Hypomethylation of the amyloid precursor protein gene in the brain of an alzheimer’s disease patient

Abstract

Aberrant expression of the amyloid precursor protein (APP) gene may contribute to the beta-amyloid deposition seen in Alzheimer's disease and Down syndrome patients. Genomic DNA was isolated from human brain tissue and digested with HpaII, an enzyme sensitive to CpG methylation. Southern-blot analysis revealed the absence of methylation at a site in the APP gene of an Alzheimer's disease subject. This site was methylated in a nondemented subject and a subject with a non-Alzheimer's type of dementia (Pick's disease). This is the first report of an epigenetic defect in an Alzheimer's disease patient and the observation suggests that hypomethylation of the APP gene may be one of several factors contributing to aberrant gene expression in Alzheimer's disease.

Genetic and Epigenetic Mechanisms in Down Syndrome Brain

“…The methylation pattern in the APP promoter is different in different tissues and even in different brain areas [85]. Hypomethylation of APP is found in the cerebral cortex of aging people and AD patients [86,87]; the methylation frequency of CpG sites on APP promoter in younger people (26%) is higher than that in older people (8%), suggesting an age related methylation difference [86]. Altered methylation patterns have also been implicated in deregulation of APP processing enzymes PS1 and BACE in AD [88].…”

Epigenetics in the Human Brain

“…Thus, more than a decade ago, epigenetic exploration of the diseased human brain started out with restrictionenzyme-based DNA cytosine methylation mapping at a predetermined set of CpG dinucleotides surrounding the 5 0 end of amyloid beta precursor (Rogaev et al, 1994) and FMR1 genes in single cases diagnosed with Alzheimer's disease and fragile X-mental retardation syndrome (Tassone et al, 1999;Tohgi et al, 1999;West et al, 1995). In case of fragile X, the expansion of CGG codon from (normally) 5-40 repeats from 50 to over 200 triggers excessive DNA methylation at the promoter, effectively shutting down gene expression by silencing the surrounding chromatin (Oberle et al, 1991).…”

Alzheimer's Disease: Definition, Molecular and Genetic Factors

“…In AD twin was observed decreased DNA methylation compared to non AD twin (Mastroeni et al, 2009). Amyloid precursor protein has been shown to be normally methylated, and hypomethylated with age (Tohgi at al., 1999) and in AD patients (West et al, 1995), which subsequently enhanced production of A . Hypomethylation occurs with age and A may be involved in the generation of amyloid peptide itself.…”