Apolipoprotein E
Apolipoprotein E (APOE) je protein uključen u metabolizam masti u tijelu sisara. Podtip je uključen u Alzheimerovu i kardiovaskularne bolesti.[5]
APOE pripada porodici proteina koji vežu masti, pod nazivom apolipoproteini. U cirkulaciji je prisutan kao dio nekoliko klasa lipoproteinskih čestica, uključujući ostatke hilomikrona, VLDL, IDL i neke HDL.[6] APOE značajno komunicira sa lipoproteinskim receptorom male gustoće (LDLR), što je neophodno za normalnu preradu (katabolizam) lipoproteina bogatih trigliceridima.[7] U perifernim tkivima primarno ga proizvode jetra i makrofagi i posreduje u metabolizmu holesterola. U centralnom nervnom sistemu, APOE uglavnom proizvode astrociti i transportuje holesterol u neurone[8] putem APOE receptora, koji su članovi porodice gena lipoproteinskih receptora male gustoće.[9] APOE je glavni nositelj holesterola u mozgu.[10] APOE je potreban za transport holesterola iz astrocita u neurone.[8] Kvalificira se kao inhibitor kontrolne tačke klasičnog puta komplementa, formiranjem kompleksa sa aktiviranim C1q.[11]
Evolucija uredi
Apolipoproteini nisu jedinstveni za sisare. Mnogi kopneni i morski kičmenjaci imaju svoje verzije.[12] Proteini slične funkcije pronađeni su u hoanoflagelatama, što upućuje na to da su oni vrlo stara klasa proteina koji prethode zori svih živih životinja. Smatra se da je APOE nastao duplikacijom gena APOC-I, prije nego što su se sisari i ribe podijelili, prije 400 miliona godina.[13]
Tri glavna ljudska alela (E4, E3, E2) nastala su nakon razdvajanja ostalih primata i čovjeka, prije oko 7,5 miliona godina. Ovi aleli su nusprodukt nesinonimnih mutacija koje su dovele do promjena u funkcionalnosti. Prvi alel koji se pojavio bio je E4. Nakon razdvajanja primata i čovjeka, dogodile su se četiri aminokiselinske promjene u ljudskoj lozi, od kojih tri nisu uticale na funkciju proteina (V174L, A18T, A135V). Četvrta supstitucija zamjenjuje treonin za arginin, koji mijenja funkcionalnost proteina. Ova supstitucija dogodila se negdje u razmaku od oko šest miliona godina između razdvajanja primata i čovjeka i razdvajanja Denisovskih ljudi, jer su potpuno iste zamjene pronađene u Denisovskom APOE.[14]
Prije oko 220.000 godina, dogodila se supstitucija arginina u cistein u aminokiselini 112 (Arg112Cys) gena APOE4, što je rezultiralo alelom E3. Konačno, prije 80.000 godina, druga supstitucija arginina u cistein na aminokiselini 158 (Arg158Cys) gena APOE3 stvorila je alel E2.[13][15]
Struktura uredi
Gen uredi
Gen, APOE , mapiran je na hromosomu 19 u klasteru sa apoliproteinom C1 (APOC1) i apolipoproteinom C2 (APOC2). Gen APOE sastoji se od četiri egzona i tri introna, što ukupno iznosi 3.597 baznih parova. APOE transkripcijski aktiviraju jetreni X receptor (važan regulator homeostaza holesterola, masnih kiselina i glukoze) i receptor aktiviran proliferatorom peroksizoma γ, jedarni receptor koji tvore heterodimere sa retinoidnim X receptorima.[16] U melanocitnim ćelijama ekspresija gena APOE može se regulirati pomoću transkripcijskog faktora povezanog sa mikroftalmijom ( MITF).[17]
Protein uredi
APOE je dugačak 299 aminokiselina i sadrži višestruke amfipatijske α-helikse. Prema studijama kristalografije, zglobna regija povezuje regije N– i C-kraja proteina. N-terminalno područje (ostaci 1–167) tvori antiparalelni snop od četiri zavojnice, tako da su nepolarne strane okrenute unutar proteina. U međuvremenu, C-terminalni domen (ostaci 206–299) sadrži tri α-heliksa koji čine veliku izloženu hidrofob nu površinu i u interakciji s onima u N-terminalnom domenu spirale vodikovih veza i mostova soli. C-terminalna regija takođe sadrži mjesto vezanja lipoproteinskog receptora male gustoće (LDLR).[18]
- Aminokiselinska sekvenca
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MKVLWAALLV | TFLAGCQAKV | EQAVETEPEP | ELRQQTEWQS | GQRWELALGR | ||||
| FWDYLRWVQT | LSEQVQEELL | SSQVTQELRA | LMDETMKELK | AYKSELEEQL | ||||
| TPVAEETRAR | LSKELQAAQA | RLGADMEDVC | GRLVQYRGEV | QAMLGQSTEE | ||||
| LRVRLASHLR | KLRKRLLRDA | DDLQKRLAVY | QAGAREGAER | GLSAIRERLG | ||||
| PLVEQGRVRA | ATVGSLAGQP | LQERAQAWGE | RLRARMEEMG | SRTRDRLDEV | ||||
| KEQVAEVRAK | LEEQAQQIRL | QAEAFQARLK | SWFEPLVEDM | QRQWAGLVEK | ||||
| VQAAVGTSAA | PVPSDNH |
- Simboli
C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin
Polimorfizmi uredi
APOE je polimorfan,[19][20] s tri glavna alela (epsilon 2, epsilon 3 i epsilon 4): APOE-ε2 (cys112, cys158), APOE-ε3 (cys112, arg158) i APOE-ε4 (arg112, arg158).[5][21][22]
Iako se ovi alelni oblici međusobno razlikuju po samo jednoj ili dvije aminokiseline na položajima 112 i 158,[23][24][25] ove razlike mijenjaju strukturu i funkciju APOE-a.
| Polimorfizam | Svjetska učestalost alela | Značaj za bolest |
|---|---|---|
| ε2 (rs7412-T, rs429358-T) | 8,4%[9] | Ova varijanta apoproteina veže se slabo za receptore na ćelijskoj površini, dok se E3 i E4 dobro vežu.[26] E2 je povezan i sa povećanim i sa smanjenim rizikom od ateroskleroze. Osobe s kombinacijom E2 / E2 mogu polahko očistiti prehrambene masnoće i biti izloženi većem riziku od ranih vaskularnih bolesti i genetičkih poremećaja hiperlipoproteinemija tipa III – 94,4% oboljelih od takve bolesti su E2 / E2, ali samo ∼2% E2 / E2 je razvija, pa će vjerovatno biti uključeni i drugi okolišni i genetički faktori (poput holesterola u prehrani i starosti).[27][28][29] Smatra se da je E2 također uključen u Parkinsonovu bolest,[30] ali ovaj nalaz nije ponovljen u većoj studiji stanovništva.[31] |
| ε3 (rs7412-C, rs429358-T) | 77,9%[9] | Ova varijanta se smatra "neutralnim" genotipom APOE . |
| ε4 (rs7412-C, rs429358-C) | 13,7%[9] | E4 je upleten u aterosklerozu, Alzheimerova bolest,[32][33] oštećena kognitivne funkcije,[34][35] smanjen hipokampusni volumen,[35] HIV,[36] brže napredovanje bolesti multipla skleroza,[37][38] nepovoljan ishod nakon traumatske ozljede mozga,[39] ishemijska cerebrovaskularna bolest,[40] apneja u snu,[41][42] ubrzano skraćivanje telomera,[43] smanjeno izrastanje neurita,[44] i COVID-19.[45] Međutim, E4 je takođe povezan sa poboljšanim statusom za vitamin D i kalcij,[46] veća plodnost,[47] zaštita od infekcija i neuhranjenosti ranog djetinjstva[48] i smanjena smrtnost fetusa, perinatalna i novorođenčadi.[49] |
Od 2007. godine još je mnogo toga trebalo naučiti o izoformama APOE, uključujući interakciju drugih potencijalno zaštitnih genetičkih polimorfizama, pa se savjetuje oprez prije davanja odlučujućih izjava o utjecaju polimorfizama APOE na kogniciju i razvoj Alzheimerove bolesti. Od 2007. godine nije bilo dokaza da APOE polimorfizmi utiču na kogniciju u mlađim dobnim skupinama (osim moguće povećane epizodne sposobnosti pamćenja i neuronske efikasnosti u mlađim dobnim skupinama APOE4), niti da izoforma APOE4 dovodi pojedince u povećani rizik od bilo koje zarazne bolesti.[50]
Funkcija uredi
APOE transportuje lipide, rastvorljive u mastima vitamine i holesterol u limfni sistem, a zatim u krvotok. Sintetizira se uglavnom u jetri, ali je pronađen i u drugim tkivima kao što su mozak, bubreg i slezena.[21] U nervnom sistemu, tipovi neuronskih ćelija, posebno astroglija i mikroglija, su primarni proizvođači APOE, dok neuroni preferencijalno eksprimiraju receptore za APOE.[51] Postoji sedam identificiranih sisarskih receptora za APOE, koji pripadaju evolucijski konzerviranoj porodici LDLR.[52]
APOE je u početku prepoznat po važnosti u metabolizmu lipoproteina i kardiovaskularna bolest. Defekti u APOE rezultiraju porodičnom disbetalipoproteinemijom aka tip III hiperlipoproteinemija (HLP III), u kojima su povećani plazmatski holesterol i trigliceridi posljedica oštećenog klirensa hilomikrona, VLDL i LDL.[7][53] U novije vrijeme proučavan je zbog njegove uloge u nekoliko bioloških procesa koji nisu izravno povezani sa transportom lipoproteina, uključujući Alzheimerovu bolest (AD), imunoregulaciju i kogniciju.[54] Iako tačni mehanizmi tek trebaju biti razjašnjeni, izoforma 4 APOE, kodirana alelom APOE, povezana je s povećanim nivoima kalcijevih iona i apoptoza nakon mehaničkih povreda.[55]
Na polju imunske regulacije, sve veći broj studija ukazuje na interakciju APOE sa mnogim procesima, uključujući suzbijanje proliferacije T-ćelija, regulaciju funkcionisanja makrofaga, olakšavanje prezentacije lipidnog antigena (CD1)[56] do T-ćelija prirodnih ubicea, kao i modulacij upala i oksidacija.[57] APOE proizvode makrofagi, a pokazalo se da je sekrecija APOE ograničena na klasične monocite u PBMC, a sekrecija APOE monocitima dolje je regulirana upalnim citokinima, a pojačana putem TGF-beta.[58]
Klinički značaj uredi
Alzheimerova bolest uredi
Od 2012. godine, varijanta E4 bila je najveći poznati genetički faktor rizika za sporadični kasni nastup Alzheimerove bolesti (AD) u različitim etničkim skupinama.[59] However, the E4 variant does not correlate with risk in every population. Nigerian people have the highest observed frequency of the APOE4 allele in world populations,[60] but AD is rare among them.[60][61] This may be due to their low cholesterol levels.[60][61][62][63] Kavkazoidni i japanski nositelji dva alela E4 imaju između 10 i 30 puta veći rizik od razvoja AD do 75. godine života, u odnosu na one koji nemaju alele E4. To može biti uzrokovano interakcijom s amiloidom.[64] Alzheimerovu bolest karakteriziraju nakupine agregata peptidnih beta-amiloida. Apolipoprotein E pojačava proteolitsku razgradnju ovog peptida, kako unutar tako i između ćelija. Izoforma APOE-ε4 nije toliko učinkovita kao ostali u podsticanju ovih reakcija, što rezultira povećanom ranjivošću na AD kod osoba s tom genskom varijacijom.[65]
Iako 40–65% pacijenata sa AD ima barem jednu kopiju alela ε4, APOE4 nije determinanta bolesti. Najmanje jedna trećina pacijenata sa AD je negativna na APOE4, a neki homozigoti na APOE4 nikada ne razviju bolest. Ipak oni sa dva alela ε4 imaju i do 20 puta veći rizik od razvoja AD.[66] Također postoje dokazi da alel APOE2 može imati zaštitnu ulogu u AD.[67] Dakle, genotip koji je najugroženiji za Alzheimerovu bolest i u ranijoj dobi je APOE4,4. Koristeći genotip APOE3,3 kao referentnu vrijednost (s osobama za koje se ovaj genotip smatra rizikom od 1,0), osobe sa genotipom APOE4,4 imaju omjer šansi od 14,9 za razvoj Alzheimerove bolesti. Osobe s genotipom APOE 3,4 suočavaju se s omjerom šansi 3,2, a ljudi s kopijom 2 alela i 4 alela (APOE2,4) imaju omjer izgleda 2,6. Osobe s po jednom kopijom od 2 alela i 3 alela (APOE2,3) imaju omjer šansi 0,6. Osobe s dvije kopije alela 2 (APOE2,2) također imaju omjer šansi 0,6.[68]
| Procijenjena frekvencija (%) alela APOE u svjetskoj kavkazoidnoj populaciji[68] | ||||
| Alel | ε2 | ε3 | ε4 | |
|---|---|---|---|---|
| Opća frekvencija | 8,4 | 77,9 | 13,7 | |
| Frekvencija AD | 3,9 | 59,4 | 36,7 | |
Iako je utvrđeno da ApoE4 uveliko povećava izglede da će osoba razviti Alzheimerovu bolest, istraživanje iz 2002. godine zaključilo je da su osobe s bilo kojom kombinacijom alela APOE, visoki ukupni holesterol u serumu i povišeni krvni pritisak u srednjem vijeku života neovisni faktori rizika, koji zajedno mogu gotovo utrostručiti rizik da će kasnije razviti AD. Projektirajući na osnovu svojih podataka, neki istraživači sugeriraju da snižavanje nivoa holesterola u serumu može smanjiti rizik osobe za Alzheimerovu bolest, čak i ako ima dva alela ApoE4, smanjujući tako rizik od devet ili deset puta veće šanse za smanjenje AD na samo dva puta veće šanse.
U žena je vjerovatnije da će razviti AD od muškaraca u većini dobnih skupina i APOE genotipova. Premorbidne žene sa alelom ε4 imaju znatno više nervne disfunkcije od muškaraca.[69]
Ateroskleroza uredi
Nokaut-miševi kojima nedostaje gen apolipoprotein-E (APOE– /–) razvija ekstremnu hiperholesterolemiju, kada se hrani hranom sa puno masnoće.[70]
Malarija uredi
Nokaut-miševi APOE−/− pokazuju izrazito slabljenje cerebralne malarije i povećano preživljavanje, kao i smanjenu sekvestraciju parazita i T-ćelija u mozgu, vjerovatno zbog zaštite krvno-moždane barijere.[71] Studije na ljudima pokazale su da polimorfizam APOE2 korelira s ranijom infekcijom, a polimorfizmi APOE3 / 4 povećavaju vjerovatnoću teške malarije.[72]
Interakcije uredi
Mapa interaktivnog puta uredi
Reference uredi
- ^ a b c GRCh38: Ensembl release 89: ENSG00000130203 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000002985 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b Stolerman IP, ured. (2010). Encyclopedia of Psychopharmacology (Online izd.). Berlin: Springer. ISBN 978-3540686989.
- ^ Mahley RW, Weisgraber KH, Huang Y (april 2009). "Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS". Journal of Lipid Research. 50 Suppl (Suppl): S183-8. doi:10.1194/jlr.R800069-JLR200. PMC 2674716. PMID 19106071.
- ^ a b "Entrez Gene: APOE apolipoprotein E".
- ^ a b Wang, Hao; Kulas, Joshua A.; Ferris, Heather A.; Hansen, Scott B. (14. 10. 2020). "Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol". bioRxiv (jezik: engleski): 2020.06.18.159632. doi:10.1101/2020.06.18.159632.
- ^ a b c d Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (februar 2013). "Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy". Nature Reviews. Neurology. 9 (2): 106–18. doi:10.1038/nrneurol.2012.263. PMC 3726719. PMID 23296339.
- ^ Puglielli L, Tanzi RE, Kovacs DM (april 2003). "Alzheimer's disease: the cholesterol connection". Nature Neuroscience. 6 (4): 345–51. doi:10.1038/nn0403-345. PMID 12658281. S2CID 5407666.
- ^ Yin C, Ackermann S, Ma Z, Mohanta SK, Zhang C, Li Y, et al. (mart 2019). "ApoE attenuates unresolvable inflammation by complex formation with activated C1q". Nature Medicine. 25 (3): 496–506. doi:10.1038/s41591-018-0336-8. PMC 6420126. PMID 30692699.
- ^ Babin PJ, Thisse C, Durliat M, Andre M, Akimenko MA, Thisse B (august 1997). "Both apolipoprotein E and A-I genes are present in a nonmammalian vertebrate and are highly expressed during embryonic development". Proceedings of the National Academy of Sciences of the United States of America. 94 (16): 8622–7. Bibcode:1997PNAS...94.8622B. doi:10.1073/pnas.94.16.8622. PMC 23048. PMID 9238027.
- ^ a b Huebbe P, Rimbach G (august 2017). "Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors". Ageing Research Reviews. 37: 146–161. doi:10.1016/j.arr.2017.06.002. PMID 28647612. S2CID 3758905.
- ^ McIntosh AM, Bennett C, Dickson D, Anestis SF, Watts DP, Webster TH, et al. (2012). "The apolipoprotein E (APOE) gene appears functionally monomorphic in chimpanzees (Pan troglodytes)". PLOS ONE. 7 (10): e47760. Bibcode:2012PLoSO...747760M. doi:10.1371/journal.pone.0047760. PMC 3480407. PMID 23112842.
- ^ Finch CE, Stanford CB (mart 2004). "Meat-adaptive genes and the evolution of slower aging in humans". The Quarterly Review of Biology. 79 (1): 3–50. doi:10.1086/381662. PMID 15101252. S2CID 14225962.
- ^ Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, et al. (januar 2001). "A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis". Molecular Cell. 7 (1): 161–71. doi:10.1016/S1097-2765(01)00164-2. PMID 11172721.
- ^ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, et al. (decembar 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971. S2CID 24698373.
- ^ Phillips MC (septembar 2014). "Apolipoprotein E isoforms and lipoprotein metabolism". IUBMB Life. 66 (9): 616–23. doi:10.1002/iub.1314. PMID 25328986. S2CID 6159310.
- ^ Singh PP, Singh M, Mastana SS (2006). "APOE distribution in world populations with new data from India and the UK". Annals of Human Biology. 33 (3): 279–308. doi:10.1080/03014460600594513. PMID 17092867. S2CID 34696595.
- ^ Eisenberg DT, Kuzawa CW, Hayes MG (septembar 2010). "Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history". American Journal of Physical Anthropology. 143 (1): 100–11. doi:10.1002/ajpa.21298. PMID 20734437.
- ^ a b Baars HF, van der Smagt JJ, Doevandans P (2011). Clinical Cardiogenetics. London: Springer. ISBN 978-1849964715.
- ^ Ghebranious N, Ivacic L, Mallum J, Dokken C (oktobar 2005). "Detection of ApoE E2, E3 and E4 alleles using MALDI-TOF mass spectrometry and the homogeneous mass-extend technology". Nucleic Acids Research. 33 (17): e149. doi:10.1093/nar/gni155. PMC 1243648. PMID 16204452.
- ^ OMIM: APOE3 isoform, hyperlipoproteinemia, type III, autosomal recessive -107741#0015
- ^ OMIM: APOE3 isoform, APOE, CYS112 and ARG158 -107741#0001
- ^ Zuo L, van Dyck CH, Luo X, Kranzler HR, Yang BZ, Gelernter J (april 2006). "Variation at APOE and STH loci and Alzheimer's disease". Behavioral and Brain Functions. 2 (1): 13. doi:10.1186/1744-9081-2-13. PMC 1526745. PMID 16603077.
- ^ Weisgraber KH, Innerarity TL, Mahley RW (mart 1982). "Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site". The Journal of Biological Chemistry. 257 (5): 2518–21. doi:10.1016/S0021-9258(18)34954-8. PMID 6277903.
- ^ Breslow JL, Zannis VI, SanGiacomo TR, Third JL, Tracy T, Glueck CJ (novembar 1982). "Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2". Journal of Lipid Research. 23 (8): 1224–35. doi:10.1016/S0022-2275(20)38060-3. PMID 7175379.
- ^ Feussner G, Feussner V, Hoffmann MM, Lohrmann J, Wieland H, März W (1998). "Molecular basis of type III hyperlipoproteinemia in Germany". Human Mutation. 11 (6): 417–23. doi:10.1002/(SICI)1098-1004(1998)11:6<417::AID-HUMU1>3.0.CO;2-5. PMID 9603433.
- ^ Civeira F, Pocoví M, Cenarro A, Casao E, Vilella E, Joven J, et al. (decembar 1996). "Apo E variants in patients with type III hyperlipoproteinemia". Atherosclerosis. 127 (2): 273–82. doi:10.1016/S0021-9150(96)05969-2. PMID 9125318.
- ^ Huang X, Chen PC, Poole C (juni 2004). "APOE-[epsilon]2 allele associated with higher prevalence of sporadic Parkinson disease". Neurology. 62 (12): 2198–202. doi:10.1212/01.wnl.0000130159.28215.6a. PMID 15210882. S2CID 10445412.
- ^ Federoff M, Jimenez-Rolando B, Nalls MA, Singleton AB (maj 2012). "A large study reveals no association between APOE and Parkinson's disease". Neurobiology of Disease. 46 (2): 389–92. doi:10.1016/j.nbd.2012.02.002. PMC 3323723. PMID 22349451.
- ^ Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. (august 1993). "Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families". Science. 261 (5123): 921–3. Bibcode:1993Sci...261..921C. doi:10.1126/science.8346443. PMID 8346443.
- ^ Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (mart 1993). "Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease". Proceedings of the National Academy of Sciences of the United States of America. 90 (5): 1977–81. Bibcode:1993PNAS...90.1977S. doi:10.1073/pnas.90.5.1977. PMC 46003. PMID 8446617.
- ^ Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C, Wright AF, et al. (august 2002). "Cognitive change and the APOE epsilon 4 allele". Nature. 418 (6901): 932. doi:10.1038/418932a. hdl:1842/702. PMID 12198535.
- ^ a b Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC (novembar 2004). "Impact of APOE in mild cognitive impairment". Neurology. 63 (10): 1898–901. doi:10.1212/01.wnl.0000144279.21502.b7. PMID 15557508. S2CID 21131734.
- ^ Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, et al. (juni 2008). "Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression". Proceedings of the National Academy of Sciences of the United States of America. 105 (25): 8718–23. doi:10.1073/pnas.0803526105. PMC 2438419. PMID 18562290.
- ^ Chapman J, Vinokurov S, Achiron A, Karussis DM, Mitosek-Szewczyk K, Birnbaum M, et al. (februar 2001). "APOE genotype is a major predictor of long-term progression of disability in MS". Neurology. 56 (3): 312–6. doi:10.1212/wnl.56.3.312. PMID 11171894. S2CID 40761206.
- ^ Schmidt S, Barcellos LF, DeSombre K, Rimmler JB, Lincoln RR, Bucher P, et al. (mart 2002). "Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis". American Journal of Human Genetics. 70 (3): 708–17. doi:10.1086/339269. PMC 384947. PMID 11836653.
- ^ Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M, Tsenter J, et al. (januar 1999). "Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury". Neurology. 52 (2): 244–8. doi:10.1212/wnl.52.2.244. PMID 9932938. S2CID 131908791.
- ^ McCarron MO, Delong D, Alberts MJ (oktobar 1999). "APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis". Neurology. 53 (6): 1308–11. doi:10.1212/wnl.53.6.1308. PMID 10522889. S2CID 23443430.
- ^ Kadotani H, Kadotani T, Young T, Peppard PE, Finn L, Colrain IM, et al. (juni 2001). "Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults". JAMA. 285 (22): 2888–90. doi:10.1001/jama.285.22.2888. PMID 11401610.
- ^ Gottlieb DJ, DeStefano AL, Foley DJ, Mignot E, Redline S, Givelber RJ, Young T (august 2004). "APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study". Neurology. 63 (4): 664–8. doi:10.1212/01.wnl.0000134671.99649.32. PMID 15326239. S2CID 12280483.
- ^ Jacobs EG, Kroenke C, Lin J, Epel ES, Kenna HA, Blackburn EH, Rasgon NL (februar 2013). "Accelerated cell aging in female APOE-ε4 carriers: implications for hormone therapy use". PLOS ONE. 8 (2): e54713. doi:10.1371/journal.pone.0054713. PMC 3572118. PMID 23418430.
- ^ Raber J (maj 2008). "AR, apoE, and cognitive function". Hormones and Behavior. 53 (5): 706–15. doi:10.1016/j.yhbeh.2008.02.012. PMC 2409114. PMID 18395206.
- ^ Kuo CL, Pilling LC, Atkins JL, Masoli JA, Delgado J, Kuchel GA, Melzer D (oktobar 2020). "APOE e4 Genotype Predicts Severe COVID-19 in the UK Biobank Community Cohort". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 75 (11): 2231–2232. doi:10.1093/gerona/glaa131. PMC 7314139. PMID 32451547.
- ^ Huebbe P, Nebel A, Siegert S, Moehring J, Boesch-Saadatmandi C, Most E, et al. (septembar 2011). "APOE ε4 is associated with higher vitamin D levels in targeted replacement mice and humans". FASEB Journal. 25 (9): 3262–70. doi:10.1096/fj.11-180935. PMID 21659554.
- ^ Jasienska G, Ellison PT, Galbarczyk A, Jasienski M, Kalemba-Drozdz M, Kapiszewska M, et al. (mart 2015). "Apolipoprotein E (ApoE) polymorphism is related to differences in potential fertility in women: a case of antagonistic pleiotropy?". Proceedings. Biological Sciences. 282 (1803): 20142395. doi:10.1098/rspb.2014.2395. PMC 4345437. PMID 25673673.
- ^ Oriá RB, Patrick PD, Oriá MO, Lorntz B, Thompson MR, Azevedo OG, et al. (mart 2010). "ApoE polymorphisms and diarrheal outcomes in Brazilian shanty town children". Brazilian Journal of Medical and Biological Research. 43 (3): 249–56. doi:10.1590/s0100-879x2010007500003. PMC 3057459. PMID 20401432.
- ^ Becher JC, Keeling JW, Bell J, Wyatt B, McIntosh N (august 2008). "Apolipoprotein E e4 and its prevalence in early childhood death due to sudden infant death syndrome or to recognised causes". Early Human Development. 84 (8): 549–54. doi:10.1016/j.earlhumdev.2008.01.002. PMID 18280677.
- ^ Mondadori CR, de Quervain DJ, Buchmann A, Mustovic H, Wollmer MA, Schmidt CF, et al. (august 2007). "Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers". Cerebral Cortex. 17 (8): 1934–47. doi:10.1093/cercor/bhl103. PMID 17077159.
- ^ Zhang Z, Mu J, Li J, Li W, Song J (januar 2013). "Aberrant apolipoprotein E expression and cognitive dysfunction in patients with poststroke depression". Genetic Testing and Molecular Biomarkers. 17 (1): 47–51. doi:10.1089/gtmb.2012.0253. PMC 3525887. PMID 23171142.
- ^ Rogers JT, Weeber EJ (august 2008). "Reelin and apoE actions on signal transduction, synaptic function and memory formation". Neuron Glia Biology. 4 (3): 259–70. doi:10.1017/S1740925X09990184. PMID 19674510.
- ^ Sacks FM (februar 2015). "The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia". Current Opinion in Lipidology. 26 (1): 56–63. doi:10.1097/MOL.0000000000000146. PMC 4371603. PMID 25551803.
- ^ Greška kod citiranja: Nevaljana oznaka
<ref>; nije naveden tekst za reference s imenomenciklopedija - ^ Jiang L, Zhong J, Dou X, Cheng C, Huang Z, Sun X (august 2015). "Effects of ApoE on intracellular calcium levels and apoptosis of neurons after mechanical injury". Neuroscience. 301: 375–83. doi:10.1016/j.neuroscience.2015.06.005. PMID 26073697. S2CID 42716198.
- ^ van den Elzen P, Garg S, León L, Brigl M, Leadbetter EA, Gumperz JE, et al. (oktobar 2005). "Apolipoprotein-mediated pathways of lipid antigen presentation". Nature. 437 (7060): 906–10. Bibcode:2005Natur.437..906E. doi:10.1038/nature04001. PMID 16208376. S2CID 3109596.
- ^ Zhang HL, Wu J, Zhu J (2010). "The role of apolipoprotein E in Guillain-Barré syndrome and experimental autoimmune neuritis". Journal of Biomedicine & Biotechnology. 2010: 357412. doi:10.1155/2010/357412. PMC 2825561. PMID 20182542.
- ^ Braesch-Andersen S, Paulie S, Smedman C, Mia S, Kumagai-Braesch M (2013). "ApoE production in human monocytes and its regulation by inflammatory cytokines". PLOS ONE. 8 (11): e79908. Bibcode:2013PLoSO...879908B. doi:10.1371/journal.pone.0079908. PMC 3828220. PMID 24244577.
- ^ Sadigh-Eteghad S, Talebi M, Farhoudi M (oktobar 2012). "Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer's disease. A meta-analysis". Neurosciences. 17 (4): 321–6. PMID 23022896.
- ^ a b c Sepehrnia B, Kamboh MI, Adams-Campbell LL, Bunker CH, Nwankwo M, Majumder PP, Ferrell RE (oktobar 1989). "Genetic studies of human apolipoproteins. X. The effect of the apolipoprotein E polymorphism on quantitative levels of lipoproteins in Nigerian blacks". American Journal of Human Genetics. 45 (4): 586–91. PMC 1683508. PMID 2491016.
- ^ a b Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen P, et al. (1. 1. 1998). "Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease". Neuroepidemiology. 17 (1): 14–20. doi:10.1159/000026149. PMID 9549720. S2CID 71543885.
- ^ Petanceska SS, DeRosa S, Sharma A, Diaz N, Duff K, Tint SG, et al. (1. 1. 2003). "Changes in apolipoprotein E expression in response to dietary and pharmacological modulation of cholesterol". Journal of Molecular Neuroscience. 20 (3): 395–406. doi:10.1385/JMN:20:3:395. PMID 14501024. S2CID 35969696.
- ^ Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, et al. (august 2002). "Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease". Annals of Internal Medicine. 137 (3): 149–55. doi:10.7326/0003-4819-137-3-200208060-00006. PMID 12160362. S2CID 23780605.
- ^ Wisniewski T, Frangione B (februar 1992). "Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid". Neuroscience Letters. 135 (2): 235–8. doi:10.1016/0304-3940(92)90444-C. PMID 1625800. S2CID 8839627.
- ^ Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, et al. (juni 2008). "ApoE promotes the proteolytic degradation of Abeta". Neuron. Cell Press. 58 (5): 681–93. doi:10.1016/j.neuron.2008.04.010. PMC 2493297. PMID 18549781. Sažetak – ScienceDaily (13. 6. 2008).
- ^ Hauser PS, Ryan RO (oktobar 2013). "Impact of apolipoprotein E on Alzheimer's disease". Current Alzheimer Research. 10 (8): 809–17. doi:10.2174/15672050113109990156. PMC 3995977. PMID 23919769.
- ^ Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, et al. (juni 1994). "Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease". Nature Genetics. 7 (2): 180–4. doi:10.1038/ng0694-180. PMID 7920638. S2CID 11137478.
- ^ a b Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. (1997). "Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium". JAMA. 278 (16): 1349–56. doi:10.1001/jama.1997.03550160069041. PMID 9343467.
- ^ Damoiseaux JS, Seeley WW, Zhou J, Shirer WR, Coppola G, Karydas A, et al. (juni 2012). "Gender modulates the APOE ε4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels". The Journal of Neuroscience. 32 (24): 8254–62. doi:10.1523/JNEUROSCI.0305-12.2012. PMC 3394933. PMID 22699906.
- ^ McNeill E, Channon KM, Greaves DR (mart 2010). "Inflammatory cell recruitment in cardiovascular disease: murine models and potential clinical applications". Clinical Science. 118 (11): 641–55. doi:10.1042/CS20090488. PMID 20210786.
- ^ Kassa FA, Van Den Ham K, Rainone A, Fournier S, Boilard E, Olivier M (septembar 2016). "Absence of apolipoprotein E protects mice from cerebral malaria". Scientific Reports. 6: 33615. Bibcode:2016NatSR...633615K. doi:10.1038/srep33615. PMC 5028887. PMID 27647324.
- ^ Wozniak MA, Riley EM, Itzhaki RF (mart 2004). "Apolipoprotein E polymorphisms and risk of malaria". Journal of Medical Genetics. 41 (3): 145–6. doi:10.1136/jmg.2003.014613. PMC 1735716. PMID 14985370.
Dopunska literatura uredi
- Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (februar 2013). "Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy". Nature Reviews. Neurology. 9 (2): 106–18. doi:10.1038/nrneurol.2012.263. PMC 3726719. PMID 23296339.
- Gunzburg MJ, Perugini MA, Howlett GJ (decembar 2007). "Structural basis for the recognition and cross-linking of amyloid fibrils by human apolipoprotein E". The Journal of Biological Chemistry. 282 (49): 35831–41. doi:10.1074/jbc.M706425200. PMID 17916554.
- Kolovou GD, Anagnostopoulou KK (august 2007). "Apolipoprotein E polymorphism, age and coronary heart disease". Ageing Research Reviews. 6 (2): 94–108. doi:10.1016/j.arr.2006.11.001. PMID 17224309. S2CID 35607578.
- Lambert JC, Amouyel P (august 2007). "Genetic heterogeneity of Alzheimer's disease: complexity and advances". Psychoneuroendocrinology. 32 Suppl 1 (Suppl 1): S62-70. doi:10.1016/j.psyneuen.2007.05.015. PMID 17659844. S2CID 8114580.
- Raber J (2007). "Role of apolipoprotein E in anxiety". Neural Plasticity. 2007: 91236. doi:10.1155/2007/91236. PMC 1940061. PMID 17710250.
- Ye J (august 2007). "Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus". PLOS Pathogens. 3 (8): e108. doi:10.1371/journal.ppat.0030108. PMC 1959368. PMID 17784784.
- Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, et al. (septembar 2007). "Association of apolipoprotein E genotypes with lipid levels and coronary risk". JAMA. 298 (11): 1300–11. doi:10.1001/jama.298.11.1300. PMID 17878422.
- Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA (juni 2004). "The role of viruses and of APOE in dementia". Annals of the New York Academy of Sciences. 1019 (1): 15–8. Bibcode:2004NYASA1019...15I. doi:10.1196/annals.1297.003. PMID 15246985. S2CID 28979273.
- Ashford JW (2004). "APOE genotype effects on Alzheimer's disease onset and epidemiology". Journal of Molecular Neuroscience. 23 (3): 157–65. doi:10.1385/JMN:23:3:157. PMID 15181244. S2CID 14864342.
- Huang Y, Weisgraber KH, Mucke L, Mahley RW (2004). "Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease". Journal of Molecular Neuroscience. 23 (3): 189–204. doi:10.1385/JMN:23:3:189. PMID 15181247. S2CID 40135107.
- Masterman T, Hillert J (juni 2004). "The telltale scan: APOE epsilon4 in multiple sclerosis". The Lancet. Neurology. 3 (6): 331. doi:10.1016/S1474-4422(04)00763-X. PMID 15157846. S2CID 54404547.
- Bocksch L, Stephens T, Lucas A, Singh B (decembar 2001). "Apolipoprotein E: possible therapeutic target for atherosclerosis". Current Drug Targets. Cardiovascular & Haematological Disorders. 1 (2): 93–106. doi:10.2174/1568006013337944. PMID 12769659.
- Mahley RW, Rall SC (2002). "Apolipoprotein E: far more than a lipid transport protein". Annual Review of Genomics and Human Genetics. 1 (1): 507–37. doi:10.1146/annurev.genom.1.1.507. PMID 11701639.
- Parasuraman R, Greenwood PM, Sunderland T (april 2002). "The apolipoprotein E gene, attention, and brain function". Neuropsychology. 16 (2): 254–74. doi:10.1037/0894-4105.16.2.254. PMC 1350934. PMID 11949718.
- Mahley RW, Ji ZS (januar 1999). "Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E". Journal of Lipid Research. 40 (1): 1–16. doi:10.1016/S0022-2275(20)33334-4. PMID 9869645.
- Beffert U, Danik M, Krzywkowski P, Ramassamy C, Berrada F, Poirier J (juli 1998). "The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease". Brain Research. Brain Research Reviews. 27 (2): 119–42. doi:10.1016/S0165-0173(98)00008-3. PMID 9622609. S2CID 28731779.
- Roses AD, Einstein G, Gilbert J, Goedert M, Han SH, Huang D, et al. (januar 1996). "Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism". Annals of the New York Academy of Sciences. 777 (1): 146–57. Bibcode:1996NYASA.777..146R. doi:10.1111/j.1749-6632.1996.tb34413.x. PMID 8624078. S2CID 9145181.
- Strittmatter WJ, Roses AD (maj 1995). "Apolipoprotein E and Alzheimer disease". Proceedings of the National Academy of Sciences of the United States of America. 92 (11): 4725–7. Bibcode:1995PNAS...92.4725S. doi:10.1073/pnas.92.11.4725. PMC 41779. PMID 7761390.
- de Knijff P, van den Maagdenberg AM, Frants RR, Havekes LM (1995). "Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels". Human Mutation. 4 (3): 178–94. doi:10.1002/humu.1380040303. PMID 7833947. S2CID 41959843.
- Moriyama K, Sasaki J, Matsunaga A, Arakawa F, Takada Y, Araki K, et al. (septembar 1992). "Apolipoprotein E1 Lys-146----Glu with type III hyperlipoproteinemia". Biochimica et Biophysica Acta. 1128 (1): 58–64. doi:10.1016/0005-2760(92)90257-V. PMID 1356443.
- Mahley RW (april 1988). "Apolipoprotein E: cholesterol transport protein with expanding role in cell biology". Science. 240 (4852): 622–30. Bibcode:1988Sci...240..622M. doi:10.1126/science.3283935. PMID 3283935.
- Utermann G, Pruin N, Steinmetz A (januar 1979). "Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man". Clinical Genetics. 15 (1): 63–72. doi:10.1111/j.1399-0004.1979.tb02028.x. PMID 759055. S2CID 34127430.
Vanjski linkovi uredi
- Apolipoproteins E na US National Library of Medicine Medical Subject Headings (MeSH)
- apoe4.info – website for APOE-epsilon-4 carriers
- Lokacija ljudskog genoma APOE i stranica sa detaljima o genu APOE u UCSC Genome Browseru.
- P02649