hauv cov hlwb ncecov teeb meem tshiab ntawm kev tswj hwm ntawm GTPaseslos ntawm lub zos muaj GTP. Hauv kev tshuaj xyuas no, peb qhia txog qhovmetabolism ntawm GTPHauv kev cuam tshuam rau Rab GTPases koom nrog kev tsim cov endosomes ntxov, lig endosomes, thiab lysosomal thauj mus rau execute autophagic degradation ntawm cov khoom puas. Tshwj xeeb GTPases tswj macroautophagy (mitophagy), microautophagy, thiab chaperone-mediated autophagy (CMA). Los ntawm kev xav, qib GTP hauv zos yuav tswj tau autophagy, yog tias tsis dhau. Kev tswj hwm qib ntxiv yog tswj hwm los ntawm lub xeev redox ntawm lub cell, suav nrog kev koom tes ntawm thioredoxin. Hauv qhov kev tshuaj xyuas no, peb hais txog qhovmuaj hnub nyoog hloov pauvuas ua taupab txhawb rau qhov tsis txaus hauv GTP thiab AD. Peb xaus nrog kev cia siab rau kev txhawb nqa GTP qib thiab thim rov qab hnub nyoog ntsig txog oxidative redox hloov mus rau autophagy. Yog li, GTP qib tuaj yeem tswj hwm ntau GTPases koom nrog endocytosis, autophagy, thiab vesicular trafficking. Nyob rau hauv kev laus, metabolic adaptation rau ib tug sedentary txoj kev ua neej yuav cuam tshuam mitochondrial muaj nuj nqi tsim tsawg GTP thiab redox zog rau kev noj qab haus huv ntawm amyloid thiabtau proteostasis, synaptic muaj nuj nqi, thiabmob.

Keywords GTP · Energetics · Autophagy · Mitophagy ·Endocytosis· Lysosomes ·Alzheimer tus kab mob · Kev laus

Nyem qhov no kom tau txais Herbal Cistanhe Rau Kev Tiv Thaiv-Alzheimer's Disease

GTP, lwm lub zog txiaj, hauv kev laus thiab AD

Synthesis ntawm high-zog molecules ATP thiab GTP ob leeg tso siab rau lub redox lub xeev ntawm NAD ntxiv / NADH thiab lawv cov concentrations txaus. ATP synthesis los ntawm glycolysis feem ntau yog siv los ntawm oxidative zog ntawm NAD ntxiv rau kev txo cov suab thaj. ATP synthesis los ntawm oxidative phosphorylation nyob rau hauv mitochondria yog powered los ntawm NADH tiam nyob rau hauv lub TCA voj voog rau txo cov pyruvate, glycerol, los yog fatty acids nrog oxygen raws li lub davhlau ya nyob twg electron txais nyob rau hauv lub electron thauj saw. Peb cov kev tshawb fawb tsis muaj daim ntawv lo hauv cov nas nyob lossis nas hippocampal neurons qhia txog hnub nyoog cuam tshuam ntawm NAD thiab NADH, uas tuaj yeem cuam tshuam kev sib txuas ntawm ATP thiab GTP [1–4]. Qhov no depletion tau ntxiv rau hauv cov neurons los ntawm nas nqa transgenes rau tib neeg beta-amyloid thiab tau. Tsis tas li ntawd, kev soj ntsuam tom qab ntawm TCA lub voj voog enzymes qhia txog 40 feem pua ​​​​kev puas tsuaj hauv TCA lub voj voog enzymes los ntawm AD hlwb piv rau cov hnub nyoog sib xws [5]. Yog li, muaj hnub nyoog ntsig txog kev qaug zog ntawm NAD ntxiv thiab NADH nyob rau sab saum toj ntawm AD-txog mitochondrial impairment hauv kev ua haujlwm ntawm TCA enzymes tuaj yeem cuam tshuam rau ATP thiab GTP theem, txawm tias lawv cov concentrations tsawg heev.

Lub zog muaj los ntawm GTP hydrolysis yog tib yam li ATP hydrolysis, tab sis GTP yog siv rau lub hom phiaj sib txawv dua li ATP vim qhov kev xaiv ntawm cov enzymes tshwj xeeb. GTP concentrations hauv hlwb yog nyob rau nruab nrab kaum npaug qis dua millimolar ATP. GTP yog lub luag haujlwm tseem ceeb ntawm ntau lub zog-dependant cellular txheej txheem ntawm cov protein synthesis thiab vesicular lag luam uas cuam tshuam nrog endocytosis thiab autophagy. Qhov kwv yees tag nrho cov cellular GTP concentration nyob rau hauv mammalian hlwb yog nyob rau hauv thaj tsam ntawm 250-700 μM [6], tab sis dawb GTP nyob rau hauv cov qog nqaij hlav cell protrusions yog ze rau 30 μM [7]. Cov proteins loj uas siv los ntawm GTP suav nrog dynamins rau daim nyias nyias fission thiab fusion, cov kev cai me me GTPases, thiab microtubules raws li cov lus qhia hauv qab no. Dhau li ntawm de novo synthesis los ntawm inosine los ntawm IDMPH2 thiab xanthosine los ntawm GMPS, cellular qhov chaw ntawm GTP yog feem ntau hauv zos nucleoside diphosphate kinases (NDPKs) los ntawm cov noob tsis-metastatic (NME; qee zaum hu ua NM23) uas hloov ATP rau GTP [8]. Muaj tsawg kawg yog kaum tus tswv cuab ntawm NME gene tsev neeg tab sis tsuas yog thawj plaub muaj nucleoside diphosphate kinase kev ua haujlwm. Raws li Allen Brain Atlas, NME1 txog 4 muaj zog thiab xaiv tau hais tawm hauv nas thiab tib neeg hippocampus qhov chaw nco tsis zoo hauv AD. NME1-3 yog cytoplasmic, thaum NME4 yog mitochondrial. Txij li ob qho tib si cov txheej txheem ntawm endocytosis thiab autophagy raug cuam tshuam rau kev laus thiab AD, peb pom tias kev hloov pauv ntawm cov dej ntws cuam tshuam rau ob qho tib si, tej zaum muaj hnub nyoog thiab AD-txog qhov tshwm sim ntawm kev txwv GTP qib ntawm cov amyloid-tseem ceeb functions.

Kev ntsuas ntawm GTP qib

Txawm hais tias GTP tswj hwm ntau cov txheej txheem tseem ceeb rau kev ciaj sia ntawm cellular, ntsuas GTP qib hauv cov cell nyob hauv lub cev thiab cov kab mob pathological yog qhov nyuaj vim tias muaj kev hloov pauv siab thiab qhov muaj nyob ntawm ob qho tib si protein thiab dawb lub xeev. Bianchi-Smira glia et al. [9] piav qhia txog qhov tshiab genetically encoded GTP sensor (GEVAL) raws li cov protein fluorescent daj uas pom cov kev hloov pauv hauv GTP-dawb thiab GTP-bound concentration hauv vitro thiab hauv vivo. Tsis ntev los no, tib pab pawg tau tshaj tawm txog cov txheej txheem rau kev tswj hwm ntawm GTPase Rac1 hauv kev cuam tshuam ntawm tes los ntawm tib neeg melanoma cell kab uas tau tsav los ntawm GTP hauv zos [7] thiab tshuaj xyuas lawv cov txheej txheem [10]. Raws li peb yuav pom hauv qhov kev tshuaj xyuas no, GTP ua lub luag haujlwm tseem ceeb thaum lub sijhawm endocytosis thiab autophagy-txog rau amyloid ua. Tam sim no, peb tab tom kawm txog cov hnub nyoog ntsig txog GTP kev hloov pauv hauv kev ua ntawm A hauv cov kab lis kev cai ntawm hippocampal neurons los ntawm triple transgenic 3xTg-AD nas thiab nws cov txiaj ntsig ntawm kev hloov pauv hauv autophagy. Daim duab 1 qhia txog cov txiaj ntsig ua ntej ntawm GEVAL530 kev hloov pauv mus rau thawj cov neeg laus cov neurons los ntawm tus qauv AD nas piv rau cov neurons uas tsis yog transgenic nas. Raws li pom los ntawm Bianchi-Smiraglia li al. [7], peb pom qhov tsis sib xws ntawm GTP hauv cov txheej txheem thiab cov npoo ntawm soma thaum ntsuas GTP dawb (Fig. 1Aa), nrog qis qis GTP qib hauv 3xTg-AD neurons (Fig. 1Ac). Raws li cov ncauj lus kom ntxaws hauv Tshooj 10, pretreatment ntawm cov neurons nrog NAD ntxiv -precursor, nicotinamide, tsa cov qib GTP dawb (Fig. 1Ab, d). Lub 530-µM Kd rau GEVAL530 siv nyob rau hauv cov kev sim no qhia tias lub zos dawb GTP concentration nyob rau hauv ob peb-fold ntawm 530 µM. Nyob rau hauv daim duab 1B, peb tau tshuaj xyuas qhov khi GTP uas zoo nkaus li nyob rau hauv vesicles thiab nce los ntawm nicotinamide (Fig. 1Bf, h), tshwj xeeb tshaj yog nyob rau hauv 3xTg AD neurons. Cov pov thawj ua ntej qhia tias cov neurons kho nrog NME1 siRNA txo lawv cov qib GTP dawb (Santana Martinez, tsis tau tshaj tawm). Cov kev tshawb fawb ntxiv nrog rau cov neeg laus neurons thoob plaws lub hnub nyoog spectrum yuav txiav txim siab lub hnub nyoog-kev vam khom ntawm GTP tsis txaus thiab muaj peev xwm los kho lawv nrog NAD ntxiv -precursors. Muab lub luag haujlwm tseem ceeb ntawm GTP hauv cov txheej txheem kev lag luam vesicular ntawm endocytosis thiab autophagy thiab cov pov thawj ua ntej rau kev hloov hauv GTP nrog AD-zoo li cov noob caj noob ces, cov ntu hauv qab no muab cov ntsiab lus ntawm cov txheej txheem no thiab cov teebmeem ntawm kev laus thiab Alzheimer's kab mob rau lawv. Qhov tshwm sim ntawm qhov kev tshuaj xyuas no ua rau pom qhov xav tau rau txoj hauv kev tshiab xws li GEVAL kev sojntsuam ncaj qha rau kev ntsuas kev hloov pauv hauv kev khi thiab pub dawb GTP thiab tag nrho GTP concentrations.

Daim duab 1 Ratiometric GTP ntsuas hauv thawj nas hippocampal neurons los ntawm nruab nrab-hnub nas kis nrog GEVAL530 sensor False-coloured pixel-los-pixel ratiometric dluab ntawm neurons qhia non-uniform distributions ntawm GTP. (a) Tshaj dawb-GTP/bound-GTP ntawm nruab nrab-hnub nyoog (14 mo.) nontransgenic (NTg) ntawm ntug thiab apical dendrite piv rau (c) nruab nrab hnub nyoog (10 mo.) 3xTg-AD neuron. (b, d) nce hauv GTP dawb hauv cov neurons kho nrog 2 mM nicotinamide los ntawm 24 teev. (e, g) Cov neurons tsis kho pom muaj vesicular bound GTP uas tau nce hauv (f, h) neurons kho nrog 2 mM nicotinamide los ntawm 24 h

Endocytosis: GTP dependence nyob rau hauv kev laus thiab AD

Nyob rau hauv cov txheej txheem endocytosis, lub cell internalizes macromolecules thiab ligand-bound receptors thiab nto proteins nrog rau cov amyloid precursor protein (APP) [11] (Fig. 2A). Ntawm ob txoj hauv kev endocytic tseem ceeb, plasma membrane-embedded APP uptake tshwm sim feem ntau los ntawm clathrin-mediated uptake (Fig. 2B.1) es tsis yog caveola-mediated los ntawm choles terol-nplua nuj thaj ua rau thaj (Fig. 2B.2). Txawm li cas los xij, hydrophobic A , muab faib rau hauv cov roj cholesterol-nplua nuj thaj ua rau thaj lipid rafts nyob rau hauv lub plasma membrane nrog tom qab uptake los ntawm caveola txoj kev [12] (Fig. 2B.2). Nyob rau hauv ob qho tib si, dynamin GTPase complexes sib sau ua ke ntawm invagination rau catalyze GTP-nyob ntawm daim nyias nyias curvature rau zaum kawg fusion thiab tso tawm ntawm cov hlwv vesicles los ntawm cov plasma membrane [13-15]. Local GTP fueling yog catalyzed los ntawm NME1 thiab 2 nucleotide phosphate kinases uas khi rau dynamin [16]. Thaum ntxov endosome Rab5 GTPase kev txiav txim siab rau exocytosis thiab receptor recycling los yog hloov mus rau lig endosome Rab7 GTPase rau degradation.

Rab5 GTPase yog suav hais tias yog ib qho cim rau qhov endosome thaum ntxov [17]. Rab5 protein muaj nyob rau hauv plasma membrane, nyob rau hauv clathrin-coated vesicles, thiab thaum ntxov endosomes (Fig. 2). Nyob rau hauv cell thiab fy qauv ntawm Huntington tus kab mob, Rab5 koom nyob rau hauv autophagosome tsim los tswj autophagy thiab tshem tawm toxic mutant huntingtin [18]. Inhibition ntawm Rab5 txo autophagy-regulating proteases Atg5-Atg12 conjugation, ua rau txo qis autophagosome tsim. Lub Atg12-Atg5 conjugate txhawb nqa lub lipidation ntawm Atg8, thiab lipidated Atg8 pab txhawb kev tsim autophagosome thiab xaiv cov khoom thauj thaum lub sij hawm autophagy [19].

Lwm qhov ua tau zoo rau Rab5-mediated autophagy yog phosphatidylinositol-3-kinase (PI3K). PI3-kinase complex inhibits autophagy los ntawm activating Akt/mTOR-signaling pathway [20]. P110 subunit ntawm PI3K complex tswj cov kev ua haujlwm catalytic ntawm Vps34 complex los txhawb PI3P tiam [21]. Cov kauj ruam no yog qhov tseem ceeb rau kev tsim autophagosome. P110 txhawb kev hloov pauv ntawm Rab5- GDP mus rau Rab5-GTP. P110 overexpression mitigates autophagic deficiency tom qab ua kom cov macromolecular complex tsim ntawm Rab5, Vps34, thiab Beclin1, uas nyob rau hauv lem ua rau autophagosome tsim [22]. Targeting cov proteins tshwj xeeb no tuaj yeem piav qhia txoj hauv kev kho mob kom txo qis AD pathology.

Daim duab 2 Endocytosis ntawm amyloid precursor protein (APP). N-terminal feem ntawm 770 residue APP protein nrog ntsuab shading ntawm aggregation-prone A yuav tsum tau cleavage los ntawm BACE thiab Gamma peptidases. B Endocytosis ntawm APP. (1) Kev tsim cov pob txha sab hauv los ntawm cov plasma membrane orchestrated los ntawm clathrin nrog endoproteases BACE thiab 훾 -secretase. Endocytosis txhawb nqa los ntawm dynamin tau txais GTP hauv zos los ntawm NME1. (2) Microdomains enriched hauv cholesterol (lipid rafts) khi APP ua tiav rau A lossis A adsorbed los ntawm parenchyma. (3) Thaum ntxov endosome nyiam GTPase Rab5 uas tau lees paub los ntawm lwm tus GTPase, Rab11, los kho (4) endocytic recycling ntawm receptors rov qab mus rau plasma membrane. Xwb, (5) Rab7 kho kom haum rau kev sib cais thaum ntxov mus rau lig endosomes tso cai ntxiv kev ua APP thiab tsub zuj zuj ntawm A . (6) Late endosome fusion nrog (7) lysosome kom degrade cov ntsiab lus. Qee qhov sib sau A tuaj yeem tiv taus kev zom zaub mov, thiab nrog kev cuam tshuam endosome, A tuaj yeem khaws cia hauv cytosol.

Membrane-bound Rab5 yog qhov tseem ceeb hauv kev txhawb nqa ncaj qha Mon1-Ccz1-dependent Rab7 activation thiab Rab7-dependent membrane fusion [23]. Mon1-Ccz1 yog heterodimeric guanine nucleotide exchange factor GEF-complex uas activates Rab5. Mon1-Kev hloov pauv hloov pauv ntawm Rab5 GEF tau tshwm sim hauv kev hloov pauv ntawm Rab5 los ntawm Rab7. C-Vps complex ua raws li GEF rau Rab7 thiab txhawb nqa Rab7 hloov ntawm GDP-txheej txheem rau GTP-txheej lub xeev rau Rab7 ua kom. Ultraviolet radiation resistance–associated gene (UVRAG) stimulates Rab7 activation by UVRAG-C-Vps interaction through GDP/GTP exchange of Rab7 [24]. Lwm qhov kev tswj hwm hauv cov txheej txheem autophagic yog homotypic fusion thiab vacuole protein-sort ing (HOPS) complex uas ua rau cov poov xab vacuolar Ypt-Rab GTPase thaum lub sij hawm membrane fusion [25]. Ib qho ntawm 6 subunits ntawm HOPS complex yog Class C vacuolar protein sorting (C-Vps) complex uas muaj Vps11, Vps16, Vps18, thiab Vps33. Rab7 lig endocytic vesicles tom qab fuse nrog lysosomes rau cargo degradation (Fig. 2).

Kev hloov pauv hauv Rab 5 thiab Rab 7 endosomal kev lag luam hauv cov qauv nas thiab hauv AD

Hauv cov qauv nas ntawm AD nrog kev hloov pauv hauv amyloid precursor protein (APP) lossis A -producing presenilin, txoj hauv kev endosome-autophagosome-lysosome zoo li dysregulated ib feem vim tsis muaj acidification ntawm lysosomes uas tsis ua kom txaus protease thiab lipases [26]. Hauv cov qauv nas ntawm AD, lub cev loj perinuclear uas muaj A aggregates daim ntawv lo nrog autophagosome marker LC3 colocalized nrog Rab7 thiab lig endosomal thiab lysosomal Cheebtsam. Qhov no tuaj yeem yog vim tsis ua tiav kev tiv thaiv kev tiv thaiv lossis kev puas tsuaj pathologic. Hauv cov neurons kab lis kev cai los ntawm 3xTg-AD nas nyob thoob plaws lub hnub nyoog, peb pom cov vesicular A sib sau ua ke kom nce 30-50 npaug nrog lub hnub nyoog, feem ntau tseem ceeb hauv Rab5- sau npe thaum ntxov endosomes thiab mitochondria, tab sis kuj nyob rau hauv Rab {{9} }labeled lig endosomes thiab autophagosomes [27]. Cov pob zeb zoo li pob zeb ntawm A 42 thiab A 45 qhia tias cov neurons qub tsis tuaj yeem ua kom tiav autophagic degradation ntawm cov aggregates ntev dua ntawm A. Peb xav hais tias qhov tsis muaj zog tsim tawm hauv cov laus neurons txwv lub zog muaj peev xwm ua kom tiav ntawm autophagy. Piv rau cov qib hauv cov tub ntxhais hluas hippocampus thiab cortex, hauv 7–{16}}hli APP/PS1 nas hippocampus, Rab7 qib tau txo qis nrog rau kev txo qis hauv Beclin1 thiab Rubicon activators thiab nce hauv Rubicon inhibitor [28]. Hauv cov tub ntxhais hluas hippocampus thiab txhua lub hnub nyoog hauv lub cortex, Beclin1 activates Rab7, thaum Rubicon inhibits kev ua haujlwm ntawm Rab7 los ntawm kev tawm tsam ntawm UV hluav taws xob tiv thaiv-txuas ntxiv cov noob protein (UVRAG)-vacuolar protein sorting gene (Vps) kev sib cuam tshuam. Rab7 deficiency nyob rau hauv poov xab thiab txiv hmab txiv ntoo yoov ua rau ib tug loj tsub zuj zuj ntawm autophagosomes [29]. Rab7 knockdown kuj tseem inactivates mTORC1/S6K1, thiab localization ntawm mTOR nyob rau hauv lig endosomes [30]. Interestingly, qhov inhibition ntawm lwm theem ntawm endocytic trafficking tsis hloov cov kev ua ntawm mTORC1 qhia hais tias tsis tu ncua lig endosomes yog ib qho tseem ceeb rau mTORC1 signaling nyob rau hauv autophagy. Qhov no yog ib qho laj thawj tseem ceeb vim li cas lub hom phiaj mTOR yuav tsis qeeb kev laus lossis AD.

Kev xaiv tsa hauv cheeb tsam ntawm Rab 5 thiab Rab7 proteins thiab mRNAs hauv AD, qhia txog kev xaiv cov kev pab cuam rau cov kab mob pathology lossis kev tiv thaiv tsis txaus [31]. A accumulates feem ntau nyob rau hauv Rab7-zoo lig endosomes thiab autophagic vacuoles ntawm neuronal hlwb [32] nyob rau hauv ib tug muaj hnub nyoog hais txog [27] ua rau internalization ntawm A thiab tom qab nce ntawm Rab7 triggering neuronal degeneration [33]. Thaiv txoj kev lig endocytic los ntawm Rab7 suppression induces A-dependent amyloid fibril tsim rau ntawm lub xovtooj ntawm tes ua rau endosomal o [34] ua rau kom ceev rov ua dua ntawm Rab7 thiab endocytic trafficking ntawm A rau lysosomes rau degradation [35]. Inhibition ntawm Iysoso mal proteolysis tuaj yeem cuam tshuam rau axonal retrograde thauj ntawm autophagic organelles ua rau AD-zoo li axonal dystrophy [36]. Txawm li cas los xij, kev cuam tshuam zoo los txhawb Rab7-kev kho mob autophagy tuaj yeem ncua lossis thim rov qab AD kev nce qib. Piv txwv suav nrog kev hloov ntawm lub xeev sedentary mus rau kev tawm dag zog, noj zaub mov Mediterranean, thiab cov khoom siv zog txhawb zog xws li NAD precursors los tsim redox hloov [4] (Tshooj 10). Lwm txoj hauv kev yog qhov kev tshawb pom txawv txawv uas guanosine monophosphate reductase 1 (NADPH-dependent GMPR1) qib tau nce hauv AD hlwb uas tuaj yeem txo qis GTP qib thiab nce AMP signaling [37]. Neurofibrillary tangles ntawm tau raug txo qis thaum qhov kev ua haujlwm no tau cuam tshuam hauv AD nas.

Nrog rau kev nce qib ntawm kev paub tsis meej me ntsis mus rau AD, ob qho tib si endosomal Rab5 thiab Rab7 kab lus tau raug kho nyob rau hauv hippocampal CA1 neurons raws li ntsuas los ntawm transcriptional microarray [31]. Kev nthuav dav ntawm Rab5- cov endosomes zoo tau cuam tshuam nrog neurofibrillary tangles thiab amyloid deposition. Neurotrophic yam xws li paj hlwb kev loj hlob (NGF) khi rau lawv cov Trk receptors thiab internalize rau Rab5-zoo endosomes los pib downstream signaling [38]. Nws yog qhov nthuav kom nco ntsoov tias, qhov taw qhia endosome tau khaws cia raws li Rab5 thaum ntxov endosomes thiab tsis tau nce mus rau Rab7 lig endosomes, thaum lawv hloov mus nyob rau hauv ntev axons [39]. Qhov no dif sib txawv receptor-mediated teeb liab xa los ntawm endosome ua rau autophagy [40]. Ua raws li kev ua haujlwm los ntawm NGF, TrkA nrhiav Rab5-GAP kom sai hloov GTP-Rab5 rau GDP-Rab5 kom khaws qib ntawm GTP-Rab5 hauv kev txheeb xyuas, uas tiv thaiv Rab5 rau Rab7 hloov pauv uas ua rau inhibition ntawm NGF / TrkA signaling thiab degradation ntxov ntxov.

Rab5 muaj nuj nqi yog cuam tshuam nyob rau theem pib ntawm AD [41]. Tsis tu ncua hyperactivation ntawm Rab5 pro txhawb txoj kev endocytic mus rau lig endosomes, lysosome fusion, thiab autophagy uas ua rau ntxov ntxov degradation ntawm neurotrophic yam signaling thiab neuronal atrophy. Vps35 thiab Vps26, ob qhov tseem ceeb retromer proteins, kuj tau txo qis hauv AD hlwb [42]. Vps26 khi rau SorLA uas yog ib qho sorting receptor uas tswj APP kev lag luam los ntawm endosomes mus rau Golgi. Kev txo qis hauv Vps retromer proteins ua rau qhov txawv txav ntawm Vps-SorLA complex uas cuam tshuam APP kev lag luam casing APP tsub zuj zuj hauv cov endosomes uas nws raug rau beta-secretase. Txawm li cas los xij, ua raws li APP phosphorylation ntawm S655, nyob rau hauv APP 653YTSI656 basolateral motif, tuaj yeem txhim kho APP retrieval nyob rau hauv retromer-mediated process ua rau txo qis APP lysosomal lub hom phiaj, thiab txo Abeta ntau lawm [43]. Kev nce hauv qhov ntev APP thiab APP fragment -CTF tuaj yeem ua rau nce Rab5 GTPase kev ua ub no ua rau kev loj hlob ntawm cov endosomes thaum ntxov [44]. Interestingly, neuronal atrophy induced los ntawm APP -CTFs tuaj yeem cawm tau los ntawm qhov tseem ceeb-tsis zoo Rab5 mutant ob qho tib si hauv vitro [39] thiab hauv vivo [45].

Qhov txiaj ntsig ntawm kev laus yog qhov ua tiav ntawm cov endosomes lig, lig endocytic tsis ua hauj lwm, thiab impaired lysosomal fusion. Hauv AD, endocytosis ntawm A nce mus rau qhov loj Rab5 thaum ntxov endosomes. Lub luag haujlwm ntawm Rab7 hauv AD tseem tsis tau qhia meej meej vim tias ob qho tib si upregulation ntxov thiab lig downregulation ntawm Rab7 tau pom muaj kev cuam tshuam rau neuronal noj qab haus huv nyob rau hauv ob qho tib si qhia. Raws li tau hais los ntawm Bianchi-Smiraglia li al. [7], tag nrho cellular GTP uas ntsuas hauv homogenates tsis tso cai rau kev soj ntsuam ntawm GTP dawb muaj nyob hauv zos rau Rab GTPases. Kev ntsuas GTP dawb tseem tsis tau tshaj tawm, yog li lawv lub luag haujlwm muaj peev xwm ntawm hnub nyoog thiab AD-txog kev puas tsuaj hauv endocytosis tsis tau tshawb nrhiav. Yog li ntawd, nws yuav yog ib qho tseem ceeb los ntsuas GTP dawb hauv cov hlwb nyob thiab qhov cuam tshuam ntawm kev hloov pauv hauv GTP dawb ntawm endocytosis raws li kev ua haujlwm ntawm hnub nyoog thiab AD qauv.

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