Adult Hippocampal Neurogenesis hauv Kev Laus Thiab Alzheimer's Disease Part 1

Abstract

Kev paub txog kev tsis txaus ntseeg cuam tshuam nrog Alzheimer's disease (AD) cuam tshuam rau lub neej txhua hnub rau ntau lab tus tib neeg cuam tshuam. Kev loj hlob ntawm kev nco tsis zoo hauv cov neeg mob AD yog txuam nrog degeneration ntawm hippocampus. Lub dentate gyrus ntawm lub hippocampus, ib cheeb tsam tseem ceeb rau kev kawm thiab kev nco ua haujlwm, yog qhov chaw ntawm cov neeg laus neurogenesis hauv cov tsiaj. Cov pov thawj tsis ntev los no hauv tib neeg qhia tias hippocampal neurogenesis yuav muaj nyob thoob plaws hauv lub neej, tab sis poob qis nrog hnub nyoog thiab muaj kev cuam tshuam tsis zoo hauv AD. Peb txoj kev nkag siab txog yuav ua li cas neurogenesis txhawb kev kawm thiab kev nco hauv cov neeg laus noj qab haus huv tsuas yog pib tshwm sim. Qhov uas txo qis neurogenesis ua rau kev paub tsis meej ntawm kev laus thiab AD tseem to taub tsis zoo. Txawm li cas los xij, kev tshawb fawb hauv cov qauv nas ntawm AD thiab lwm yam kab mob neurodegenerative nce qhov muaj peev xwm hais tias kev tsom mus rau neurogenesis tuaj yeem ua rau lub hlwb tsis ua haujlwm hauv AD. Ntawm no, peb tshuaj xyuas cov kev kawm tsis ntev los no hauv kev nkag siab tias cov neeg laus neurogenesis cuam tshuam li cas hauv cov ntsiab lus ntawm kev laus thiab AD.

Ntsiab lus

Alzheimer tus kab mob; Cov neeg laus Hippocampal Neurogenesis; Neurogenesis hauv Kev Noj Qab Haus Huv Kev Laus; AD thiab Neurogenic Niche;Cistanche cov teebmeem.

Nyem qhov no mus yuavCistanche ntsiav tshuaj

Taw qhia

Alzheimer's disease (AD) yog ib qho mob hnyav, tsis tu ncua ntawm cov kab mob neurodegenerative cuam tshuam rau ntau lab tus tib neeg thoob ntiaj teb. Cov tib neeg raug kev txom nyem los ntawm AD txhim kho kev nco tsis zoo uas tuaj yeem cuam tshuam rau lub neej txhua hnub. Entorhinal cortex thiab hippocampus ua lub luag haujlwm tseem ceeb hauv AD etiology (Braak and Braak, 1991; Thompson et al., 2003). Cov kev tshawb fawb histological thiab imaging qhia tau hais tias qhov nkag mus rau hauv lub cortex tau cuam tshuam thaum ntxov AD (Go´mez-Isla li al., 1996), tom qab ntawd kis mus rau hippocampus thiab cerebral cortex (Braak et al., 2006). Ntxiv rau qhov degeneration, AD yog tus cwj pwm los ntawm kev tsim cov kab mob pathological, suav nrog cov plaques extracellular muaj li ntawm amyloid beta (Ab), cleavage khoom ntawm amyloid precursor protein (APP), thiab intracellular tangles muaj hyperphosphorylated tau. Lub xub ntiag ntawm cov plaques thiab tangles nyob rau hauv lub hippocampus muaj kev cuam tshuam nrog kev txawj ntse poob (Naslund li al., 2000). Txawm li cas los xij, cov yam ntxwv ntxiv ntawm hippocampus yuav yog qhov tseem ceeb rau kev nkag siab txog kev paub txog kev poob qis hauv AD thiab tsim kho tshiab. Tsis zoo li feem ntau thaj tsam ntawm cov neeg laus lub hlwb, hippocampus harbors neural stem cells (NSCs) uas tuaj yeem tsim cov neurons tshiab, cov txheej txheem hu ua neurogenesis. Txawm li cas los xij, peb txoj kev nkag siab txog yuav ua li cas hippocampal neurogenesis cuam tshuam hauv AD lossis txawm tias thaum noj qab haus huv laus tsuas yog pib tshwm sim. Ntawm no, peb tshuaj xyuas qhov kev nce qib tsis ntev los no hauv kev nkag siab tias tus neeg laus hippocampal neurogenesis cuam tshuam li cas hauv cov ntsiab lus ntawm kev laus thiab AD.

Adult Hippocampal Neurogenesis

Cov neeg laus neurogenesis hauv nas thiab tsis yog tib neeg primates tau tshawb xyuas qhov tob rau ntau xyoo lawm (Altman thiab Das, 1965; Gould et al., 1999), nrog rau ntau qhov kev tshawb fawb tsim kom muaj qhov ua rau lub neej neurogenesis tshwm sim hauv tib neeg (Boldrini li al., 2018; Eriksson et al., 1998; Ernst et al., 2014; Johansson et al., 1999a, 1999b; Knoth et al., 2010; Moreno-Jimenez et al., 2019; To 21, Spalding; ib., 2019). Hippocampal NSCs nyob rau hauv thaj tsam subgranular (SGZ) feem ntau tsim cov dentate granule neurons, uas yog excitatory neurons uas ua rau feem ntau ntawm cov hniav gyrus (DG) (Daim duab 1). Ua haujlwm tau zoo, DG tau txais cov tswv yim los ntawm lub cev nkag mus, xa cov ntaub ntawv los ntawm trisynaptic Circuit Court rau CA3 thiab CA1, yog li ua lub luag haujlwm tseem ceeb hauv kev kawm thiab kev nco. Ntawm no, peb tham txog cov kev hloov pauv ntawm cov neeg laus neurogenesis hauv nas DG thiab cov pov thawj rau neurogenesis hauv cheeb tsam no hauv tib neeg.

Cov Neeg Laus Neurogenesis hauv Rodents

Feem ntau ntawm peb qhov kev paub txog cov neeg laus hippocampal neurogenesis los ntawm kev ua haujlwm hauv nas. Kev sim thaum ntxov hauv cov nas uas siv thymidine-H3 tau txheeb xyuas qhov tsim ntawm cov granule neurons tshiab hauv cov neeg laus DG (Altman thiab Das, 1965; Cameron li al., 1993). Tom qab ntawd cov kev tshawb fawb tau ua ke nrog thymidine analog kev koom ua ke nrog cov cim ntawm cov laus neurons (NeuN), ntxiv kev lees paub tias NSCs faib thiab tuaj yeem sib txawv rau hauv cov laus granule neurons hauv SGZ ntawm DG (Kuhn li al., 1996). Siv cov txheej txheem zoo sib xws, lwm tus pom muaj pov thawj ntawm lub neej neurogenesis nyob rau hauv subventricular cheeb tsam (SVZ) ntawm lateral ventricles (Luskin, 1993). Thaiv tsis tu ncua tshiab neuron tsim cuam tshuam kev paub txog kev ua haujlwm, qhia tias cov neeg laus neurogenesis yog ib qho tseem ceeb ntawm hippocampal circuitry (Imayoshi li al., 2008). Ntau qhov kev tshawb fawb ntxiv txhawb qhov kev xav no thiab qhia tias cov neeg laus hippocampal neurogenesis tsim cov neurons uas tseem ceeb hauv kev kawm thiab kev nco, nrog rau kev tswj kev xav (Sahay et al., 2011; Shors et al., 2001). Qhov tseem ceeb, cov neeg laus neurogenesis yog tswj hwm los ntawm ib puag ncig thiab kev coj tus cwj pwm. Kev tawm dag zog thiab kev ua kom zoo ib puag ncig (EE) paub zoo tias yuav ua rau muaj cov kab mob neurogenesis thiab kev txawj ntse hauv cov nas noj qab haus huv. Tsis tas li ntawd, kev cob qhia ntawm hippocampal-dependent kev kawm thiab kev nco ua haujlwm ua rau muaj txiaj ntsig zoo rau kev muaj sia nyob ntawm cov cell granule tshiab hauv DG (Aimone et al., 2006; van Praag et al., 2005). Hauv qhov sib piv, kev ntxhov siab, kev laus, thiab neurodegeneration yog lub zog tsis zoo ntawm cov neeg laus neurogenesis (Gould thiab Tanapat, 1999; Kuhn li al., 1996).

Feem ntau NSCs nyob rau hauv cov neeg laus lub hlwb yog nyob rau hauv lub xeev quiescent thiab tsis nquag proliferating. Quiescent NSCs tuaj yeem ua kom qhib tau thiab sib faib los tsim cov menyuam ntxhais uas rov qab mus rau qhov qub (kev rov ua dua tshiab ntawm tus kheej) lossis sib txawv rau hauv cov neurons lossis glia (Codega li al., 2014). Hauv cov nas, cov txheej txheem ntawm neurogenesis tshwm sim li ntawm 7 lub lis piam thiab tuaj yeem tawg mus rau plaub theem: (1) kev ua haujlwm ntawm tes ua ntej, (2) kev muaj sia nyob thaum ntxov, (3) kev loj hlob ntxov postmitotic, thiab (4) lig maturation (Ambrogini et al., 2004; Kempermann et al., 2015) (Daim duab 1). Thaum lub sijhawm ua ntej, astrocyte-zoo li quiescent NSCs qhib thiab sib faib symmetrically los tsim NSCs tshiab lossis asymmetrically los tsim ib tug progenitor thiab NSC (Bond et al., 2015). NSCs tuaj yeem rov ua nws tus kheej, thaum cov hlwb progenitor muaj peev xwm loj hlob thiab tuaj yeem sib txawv rau hauv cov neurons lossis glia. Newly generated neuroblasts, progenitors nrog neuronal txoj hmoo, tau txais GABAergic input thiab loj hlob mus rau hauv tsis paub qab hau neurons (Tozuka li al., 2005). Thaum lub sijhawm muaj sia nyob thaum ntxov, txog li 50 feem pua ​​​​ntawm cov hlwb raug tshem tawm los ntawm apoptosis, txo cov naj npawb ntawm cov neurons tshiab (Dayer et al., 2003). Cov neurons tshiab uas muaj sia nyob dhau 2 lub lis piam tsiv mus rau granule cell txheej (GCL), pib tsim axons thiab dendrites, thiab nws thiaj li koom ua ke rau hauv hippocampal network (Kempermann li al., 2003). Thaum ntxov postmitotic maturation theem muaj xws li axon elongation, dendritic spine tsim, thiab synapse tsim (Sun li al., 2013), uas yog feem ntau tswj los ntawm network kev ua si, xws li GABAergic inputs (Piatti li al., 2011). Thaum kawg, lub sijhawm maturation lig yog tus cwj pwm los ntawm kev hloov ntawm calretinin qhia rau calbindin qhia, thiab kev txhim kho ntawm electrophysiological kos npe ntawm cov laus granule hlwb (Ambrogini li al., 2004; Brandt li al., 2003). Lub sijhawm no, cov neurons tshiab tsim glutamatergic synapses thiab nkag mus rau lub sijhawm tseem ceeb nrog rau qhov txo qis rau lub sijhawm ntev zog piv nrog cov menyuam mos liab. Cov kev hloov no yog ib qho tseem ceeb rau kev ciaj sia ntawm cellular, mediating synaptic plasticity, thiab nco encoding (Aimone li al., 2006; Schmidt-Hieber et al., 2004).

Cov txheej txheem ntawm neurogenesis tshwm sim nyob rau hauv ib qho tshwj xeeb niche uas suav nrog cov yam ntxwv extracellular matrix Cheebtsam, txawv vasculature qauv, thiab ib tug tswv tsev ntawm secreted yam. Thaum tag nrho cov lus piav qhia ntawm lub niche architecture thiab nws cov kev cuam tshuam ntawm neurogenesis yog dhau ntawm qhov kev tshuaj xyuas no (saib Bond li al., 2015), lub niche tseem ceeb heev rau kev txhawb nqa kev noj qab haus huv neurogenesis. Kev cuam tshuam rau lub niche neurogenic tuaj yeem ua rau kev kawm thiab kev nco tsis zoo, qhov kev rov ua dua tshiab ntawm cov hnub nyoog niche tuaj yeem cawm kev paub (Navarro Negredo li al., 2020).

Cistanche ntxiv

Neurogenesis nyob rau hauv cov neeg laus lub hlwb

Peb txoj kev ywj pheej tau raug siv los ntsuas kev loj hlob thiab cov kab mob neurogenesis hauv tib neeg lub hlwb: bromodeoxyuridine (BrdU) kev koom ua ke, immunohistochemistry nrog cov cim rau cov hlwb tsis paub qab hau, thiab cov pa roj carbon monoxide -14 DNA ntsuas (Boldrini li al., 2018; Eriksson et al., 1998; Ernst et al., 2014; Knoth et al., 2010; Moreno-Jimenez li al., 2019; Sorrells et al., 2018; Spalding et al., 2013). Thawj cov pov thawj rau cov neeg laus neurogenesis hauv tib neeg los ntawm kev tshawb fawb los ntawm Eriksson li al. (1998) nyob rau hauv uas kev koom ua ke ntawm thymidine analog BrdU tau siv los txheeb xyuas cov cell proliferating hauv lub hlwb. BrdU-zoo hlwb co-expressing neuronal cov cim tau pom nyob rau hauv ob qho tib si GCL ntawm DG thiab hauv SVZ. Txij li thaum thawj tsab ntawv ceeb toom, ntau qhov kev tshawb fawb tau tshaj tawm cov neeg laus neurogenesis hauv tib neeg (Boldrini li al., 2018; Ernst li al., 2014; Johansson li al., 1999a, 1999b; Knoth et al., 2010; Moreno-Jimenez thiab al. , 2019; Spalding et al., 2013). Keeb kwm, qhov tseeb theem ntawm kev tsim cov neuron tshiab hauv tib neeg tau nyuaj rau kev txheeb xyuas, thiab muaj qee qhov kev tsis sib haum xeeb txog qhov loj ntawm neurogenesis postnatally. Ib qho kwv yees los ntawm cov ntaub ntawv sib koom ua ke ntawm carbon -14 qhia tau hais tias cov neeg laus hippocampal neurogenesis txuas ntxiv tshwm sim nrog kev kwv yees txhua xyoo hloov pauv ntawm 1.75 feem pua ​​​​hauv cheeb tsam no (Spalding li al., 2013).

Txawm li cas los xij, nws yuav tsum tau muab sau tseg tias qee qhov kev tshawb fawb tau ua tsis tiav qhov tseem ceeb ntawm cov neurons tshiab tom qab kev loj hlob hauv tib neeg (Cipriani li al., 2018; Sanai et al., 2011; Sorrells et al., 2018). Txawm hais tias muaj lwm yam tseem ceeb tuaj yeem ua lub luag haujlwm, qhov tsis muaj peev xwm txheeb xyuas cov neurons tshiab hauv cov neeg laus lub hlwb tuaj yeem yog vim muaj cov txheej txheem sib txawv ntawm kev kho cov ntaub so ntswg thiab kev tsis sib haum xeeb nyob rau hauv lub sij hawm ntev cia ntawm cov qauv kev txiav txim. Ib txoj kev tshawb fawb tsis ntev los no tau hais txog cov teeb meem hauv qab no, uas tej zaum yuav yog qhov tseem ceeb tshwj xeeb rau kev tshawb pom ntawm qhov tsis paub qab hau neuron marker DCX (Flor-Garcia li al., 2020). Txoj haujlwm no, nrog rau kev nce qib tsis ntev los no hauv kev tsim cov thev naus laus zis tshiab, xws li ib leeg-cell genomics, ua rau txoj hauv kev rau cov kev tshawb fawb yav tom ntej kom txiav txim siab qhov twg rau cov neeg laus neurogenesis tshwm sim hauv cov neeg noj qab haus huv thiab muaj mob.

Neurogenesis nyob rau hauv Healthy Aging

Nws tau zoo sau tseg tias cov neeg laus neurogenesis poob qis hauv kev laus ntawm lub cev hauv cov tsiaj. Hauv cov nas, neurogenesis txo qis nrog lub hnub nyoog hauv ob qho tib si SVZ thiab DG niches, nrog rau qhov poob loj ntawm kev loj hlob los ntawm 20-24 lub hlis (Enwere li al., 2004; Kempermann li al., 1998). Cov kev tshawb fawb thaum ntxov siv BrdU kev koom ua ke hauv cov nas tau tshaj tawm txo qis progenitor proliferation hauv cov laus hippocampus, tsawg li 10 feem pua ​​​​ntawm cov neeg laus, uas ua rau txo qis tiam ntawm cov cell granule tshiab. Nws kuj tau pom tias qhov sib piv ntawm kev caij tsheb kauj vab mus rau quiescent NSCs hloov mus thoob plaws kev laus, nrog tsawg NSCs nyob rau hauv lub xeev faib (Dı´az-Moreno li al., 2018; Kalamakis li al., 2019). Ntxiv mus, tag nrho cov pas dej ua ke ntawm NSCs zoo li yuav ploj mus thiab qhov piv ntawm symmetric rau asymmetric cell divisions ua skewed (Encinas li al., 2011; Moore li al., 2015). Cov kev tshawb fawb ntxiv tau lees paub tias muaj qhov txo qis hauv neurogenesis thaum muaj hnub nyoog 6 hli hauv nas, uas cuam tshuam nrog kev poob qis hauv kev paub thiab kev hnov ​​​​lus (Imayoshi li al., 2008; Kempermann li al., 1997).

Ob qho tib si sab hauv thiab ib puag ncig cuam tshuam rau mammalian neurogenesis, suav nrog cov tsiaj muaj hnub nyoog. Piv txwv li, kev yeem tawm dag zog tuaj yeem cawm lub hnub nyoog ntsig txog neurogenesis tsis xws luag (van Praag li al., 2005). Cov kev tshawb fawb Parabiosis tau qhia tias qhov muaj cov kab mob hauv lub hnub nyoog ib puag ncig impedes neurogenesis. Hloov pauv, thaum cov tsiaj laus raug cuam tshuam rau qhov chaw ib puag ncig ntawm cov tsiaj yau los ntawm parabiosis, neurogenesis, thiab kev txawj ntse tau nce (Villeda li al., 2014). Tsis tas li ntawd, kev sib koom ua ke ntawm cov teeb liab yuav tsum tau ua kom muaj kev noj qab nyob zoo hauv lub neej neurogenesis, thiab kev hloov pauv rau cov kev taw qhia no thaum lub sij hawm laus tau txuas rau qhov poob ntawm cov neurogenesis (xws li, BMP, Notch, Wnt, EGF, thiab IGF). Ntau lub hnub nyoog cuam tshuam nrog kev hloov pauv ntawm cov cellular cuam tshuam rau neurogenesis hauv cov tsiaj muaj hnub nyoog, suav nrog kev hloov pauv, metabolic, proteostasis, thiab kev hloov pauv ntawm epigenetic (rau kev tshuaj xyuas qhov tob saib Audesse thiab Webb, 2020). Piv txwv li, lub hnub nyoog tseem ceeb ntawm NSCs yog qhov tsis zoo ntawm kev tswj hwm cov protein, suav nrog kev ua haujlwm ntawm autophagy-lysosome, kev ua haujlwm ntawm chaperone, thiab kev ua tiav tag nrho. Tag nrho cov txheej txheem no tau hloov pauv raws li NSCs hnub nyoog (Audesse li al., 2019; Leeman li al., 2018; Moore et al., 2015; Vonk et al., 2020).

Cistanche tubulosa

Kev laus thiab tib neeg Neurogenesis

Zoo ib yam li cov nas, muaj pov thawj qhia tias kev poob qis hauv hippocampal neurogenesis thaum laus hauv tib neeg. Moreno-Jimenez et al. (2019) ntsuas DCX-positive tsis paub qab hau neurons hauv 13 cov neeg mob noj qab haus huv uas tsis muaj kab mob hauv lub paj hlwb, 43 thiab 87 xyoo. DCX-zoo hlwb raug txheeb xyuas nyob rau hauv txhua tus ntawm 13 tus neeg mob, nrog rau feem pua ​​​​ntawm DCX-zoo hlwb hauv DG poob qis nrog hnub nyoog. Cov cim ntxiv ntawm kev nce qib ntawm kev sib txawv neuronal (piv txwv li, PROX1, PSANCAM, NEUN, thiab bIII-tubulin) tau pom tias muaj kev loj hlob ntawm DCX-zoo hlwb hauv cov neeg mob AD. Cov cim no, nrog rau cov cim paub txog kev loj hlob, xws li calcium-binding proteins calretinin (thaum ntxov tsis paub qab hau neurons) thiab calbindin (lig-theem maturation), yuav pab tau rau yav tom ntej kev tshawb fawb kom tag nrho cov dynamics ntawm tsis xws luag neurogenesis nyob rau hauv cov neeg laus ( Moreno-Jimenez et al. 2019). Ib txoj kev tshawb fawb thib ob uas txheeb xyuas cov ntaub so ntswg hippocampal los ntawm 28 tib neeg cov ntsiab lus ntawm 14 thiab 79 xyoo ntawm hnub nyoog xaus lus tias neurogenesis nyob rau hauv cov laus lub hlwb, tab sis hais tias tus naj npawb ntawm neural progenitors thiab tsis paub qab hau neurons nyob rau hauv DG ntawm cov hluas thiab laus cov neeg mob tseem zoo sib xws. Hauv cov laus cov ntaub so ntswg, txawm li cas los xij, muaj tsawg dua angiogenesis, neuroplasticity, thiab lub pas dej me me hauv lub anterior DG piv nrog cov ntaub so ntswg hluas (Boldrini li al., 2018). Yog li, nyob rau hauv cov kev tshawb fawb no, cov neeg laus neurogenesis tau tshaj tawm kom pheej mus thoob plaws hauv neeg laus thiab txo qis nrog hnub nyoog. Qhov twg cov mechanisms lub luag hauj lwm rau qhov poob no yog evolutionarily txuag tseem tsis tau meej. Thaum txoj kev tshawb fawb ntawm cov neeg laus neurogenesis tseem nyuaj vim tsis muaj kev nkag mus rau tib neeg cov neeg laus NSCs, cov thev naus laus zis tsis ntev los no, xws li ib leeg-cell genomics thiab cellular reprogramming, yuav pab ua qhov sib txawv tseem ceeb hauv peb txoj kev nkag siab ntawm cov neeg laus neurogenesis.

AD thiab Neurogenic Niche

Cov tsos mob ntawm AD muaj xws li kev nco tsis zoo thiab kev paub tsis meej heev. Cov neeg mob nrog AD tau txais kev poob qis ntawm cov neurons thiab kev sib txuas ntawm cov synaptic, suav nrog hauv cov kab mob hauv nruab nrog cev thiab hippocampus (Braak li al., 2006). Tshwj xeeb tshaj yog, lub cortex entorhinal muab cov tswv yim tseem ceeb rau dentate granule hlwb, suav nrog cov neeg yug hauv cov neeg laus. Lub xub ntiag ntawm extracellular plaques thiab intracellular neurofibrillary tangles yog suav tias yog cov cim tseem ceeb ntawm AD hauv cov neeg mob.

Muaj ob chav kawm tseem ceeb ntawm AD, tsis tshua muaj tsev neeg AD (FAD) thiab muaj ntau heev AD (SAD). FAD cuam tshuam nrog kev hloov pauv hauv APP, presenilin-1 (PS-1), thiab PS-2 cov noob, thiab cov kab mob uas feem ntau tsim muaj hnub nyoog 50 thiab 60 xyoo (Scheuner li al. Ib., 1996). SAD feem ntau tom qab pib dua li FAD, thiab feem ntau cuam tshuam nrog ib qho tshwj xeeb ntawm APOE noob (Corder li al., 1993). Qhov tseem ceeb, nyob rau hauv ob chav kawm ntawm AD, cov neeg mob pom cov quav hniav, tangles, thiab debilitating kev paub tsis meej.

Cov plaques thiab tangles tam sim no nyob rau hauv AD suav nrog extracellular Ab aggregates thiab neurofibrillary, misfolded tau protein, feem. Ab plaques feem ntau tshwm sim thaum ntxov ntawm cov kab mob, ua ntej cov tsos mob ntawm kev txawj ntse yog pom tau (Glenner thiab Wong, 1984). Qhov kev tshawb pom no ua rau "amyloid hypothesis," uas yog lub tswv yim tias APP cleavage cov khoom, xws li Ab42, yog lub hauv paus ua rau AD, nws thiaj li ua rau synaptic dysfunction, gliosis, neuronal poob, thiab tau pathology (Hardy, 2009) . APP yog cleaved los ntawm beta-secretase enzyme ntawm N terminus thiab gamma-secretase ntawm C-terminal kawg. Cleavage los ntawm gamma-secretase tsim Ab proteins ntawm qhov ntev sib txawv, Ab40 thiab Ab42 (Eckman thiab Eckman, 2007). Ab42 qib tau nce hauv AD thiab Ab42 muaj feem ntau dua li Ab40 los nag thiab tsim cov aggregates (Vassar thiab Citron, 2000). Ntau qhov kev hloov pauv cuam tshuam nrog qhov pib ntxov FAD cuam tshuam rau kev sib cais ntawm APP kom muaj Ab42 ntau dua li Ab40 tsim thiab tam sim no hauv AD hlwb (Scheuner li al., 1996). Cov pov thawj qhia tias Ab deposition plays lub luag haujlwm hauv AD pathology (Hardy thiab Selkoe, 2002); Txawm li cas los xij, txoj hauv kev kho mob tsom rau amyloid deposition thiab cov txheej txheem cleavage tau ua tsis tiav los txo cov tsos mob ntawm tus kab mob hauv kev sim tshuaj (Panza li al., 2019). Yog li ntawd, seb Ab deposition yog causal tseem nyob rau hauv nqe lus nug.

Cov txiaj ntsig Cistanche

Tsis ntev los no, lwm qhov kev xav rau qhov kev xav ntawm amyloid-based mechanism rau AD causality tau raug npaj. Raws li "tau hypothesis," hyperphosphorylation ntawm microtubule-associated protein tau (MAPT) ua rau AD los ntawm kev tsim cov neurofibrillary tangles. Kev tsim ntawm tau tangles yog xav kom cuam tshuam cov txheej txheem tseem ceeb ntawm tes, xws li kev thauj khoom protein, thaum kawg ua rau kev ua haujlwm tsis zoo ntawm lub hlwb thiab kev tuag (Ebneth li al., 1998; Simic li al., 2016). Txawm hais tias nws pom tseeb tias ob qho tib si Ab plaques thiab tau tangles muaj nyob rau hauv AD hlwb, yuav ua li cas ob lub ntsiab lus no cuam tshuam thiab ua rau AD pathogenesis tseem tsis meej. Ntxiv mus, cov kev tshawb fawb tsis ntev los no hauv cheeb tsam cuam tshuam txog kev mob o, oxidative kev nyuaj siab, thiab kev ua haujlwm microglial ua rau tus kab mob (Huang li al., 2016; Sudduth et al., 2013). Lwm yam kev txhawb nqa tseem tshwm sim, suav nrog kev degeneration los ntawm kev sib cuam tshuam ntawm amyloid peptides thiab macromolecules hauv hippocampal niche (xws li, palmitic acid, hlau) uas yuav ua rau retrograde degeneration nyob rau hauv lub entorhinal cortex (Young, 2020). Cov kev tshawb fawb yav tom ntej yog tsim nyog los tshawb nrhiav cov kev xav no thiab lawv cov kev cuam tshuam mus sij hawm ntev rau kev loj hlob ntawm tus kab mob.

Kelsey R. Babcock, 1 John S. Page, 2,3 Justin R. Fallon, 3,4,5 thiab Ashley E. Webb4,5,6,7,

1. Graduate Program in Neuroscience, Brown University, Providence, RI 02912, USA

2. Warren Alpert Medical School of Brown University, Providence, RI 02912, USA

3. Department of Neuroscience, Brown University, Providence, RI 02912, USA

4. Carney Institute for Brain Science, Brown University, Providence, RI 02912, USA

5. Center for Translational Neuroscience, Brown University, Providence, RI 02912, USA

6. Department of Molecular Biology, Cell Biology, thiab Biochemistry, Brown University, Providence, RI 02912, USA

7. Center on the Biology of Aging, Brown University, Providence, RI 02912, USA