RESUMEN
Alzheimer's disease (AD) is the first most common neurodegenerative disease. Despite a large amount of research, the pathogenetic mechanism of AD has not yet been clarified. The two hallmarks of the pathology of AD are the extracellular senile plaques (SPs) of aggregated amyloid-beta (Aß) peptide and the accumulation of the intracellular microtubule-associated protein tau into fibrillar aggregates. Heat shock proteins (HSPs) play a key role in preventing protein misfolding and aggregation, and Hsp90 can be viewed as a ubiquitous molecular chaperone potentially involved in AD pathogenesis. A role of Hsp90 regulates the activity of the transcription factor heat shock factor-1 (HSF-1), the master regulator of the heat shock response. In AD, Hsp90 inhibitors may redirect neuronal aggregate formation, and protect against protein toxicity by activation of HSF-1 and the subsequent induction of heat shock proteins, such as Hsp70. Therefore, we review here to further discuss the recent advances and challenges in targeting Hsp90 for AD therapy.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/terapia , Proteínas HSP90 de Choque Térmico/química , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Terapia Molecular DirigidaRESUMEN
Recently, two large genome-wide association studies (GWASs) have identified several variants at 12q14 and 12q24 which are associated with hippocampal volume, one of the most important biological markers of Alzheimer's disease (AD). The strongest association was reported for the rs7294919 polymorphism on chromosome 12q24.22. In order to explore whether rs7294919 polymorphism was also associated with late-onset AD (LOAD) risk, we recruited 1132 LOAD patients and 1159 sex- and age-matched healthy controls in the study. The results showed that rs7294919 polymorphism was significantly associated with LOAD (genotype P<0.01, allele P=0.02). After stratification by APOE, significant difference was only observed in non-APOE É4 carriers (P=0.01). Logistic regression demonstrated that the C allele at rs7294919 was a risk factor for LOAD in dominant and recessive models after adjusting for age, gender and the APOE É4 carrier status. In conclusion, our study demonstrates an association of rs7294919 polymorphism locus on chromosome 12q24.22 with risk for LOAD in Han Chinese.
Asunto(s)
Enfermedad de Alzheimer/genética , Pueblo Asiatico , Cromosomas Humanos Par 12/genética , Sitios Genéticos , Polimorfismo de Nucleótido Simple , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/etnología , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , MasculinoRESUMEN
An expanded hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72), on chromosome 9p21, has recently been identified as a major cause of familial frontotemporal dementia (FTD). The neuropathology and clinical characteristics associated with C9ORF72 mutations are heterogeneous with the unknown pathomechanism. These cases were reported with a series of neuropathology, including TDP-43 pathology, ubiquilin (UBQLN) pathology, p62 pathology, microglial pathology, RNA-binding protein pathology and pathology associated with dipeptide-repeat (DPR) proteins. TDP-43 positive neuropathology was important in FTD patients with the mutations. Nevertheless, the majority of reports agree with a special pattern of neuropathology with p62 positive, TDP-43-negative inclusions being a consistent feature. Although subjects with the C9ORF72 mutations more frequently present with earlier onset age, earlier death, a shortened survival and a positive family history, most of the subjects present with typical clinical features of FTD. All these findings support that the C9ORF72 mutations become important newly recognized causes of FTD, providing a more detailed characterization of the associated clinical and pathological features. The following review summarizes the pathological development of FTD associated with C9ORF72, the clinical and pathological features of this cohort, some pathological mechanism hypotheses, and describes their phenotypic range and overlap with other neurodegenerative diseases.
Asunto(s)
Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Mutación/genética , Proteínas/genética , Edad de Inicio , Proteína C9orf72 , Proteínas de Unión al ADN/genética , Salud de la Familia , Humanos , FenotipoRESUMEN
Toll-like receptor 4 (TLR4) represents a reasonable functional and positional candidate gene for Alzheimer's disease (AD) as it is located within the previous identified linkage region of AD on chromosome 9q, and functionally is involved in the microglia-mediated inflammatory response, amyloid-ß (Aß) plaque formation and Aß clearance. To test whether variants in the TLR4 gene are associated with late-onset AD (LOAD), we organized a multicenter study of 785 subjects (399 cases and 386 matched controls) in a Han Chinese population. Ten single nucleotide polymorphisms (SNPs) that span the TLR4 gene, from approximately 5 kb of the predicted 5'-untranslated region (UTR) to approximately 6 kb of the predicted 3'- UTR, were selected and their associations with LOAD risk factors were assessed. With respect to allelic diversity, the minor alleles of seven SNPs (rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, rs7037117, and rs7045953) in TLR4 showed consistent protective effects against the risk of developing LOAD. With regard to genotypic diversity, individuals carrying at least one minor allele of each SNP above had a consistently lower risk of LOAD than those with no copies of the minor alleles (ORs ranging from 0.445 to 0.637). rs7045953, located in the 3'-UTR of TLR4, was most strongly associated with LOAD, and when incorporated into a haplotype with rs10759930, the strongest association was detected (P = 1.7x10-6, Pc s1.0x10-4). Our data suggests that the TLR4 gene contributes to the susceptibility for LOAD in Han Chinese.
Asunto(s)
Enfermedad de Alzheimer/etnología , Enfermedad de Alzheimer/genética , Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Receptor Toll-Like 4/genética , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/etnología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Oportunidad RelativaRESUMEN
Toll-like receptor 2 (TLR2) represents a reasonable functional and positional candidate gene for Alzheimer's disease (AD) as it is located under the linkage region of AD on chromosome 4q, and is functionally involved in the microglia-mediated inflammatory response and amyloid ß (Aß) clearance. In the current study, 7 single nucleotide polymorphisms (SNPs) that span the TLR2 were selected and their associations with late-onset AD (LOAD) risk were assessed in a case-control sample comprising 785 individuals in a Han Chinese population. No significant differences in the frequency of TLR2 alleles, genotypes, and haplotypes in the AD cases were detected compared with the controls. TLR2 gene might not play a major role in the genetic predisposition to late-onset Alzheimer's disease in this population.
Asunto(s)
Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 2/genética , Pueblo Asiatico/etnología , Pueblo Asiatico/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 4/genética , Estudios de Asociación Genética , HumanosRESUMEN
OBJECTIVES: To investigate influences of the functional polymorphisms of Cytochrome P450 isozymes 2A6 (CYP2A6), 2B6 (CYP2B6), and 2C9 (CYP2C9) on pharmacokinetics of VPA in vivo. PATIENTS AND METHODS: In the study, we analyzed the genotypes of CYP2A6, CYP2B6, and CYP2C9 and their contribution to the steady-state standardized plasma VPA concentrations in 179 subjects with epilepsy of a Northern Han Chinese population. The genotypes were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The subjects with one or two variant CYP2A6*4 alleles showed higher mean plasma VPA concentrations compared with non-*4 alleles [(3.4+/-0.4)microg kg ml(-1)mg(-1) vs. (3.6+/-0.4)microg kg ml(-1)mg(-1), p=0.0055]. A significant difference [one-way ANOVA (p=0.0203)] was also found between mean plasma VPA concentrations and the CYP2B6 genotypes. In addition, subjects with the heterozygous genotype CYP2C9*3 had higher mean plasma VPA concentrations than did those subjects with the wild-type genotype [(3.9+/-0.4)microg kg ml(-1)mg(-1) vs. (3.4+/-0.4)microg kg ml(-1)mg(-1), p=0.0001]. CONCLUSION: The presently evaluated variant alleles in the CYP2A6, CYP2B6, and CYP2C9 genes may explain part of the substantial variability in VPA pharmacokinetics between different subjects.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Epilepsia/genética , Epilepsia/metabolismo , Oxidorreductasas N-Desmetilantes/genética , Ácido Valproico/farmacocinética , Adolescente , Adulto , Alelos , Niño , Preescolar , China/epidemiología , Citocromo P-450 CYP2A6 , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP2C9 , Epilepsia/epidemiología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Ácido Valproico/sangre , Adulto JovenRESUMEN
Increasing evidence indicates that the beta2-adrenergic receptor (beta2-AR) may play an important role in Alzheimer's disease (AD). We investigated the effect of two polymorphisms in the beta2-AR gene: Gly16Arg and Gln27Glu for the risk of sporadic Late Onset Alzheimer's Disease (LOAD) in 109 patients and 109 healthy controls matched for sex and age in a Han Chinese population. Results revealed that both the 16Gly allele and the 27Glu allele of the beta2-AR gene were associated with an increased risk of LOAD (P=0.009, OR=1.652 and P=0.002, OR=2.846, respectively), and they also showed a highly significant interaction with the Apolipoprotein E gene (APOE) epsilon4 allele (OR=4.200 and 9.441, respectively). Examination of the haplotypes identified the Gly16Glu27 haplotype to increase the risk of LOAD (P=0.004). Our results suggest that variations in the beta2-AR gene play an important role in the pathogenesis of sporadic LOAD, and interact with the epsilon4 allele to markedly increase the LOAD risk.