RESUMO
MCP-1 levels are increased in CSF of patients with Alzheimer's disease (AD) compared with controls, suggesting a role in the development of dementia. Recently, a biallelic A/G polymorphism in the MCP-1 promoter at position -2518 has been found, influencing the level of MCP-1 expression in response to an inflammatory stimulus. The distribution of the A-2518G SNP was determined in 269 AD patients and in 203 healthy age matched controls, showing no differences between the two groups. On the contrary, a significant increase of MCP-1 serum levels in AD patients carrying at least one G mutated allele was observed. Moreover, the highest peaks of MCP-1 serum levels were present in patients carrying two G alleles. Stratifying by ApoE genotype, gender or age at onset, no differences in both allele frequency and MCP-1 serum concentration were observed. The A-2518G polymorphism in MCP-1 gene does not seem to be a risk factor for the development of AD, but its presence correlates with higher levels of serum MCP-1, which can contribute to increase the inflammatory process occurring in AD.
Assuntos
Doença de Alzheimer/genética , Quimiocina CCL2/genética , Quimiotaxia de Leucócito/genética , Encefalite/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético/genética , Idade de Início , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/imunologia , Quimiocina CCL2/sangue , Quimiocinas/imunologia , Quimiotaxia de Leucócito/imunologia , Análise Mutacional de DNA , Encefalite/sangue , Encefalite/imunologia , Feminino , Frequência do Gene/genética , Testes Genéticos , Genótipo , Humanos , Itália , Masculino , Mutação/genética , Fatores de Risco , Fatores Sexuais , Regulação para Cima/genética , Regulação para Cima/imunologiaRESUMO
The accumulation of altered proteins is a common pathogenic mechanism in several neurodegenerative disorders. A causal role of protein aggregation was originally proposed in Alzheimer's disease (AD) where extracellular deposition of beta-amyloid (Abeta) is the main neuropathological feature. It is now believed that intracellular deposition of aggregated proteins may be relevant in Parkinson's disease (PD), amyotrophic lateral sclerosis and polyglutamine disorders. An impairment of ubiquitin-proteasome system (UPS) appears directly involved in these disorders. We reviewed the results on the role of protein misfolding in AD and PD and the influence of mutations associated with these diseases on the expression of amyloidogenic proteins. Results of genetic screening of familial cases of AD and PD are summarized. In the familial AD population (70 subjects) we found several mutations of the presenilin 1 (PS1) gene with a frequency of 12.8% and one mutation in the gene encoding the protein precursor of amyloid (APP) (1.4%). One mutation of Parkin in the homozygous form and two in the heterozygous form were identified in our PD population. We also reported data obtained with synthetic peptides and other experimental models, for evaluation of the pathogenic role of mutations in terms of protein misfolding.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Ubiquitina-Proteína Ligases , Idoso , Amiloide/química , Amiloide/metabolismo , Cisteína Endopeptidases/metabolismo , Humanos , Ligases/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Complexos Multienzimáticos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Presenilina-1 , Presenilina-2 , Complexo de Endopeptidases do Proteassoma , Dobramento de Proteína , Sinucleínas , Ubiquitina/metabolismoRESUMO
A pathogenic role of inflammatory factors has been proposed both in Alzheimer's disease (AD) and vascular dementia (VD). A previous report indicated the presence of polymorphism C-850T of tumor necrosis factor (TNF) alpha as a genetic risk factor for VD and, associated with apolipoprotein E epsilon 4, for AD. We have assessed the association between TNF-alpha polymorphism and dementias in Italian populations of AD, VD and elderly controls. The influence of TNF-alpha polymorphism on dementia has not been confirmed in this segment of the Italian population.