摘要
背景: 早老素蛋白-1（psen-1）是参与β-淀粉样前体蛋白（aβpp）加工的γ-分泌酶复合物的组成部分。. 通常，阿尔茨海默病（AD）相关的psen-1基因突变会导致早发及增加聚集倾向肽Aβ42的产生。然而，PSEN-1 E318G变异体的致病机理尚不明确，并且近期报道为AD的遗传风险因素。特别是, E318G变异体的出现与脑脊液中总 Tau (t-tau) 和磷酸化Tau (p-tau) 水平的增多有关(CSF)。 目的: 2003年1月到2018年1月，我们跟踪调查了一个有着晚发型AD和E318G变异体的意大利大家庭, 旨在评估E318G相关脑脊液或血浆中痴呆症生物标志物的生化变化。 方法: CSF Aβ42, t-tau，p-tau以及血浆Aβ42 和 Aβ40由ELISA检验评估，CSF淀粉样肽谱采用质谱法研究。 结论: 2010年和2012年，我们没有发现无症状E318G携带者的CSF生化标记物（Aβ42, t-tau, p-tau和淀粉样肽）有任何变化，但血浆Aβ40有所增加。2003年到2018年，没有无症状的E318G携带者发展为AD。
关键词: 阿茨海默症，危险因素，家族性痴呆，淀粉样β肽，早老蛋白-1，E318G
[1]
Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349: 704-6. (1991)
[2]
Bergem AL, Engedal K, Kringlen E. The role of heredity in late-onset Alzheimer disease and vascular dementia. A twin study. Arch Gen Psychiatry 54: 264-70. (1997)
[3]
Brickell KL, Steinbart EJ, Rumbaugh M, Payami H, Schellenberg GD, Van Deerlin V, et al. Early-onset Alzheimer disease in families with late-onset Alzheimer disease: a potential important subtype of familial Alzheimer disease. Arch Neurol 63: 1307-11. (2006)
[4]
Louwersheimer E, Cohn-Hokke PE, Pijnenburg YA, Weiss MM, Sistermans EA, Rozemuller AJ, et al. Rare genetic variant in SORL1 may increase penetrance of Alzheimer’s Disease in a family with several generations of APOE-ɛ4 homozygosity. J Alzheimers Dis 56: 63-74. (2017)
[5]
Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376: 775-8. (1995)
[6]
Zhou R, Yang G, Shi Y. Dominant negative effect of the loss-of-function γ-secretase mutants on the wild-type enzyme through hetero oligomerization. Proc Natl Acad Sci USA 114: 12731-6. (2017)
[7]
Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13: 159-70. (2004)
[8]
Robinson M, Lee BY, Hanes FT. Recent progress in Alzheimer’s disease research, Part 2: Genetics and epidemiology. J Alzheimers Dis 61: 459. (2018)
[9]
1000 Genomes, a deep catalog of human genetic variation http://phase3browser.1000genomes.org/Homo_sapiens/Variation/Explore?db=core;r=14:73672678-73673678;v=rs17125721vdb=variation;vf=8537265, on May 31, 2018)
[10]
Gantier R, Dumanchin C, Campion D, Loutelier C, Lange C, Gagnon J, et al. The L392V mutation of presenilin 1 associated with autosomal dominant early-onset Alzheimer’s disease alters the secondary structure of the hydrophilic loop. Neuroreport 29: 3071-4. (1999)
[11]
Aldudo J, Bullido MJ, Frank A, Valdivieso F. Missense mutation E318G of the presenilin-1 gene appears to be a nonpathogenic polymorphism. Ann Neurol 44: 985-6. (1998)
[12]
Helisalmi S, Hiltunen M, Mannermaa A, Koivisto AM, Lehtovirta M, Alafuzoff I, et al. Is the presenilin-1 E318G missense mutation a risk factor for Alzheimer’s disease? Neurosci Lett 7: 65-8. (2000)
[13]
Arango D, Cruts M, Torres O, Backhovens H, Serrano ML, Villareal E, et al. Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. Am J Med Genet 103: 138-43. (2001)
[14]
Zekanowski C, Pepłońska B, Styczyńska M, Religa D, Pfeffer A, Czyzewski K, et al. The E318G substitution in PSEN1 gene is not connected with Alzheimer’s disease in a large Polish cohort. Neurosci Lett 357: 167-70. (2004)
[15]
Dermaut B, Cruts M, Backhovens H, Lubke U, Van Everbroeck B, Sciot R. Familial Creutzfeldt-Jakob disease in a patient carrying both a presenilin 1 missense substitution and a prion protein gene insertion. J Neurol 247: 364-8. (2000)
[16]
Berezovska O, Lleo A, Herl LD, Frosch MP, Stern EA, Bacskai BJ, et al. Familial Alzheimer’s disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein. J Neurosci 16: 3009-17. (2005)
[17]
Benitez BA, Karch CM, Cai Y, Jin SC, Cooper B, Carrell D, et al. The PSEN1, p.E318G variant increases the risk of Alzheimer’s disease in APOE-ε4 carriers. PLoS Genet 9: e1003685. (2013)
[18]
Hippen AA, Ebbert MT, Norton MC, Tschanz JT, Munger RG, Corcoran CD, et al. Presenilin E318G variant and Alzheimer’s disease risk: the Cache County study. BMC Genomics 17(3): 438. (2016)
[19]
Albani D, Roiter I, Artuso V, Batelli S, Prato F, Pesaresi M, et al. Presenilin-1 mutation E318G and familial Alzheimer’s disease in the Italian population. Neurobiol Aging 28: 1682-8. (2007)
[20]
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34: 939-44. (1984)
[21]
Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, et al. Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria. Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer’s Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA. Alzheimers Dement 12: 292-323. (2016)
[22]
Cockrell JR, Folstein MF. Mini Mental State Examination (MMSE). Psychopharmacology 24: 689-92. (1988)
[23]
Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the mini-mental state examination by age and educational level. JAMA 18: 2386-91. (1993)
[24]
Albertini V, Bruno A, Paterlini A, Lista S, Benussi L, Cereda C, et al. Optimization protocol for amyloid-beta peptides detection in human cerebrospinal fluid using SELDI TOF MS. Proteomics Clin Appl 4: 352-7. (2010)
[25]
Catania M, Di Fede G, Tonoli E, Benussi L, Pasquali C, Giaccone G, et al. Mirror image of the amyloid-β species in cerebrospinal fluid and cerebral amyloid in Alzheimer’s disease. J Alzheimers Dis 47: 877-81. (2015)
[26]
Ghidoni R, Albertini V, Squitti R, Paterlini A, Bruno A, Bernardini S, et al. Novel T719P AbetaPP mutation unbalances the relative proportion of amyloid-beta peptides. J Alzheimers Dis 18: 295-303. (2009)
[27]
Portelius E, Andreasson U, Ringman JM, Buerger K, Daborg J, Buchhave P, et al. Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer’s disease. Mol Neurodegener 5: 2. (2010)
[28]
Portelius E, Fortea J, Molinuevo JL, Gustavsson MK, Andreasson U, Sanchez-Valle R. The amyloid-β isoform pattern in cerebrospinal fluid in familial PSEN1 M139T- and L286P-associated Alzheimer’s disease. Mol Med Rep 5: 1111-5. (2012)
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