Alzheimer’s disease (AD) is a neurodegenerative disease characterized by senile plaques and neurofibrillary tangles. Senile plaques are deposits of amyloid ?-peptide (A?) produced by the cleavage of a transmembrane p...Alzheimer’s disease (AD) is a neurodegenerative disease characterized by senile plaques and neurofibrillary tangles. Senile plaques are deposits of amyloid ?-peptide (A?) produced by the cleavage of a transmembrane protein termed Amyloid Precursor Protein (APP). The amyloidogenic cleavage of APP is performed by γ-secretase complex and ?-site APP cleaving enzyme 1 (BACE1), a key enzyme in AD that can be activated by different noxious stimuli. Interestingly, some viruses could activate double-stranded RNA-activated protein kinase (PKR), which phosphorylates Eukaryotic Initiation Factor 2 alpha (eIF2α). This phosphorylation stops global translation to avoid any synthesis of viral infective proteins, but paradoxically up-regulates BACE1 translation. One of the viral mechanisms to circumvent eIF2α phosphorylation is the recruitment of protein phosphatase 1 (PP1), to fully dephosphorylate eIF2α and allow viral protein synthesis. Due to the functional relationship between BACE1, PKR, PP1 and AD we have performed a large (1122 cases and 1191 control individuals) case-control genetic analysis using two biallelic polymorphisms rs2254958 and rs7480390, located within the genes coding for PKR and the catalytic unit A of PP1, respectively. Although a trend to association of the rs2254958 TT genotype with AD risk was found, our results show that neither rs7480390 nor rs2254958 are associated with AD susceptibility.展开更多
基金supported by the Spanish Ministerio de Ciencia y Tecnología(FIS:PI07/0593 and PI10/00587,ISCIII-RETIC RED HERACLES RD06/0009/002-FEDER).
文摘Alzheimer’s disease (AD) is a neurodegenerative disease characterized by senile plaques and neurofibrillary tangles. Senile plaques are deposits of amyloid ?-peptide (A?) produced by the cleavage of a transmembrane protein termed Amyloid Precursor Protein (APP). The amyloidogenic cleavage of APP is performed by γ-secretase complex and ?-site APP cleaving enzyme 1 (BACE1), a key enzyme in AD that can be activated by different noxious stimuli. Interestingly, some viruses could activate double-stranded RNA-activated protein kinase (PKR), which phosphorylates Eukaryotic Initiation Factor 2 alpha (eIF2α). This phosphorylation stops global translation to avoid any synthesis of viral infective proteins, but paradoxically up-regulates BACE1 translation. One of the viral mechanisms to circumvent eIF2α phosphorylation is the recruitment of protein phosphatase 1 (PP1), to fully dephosphorylate eIF2α and allow viral protein synthesis. Due to the functional relationship between BACE1, PKR, PP1 and AD we have performed a large (1122 cases and 1191 control individuals) case-control genetic analysis using two biallelic polymorphisms rs2254958 and rs7480390, located within the genes coding for PKR and the catalytic unit A of PP1, respectively. Although a trend to association of the rs2254958 TT genotype with AD risk was found, our results show that neither rs7480390 nor rs2254958 are associated with AD susceptibility.
