title: A common BACE1 polymorphism is a risk factor for sporadic Creutzfeldt-Jakob disease.
abstract: The β site APP cleaving enzyme 1 (BACE1) is the rate-limiting β-secretase enzyme in the amyloidogenic processing of APP and Aβ formation, and therefore it has a prominent role in Alzheimer's disease (AD) pathology. Recent evidence suggests that the prion protein (PrP) interacts directly with BACE1 regulating its β-secretase activity. Moreover, PrP has been proposed as the cellular receptor involved in the impairment of synaptic plasticity and toxicity caused by Aβ oligomers. Provided that common pathophysiologic mechanisms are shared by Alzheimer's and Creutzfeldt-Jakob (CJD) diseases, we investigated for the first time to the best of our knowledge a possible association of a common synonymous BACE1 polymorphism (rs638405) with sporadic CJD (sCJD). Our results indicate that BACE1 C-allele is associated with an increased risk for developing sCJD, mainly in PRNP M129M homozygous subjects with early onset. These results extend the very short list of genes (other than PRNP) involved in the development of human prion diseases; and support the notion that similar to AD, in sCJD several loci may contribute with modest overall effects to disease risk. These findings underscore the interplay in both pathologies of APP, Aβ oligomers, ApoE, PrP and BACE1, and suggest that aging and perhaps vascular risk factors may modulate disease pathologies in part through these key players.
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Calero
authors.forename: María J
authors.initials: MJ
authors.lastname: Bullido
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
authors.forename: Ana
authors.initials: A
authors.lastname: Frank-García
authors.forename: Pablo
authors.initials: P
authors.lastname: Martínez-Martín
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Rey
authors.forename: Isabel
authors.initials: I
authors.lastname: Sastre
authors.forename: Alberto
authors.initials: A
authors.lastname: Rábano
authors.forename: Jesús
authors.initials: J
authors.lastname: de Pedro-Cuesta
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.forename: Miguel
authors.initials: M
authors.lastname: Calero
mesh_terms: D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D016022:Case-Control Studies; D003062:Codon / Q000235:genetics; D007562:Creutzfeldt-Jakob Syndrome / Q000201:enzymology* / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide
chemical_list: D003062:Codon; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human