RESUMO
APOE4 allele is a major risk factor for late-onset Alzheimer disease (AD). The mechanism of action of APOE in AD remains unclear. To study the effects of APOE alleles on gene expression in AD, we have analyzed the gene transcription patterns of human hippocampus from APOE3/3, APOE3/4, APOE4/4 AD patients and normal control using Serial Analysis of Gene Expression (SAGE). Using SAGE, we found gene expression patterns in hippocampus of APOE3/4 and APOE4/4 AD patients differ substantially from those of APOE3/3 AD patients. APOE3/4 and APOE4/4 allele expression may activate similar genes or gene pools with associated functions. APOE4 AD alleles activate multiple tumor suppressors, tumor inducers and negative regulator of cell growth or repressors that may lead to increased cell arrest, senescence and apoptosis. In contrast, there is decreased expression of large clusters of genes associated with synaptic plasticity, synaptic vesicle docking and fusing and axonal/neuronal outgrowth. In addition, reduction of neurotransmitter receptors and Ca2+ homeostasis, disruption of multiple signal transduction pathways, loss of cell protection, and perhaps most notably, mitochondrial oxidative phosphorylation/energy metabolism are associated with APOE3/4 and APOE4/4 AD alleles. These findings may help define the mechanisms that APOE4 contribute that increase risk for AD and identify new candidate genes conferring susceptibility to AD.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Perfilação da Expressão Gênica/métodos , Predisposição Genética para Doença/genética , Hipocampo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Análise Mutacional de DNA , Regulação para Baixo/genética , Feminino , Regulação da Expressão Gênica/genética , Frequência do Gene/genética , Biblioteca Gênica , Testes Genéticos , Genótipo , Hipocampo/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Regulação para Cima/genéticaRESUMO
Old Order Amish, founded by a small number of Swiss immigrants, exist in culturally isolated communities across rural North America. The consequences of genetic isolation and inbreeding within this group are evident by increased frequencies of many monogenic diseases and several complex disorders. Conversely, the prevalence of Alzheimer disease (AD), the most common form of dementia, is lower in the Amish than in the general American population. Since mitochondrial dysfunction has been proposed as an underlying cause of AD and a specific haplogroup was found to affect AD susceptibility in Caucasians, we investigated whether inherited mitochondrial haplogroups affect risk of developing AD dementia in Ohio and Indiana Amish communities. Ninety-five independent matrilines were observed across six large pedigrees and three small pedigrees then classified into seven major European haplogroups. Haplogroup T is the most frequent haplogroup represented overall in these maternal lines (35.4%) while observed in only 10.6% in outbred American and European populations. Furthermore, haplogroups J and K are less frequent (1.0%) than in the outbred data set (9.4-11.2%). Affected case matrilines and unaffected control lines were chosen from pedigrees to test whether specific haplogroups and their defining SNPs confer risk of AD. We did not observe frequency differences between AD cases compared to controls overall or when stratified by sex. Therefore, we suggest that the genetic effect responsible for AD dementia in the affected Amish pedigrees is unlikely to be of mitochondrial origin and may be caused by nuclear genetic factors.
Assuntos
Doença de Alzheimer/genética , Cristianismo , Etnicidade/genética , Impressão Genômica , DNA Mitocondrial/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We examined the association of mtDNA variation with Alzheimer disease (AD) risk in Caucasians (989 cases and 328 controls) testing the effect of individual haplogroups and single nucleotide polymorphisms (SNPs). Logistic regression analyses were used to assess risk of haplogroups and SNPs with AD in both main effects and interaction models. Males classified as haplogroup U showed an increase in risk (OR = 2.30; 95% CI, 1.03-5.11; P = 0.04) of AD relative to the most common haplogroup H, while females demonstrated a significant decrease in risk with haplogroup U (OR = 0.44 ; 95% CI, 0.24-0.80; P = 0.007). Our results were independent of APOE genotype, demonstrating that the effect of mt variation is not confounded by APOE4 carrier status. We suggest that variations within haplogroup U may be involved in AD expression in combination with environmental exposures or nuclear proteins other than APOE.
