Opening up the DNA methylome of dementia

Abstract

Dementia is a complex clinical condition characterized by several cognitive impairments that interfere with patient independence in executing everyday tasks. Various neurodegenerative disorders have dementia in common among their clinical manifestations. In addition, these diseases, such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies and frontotemporal dementia, share molecular alterations at the neuropathological level. In recent years, the field of neuroepigenetics has expanded massively and it is now clear that epigenetic processes, such as DNA methylation, are mechanisms involved in both normal and pathological brain function. Despite the persistent methodological and conceptual caveats, it has been reported that several genes fundamental to the development of neurodegenerative disorders are deregulated by aberrant methylation patterns of their promoters, and even common epigenetic signatures for some dementia-associated pathologies have been identified. Therefore, understanding the epigenetic mechanisms that are altered in dementia, especially those associated with the initial phases, will allow us not only to understand the etiopathology of dementia and its progression but also to design effective therapies to reduce this global public health problem. This review provides an in-depth summary of our current knowledge about DNA methylation in dementia, focusing exclusively on the analyses performed in human brain.

Figure 1

Schematic representation of the known connections between Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies and frontotemporal dementia. These disorders not only feature dementia as one of their core clinical manifestations but also share neuropathological alterations such as amyloid-β accumulation, Tau alterations (hyperphosphorylation or loss of function) and α-synuclein aggregation (Lewy bodies).

Figure 2

Illustration to summarize the major DNA (hydroxy)methylation changes described to date in Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) among different brain regions. Red, hypermethylated genes in the disorder; green, hypomethylated genes in the disorder.

Figure 3

Representation of the known intracellular location of proteins encoded by genes undergoing aberrant DNA methylation in dementia. Nuclear, cytosolic or membrane-associated genes both in neurons (blue) or glia (principally astrocytes and microglia; in pale brown) are illustrated, together with secreted (extracellular) proteins (green).