Iprotein ye-beta-amyloid (1-42) yabantu, eyaziwa ngokuba yi-Aβ 1-42, yinto ephambili ekuvuleni iimfihlelo ze-Alzheimer's disease.Le peptide idlala indima ephambili ekwenziweni kwamacwecwe e-amyloid, amaqela antsonkothileyo ayonakalisa ingqondo yezigulane ze-Alzheimer.Ngomphumo owonakalisayo, uphazamisa unxibelelwano lwe-neuronal, lubangela ukuvuvukala, kwaye lubangele i-neurotoxicity, ekhokelela ekuphazamisekeni kwengqondo kunye nomonakalo we-neural.Ukuphanda ukudityaniswa kwayo kunye neendlela zetyhefu akubalulekanga nje kuphela;luhambo olunika umdla olusingise ekusombululeni iphazili ye-Alzheimer kunye nokuphuhlisa unyango lwexesha elizayo.
I-Aβ 1-42 yiqhekeza le-peptide ye-42 amino acids ephuma kwi-cleavage ye-amyloid precursor protein (APP) nge-β- kunye ne-γ-secretases.I-Aβ 1-42 yenye yezinto eziphambili ze-amyloid plaques eziqokelela kwiingqondo zezigulane ezine-Alzheimer's disease, i-neurodeergenerative disorder ebonakaliswe ngokuphazamiseka kwengqondo kunye nokulahlekelwa kwememori.I-Aβ 1-42 ibonakaliswe ukuba inemisebenzi eyahlukeneyo kunye nokusetyenziswa kuphando lwebhayoloji kunye ne-biomedical, efana nale:
1.Neurotoxicity: I-Aβ 1-42 inokwenza i-oligomers e-soluble ekwazi ukubopha kunye nokuphazamisa umsebenzi we-neuronal membranes, i-receptors kunye ne-synapses.Ezi oligomers zinokubangela uxinzelelo lwe-oxidative, ukuvuvukala, kunye ne-apoptosis kwi-neurons, ekhokelela ekulahlekeni kwe-synaptic kunye nokufa kwe-neuronal.I-Aβ 1-42 oligomers ithathwa njenge-neurotoxic kunezinye iintlobo ze-Aβ, ezifana ne-Aβ 1-40, eyona ndlela ininzi ye-Aβ ebuchosheni.I-Aβ 1-42 i-oligomers nayo icingelwa ukuba iyakwazi ukusasaza ukusuka kwiseli ukuya kwiseli, efana ne-prions, kwaye ibangele ukungahambi kakuhle kunye nokuhlanganiswa kwezinye iiprotheni, ezifana ne-tau, eyenza i-neurofibrillary tangles kwi-Alzheimer's disease.
I-Aβ 1-42 ithathwa ngokubanzi njenge-Aβ isoform eneyona neurotoxicity iphezulu.Uphononongo oluninzi lovavanyo lubonise ubuqhophololo be-Aβ 1-42 kusetyenziswa iindlela ezahlukeneyo kunye neemodeli.Ngokomzekelo, uLesné et al.(Ubuchopho, i-2013) iphande ukubunjwa kunye ne-toxicity ye-Aβ oligomers, eziyi-soluble aggregates ye-Aβ monomers, kwaye yabonisa ukuba i-Aβ 1-42 oligomers yayinempembelelo eyingozi kakhulu kwi-neuronal synapses, ekhokelela ekunciphiseni kwengqondo kunye nokulahlekelwa kwe-neuronal.Lambert et al.(Iinkqubo ze-National Academy of Sciences, i-1998) igxininise i-neurotoxicity ye-Aβ 1-42 oligomers kwaye yafumanisa ukuba inefuthe elinobuthi elinobuthi kwinkqubo ye-nervous central, mhlawumbi ngokuchaphazela i-synapses kunye ne-neurotransmitters.Walsh et al.(Indalo, i-2002) ibonise i-inhibitory effect ye-Aβ 1-42 oligomers kwi-hippocampal ye-long-term potentiation (LTP) kwi-vivo, eyona ndlela yeselula ephantsi kokufunda kunye nememori.Olu thintelo ludibene nokukhubazeka kwememori kunye nokufunda, kugxininisa impembelelo ye-Aβ 1-42 oligomers kwi-synaptic plasticity.UShankar et al.(Nature Medicine, 2008) yodwa i-Aβ 1-42 dimers ngokuthe ngqo kwi-Alzheimer's brains kwaye ibonise umphumo wabo kwi-synaptic plasticity kunye nememori, inika ubungqina obunobungqina be-neurotoxicity ye-Aβ 1-42 oligomers.
Ukongeza, uSu et al.(I-Molecular & Cellular Toxicology, i-2019) yenza i-transcriptomics kunye nohlalutyo lweproteomics ye-Aβ 1-42-induced neurotoxicity kwiiseli ze-SH-SY5Y neuroblastoma.Bachonge iijini ezininzi kunye neeprotheni ezichatshazelwe yi-Aβ 1-42 kwiindlela ezinxulumene nenkqubo ye-apoptotic, ukuguqulelwa kweprotheyini, inkqubo ye-catabolic ye-cAMP kunye nokuphendula kwi-endoplasmic reticulum stress.Takeda et al.(I-Biological Trace Element Research, 2020) iphande indima ye-extracellular Zn2 + kwi-Aβ 1-42-induced neurotoxicity kwi-Alzheimer's disease.Baye babonisa ukuba i-Aβ 1-42-induced intracellular Zn2 + toxicity yakhawuleza ngokuguga ngenxa yokunyuka kweminyaka yobudala kwi-extracellular Zn2 +.Bacebise ukuba i-Aβ 1-42 efihliweyo ngokuqhubekayo kwi-neuron terminals ibangela ukuhla kwengqondo okunxulumene neminyaka kunye ne-neurodegeneration nge-intracellular Zn2 + dysregulation.Olu phononongo lucebisa ukuba i-Aβ 1-42 yeyona nto iphambili ekulawulweni kwe-neurotoxicity kunye nokuqhubekeka kwesifo kwi-Alzheimer's disease ngokuchaphazela iinkqubo ezahlukeneyo zeemolekyuli kunye neeseli kwingqondo.
2. Umsebenzi weAntimicrobial: I-Aβ 1-42 iye yaxelwa ukuba inomsebenzi we-antimicrobial ngokuchasene neentsholongwane ezahlukeneyo, njengebhaktheriya, umngundo, kunye neentsholongwane.I-Aβ 1-42 inokubophelela kunye nokuphazamisa i-membrane yeeseli ze-microbial, ezikhokelela kwi-lysis kunye nokufa kwazo.I-Aβ 1-42 inokuphinda isebenze isistim somzimba esizalwa kunye kwaye ifune iiseli ezosulelayo kwindawo yosulelo.Olunye uphononongo lucebise ukuba ukuqokelelana kwe-Aβ ebuchosheni kunokuba yimpendulo ekhuselayo kusulelo olungapheliyo okanye ukwenzakala.Nangona kunjalo, ukuveliswa kwe-Aβ okugqithisileyo okanye okungalawulekiyo kunokubangela umonakalo wokubambisana kwiiseli kunye nezicubu.
I-Aβ 1-42 iye yaxelwa ukuba ibonise umsebenzi we-antimicrobial ngokuchasene noluhlu lwee-pathogens, ezifana neebhaktheriya, i-fungi, kunye neentsholongwane, ezifana ne-Staphylococcus aureus, i-Escherichia coli, i-Candida albicans, kunye ne-Herpes simplex virus type 1, ngokusebenzisana neembrane zabo kubangela ukuphazamiseka kwabo kunye ne-lysis.Kumar et al.(I-Journal ye-Alzheimer's Disease, i-2016) ibonise le mpembelelo ngokubonisa ukuba i-Aβ 1-42 iguqule i-membrane permeability kunye ne-morphology yeeseli ze-microbial, ezikhokelela ekufeni kwabo.Ukongeza kwisenzo sayo esithe ngqo se-antimicrobial, i-Aβ 1-42 inokuphinda imodareyithe impendulo ye-immune yangaphakathi kwaye ifune iiseli ezivuthayo kwindawo yosulelo.Soscia et al.(i-PLoS One, i-2010) ibonakalise le nxaxheba ngokubika ukuba i-Aβ 1-42 ivuselele ukuveliswa kwe-cytokines e-pro-inflammatory kunye ne-chemokines, njenge-interleukin-6 (IL-6), i-tumor necrosis factor-alpha (TNF-α), i-monocyte i-chemoattractant protein-1 (MCP-1), kunye ne-macrophage inflammatory protein-1 alpha (MIP-1α), kwi-microglia kunye ne-astrocytes, iiseli eziphambili ze-immune kwingqondo.
Umzobo 2. I-Aβ peptides inomsebenzi we-antimicrobial.
(Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD. I-Alzheimer's ehambelana nesifo se-amyloid beta-protein yi-peptide ye-antimicrobial. PLoS One . 2010 Mar 3;5(3):e9505.)
Nangona uphando oluthile lucebise ukuba ukuqokelela kwe-Aβ kwingqondo kunokuba yimpendulo yokukhusela kwizifo ezingapheliyo okanye ukulimala, njengoko i-Aβ inokusebenza njenge-peptide ye-antimicrobial (AMP) kwaye isuse i-pathogens enokubakho, ukudibanisa okuyinkimbinkimbi phakathi kwe-Aβ kunye ne-microbial elements kuhlala kunjalo. isihloko sophando.Ibhalansi ethambileyo ibonakaliswe luphando lukaMoir et al.(Journal of Alzheimer's Disease, 2018), ecebisa ukuba ukungalingani okanye ukuveliswa kwe-Aβ ngokugqithisileyo kungonakalisa ngokungazi iiseli ezibambayo kunye nezicubu, ezibonisa ubume obuntsonkothileyo bendima ye-Aβ kusulelo kunye ne-neurodegeneration.Ukugqithiswa okanye ukuveliswa kwemveliso ye-Aβ kunokukhokelela ekudibaneni kwayo kunye nokubekwa kwingqondo, yenze i-oligomers enetyhefu kunye neefibrils eziphazamisa umsebenzi we-neuronal kwaye zenze i-neuroinflammation.Ezi nkqubo ze-pathological zinxulunyaniswa nokuncipha kwengqondo kunye nokulahleka kwememori kwi-Alzheimer's disease, i-neurodeergenerative disorder ebonakaliswe yi-dementia eqhubekayo.Ke ngoko, ulungelelwaniso phakathi kweenzuzo kunye neziphumo eziyingozi ze-Aβ zibalulekile ekugcineni impilo yobuchopho kunye nokuthintela ukubola.
3.Ukuthunyelwa ngaphandle kwentsimbi: I-Aβ 1-42 ibonakaliswe ukuba ibandakanyeka kulawulo lwe-iron homeostasis kwingqondo.I-iron yinto ebalulekileyo kwiinkqubo ezininzi zebhayoloji, kodwa i-iron egqithisileyo inokubangela uxinzelelo lwe-oxidative kunye ne-neurodegeneration.I-Aβ 1-42 inokubophelela kwintsimbi kwaye iququzelele ukuthunyelwa kwayo kwi-neurons nge-ferroportin, i-transmembrane iron transporter.Oku kunokunceda ukuthintela ukuqokelelwa kwesinyithi kunye netyhefu engqondweni, njengoko i-iron engaphezulu inokubangela uxinzelelo lwe-oxidative kunye ne-neurodegeneration.Duce et al.(Iseli, i-2010) ibike ukuba i-Aβ 1-42 ibophelelwe kwi-ferroportin kwaye yandisa intetho yayo kunye nomsebenzi kwi-neurons, ekhokelela ekunciphiseni amanqanaba ensimbi ye-intracellular.Baye babonisa kwakhona ukuba i-Aβ 1-42 inciphise ukubonakaliswa kwe-hepcidin, ihomoni evimbela i-ferroportin, kwi-astrocytes, iphucula ngakumbi ukuthunyelwa kwentsimbi kwi-neurons.Nangona kunjalo, i-Aβ ebotshwe ngentsimbi inokuthi ithandeke ngakumbi kwi-aggregation kunye ne-deposition kwi-extracellular space, yenze i-amyloid plaques.Ayton et al.(I-Journal ye-Biological Chemistry, i-2015) ibike ukuba isinyithi sikhuthaza ukubunjwa kwe-Aβ oligomers kunye ne-fibrils in vitro kunye ne-vivo.Baye babonisa kwakhona ukuba i-iron chelation iyanciphisa i-Aβ aggregation kunye nokubekwa kwiigundane ze-transgenic.Ke ngoko, ulungelelwaniso phakathi kweziphumo eziluncedo kunye neziyingozi ze-Aβ 1-42 kwi-iron homeostasis ibalulekile ekugcineni impilo yobuchopho kunye nokuthintela i-neurodegeneration.
Singumenzi wepolypeptide eTshayina, esineminyaka eliqela yamava aqolileyo kwimveliso yepolypeptide.I-Hangzhou Taijia Biotech Co., Ltd. yingcali yomenzi we-polypeptide ekrwada, enokubonelela amashumi amawaka ezinto ezikrwada ze-polypeptide kwaye inokwenziwa ngokweemfuno.Umgangatho weemveliso ze-polypeptide ugqwesileyo, kwaye ukucoceka kunokufikelela kwi-98%, eye yaqatshelwa ngabasebenzisi emhlabeni wonke.
