Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by synapse dysfunction and cognitive impairment. Understanding the development and progression of AD is challenging, as the disease is highly complex and multifactorial. Both environmental and genetic factors play a role in AD pathogenesis, highlighted by observations of complex DNA modifications at the single gene level, and by new evidence that also implicates changes in genome architecture in AD patients. The four-dimensional structure of chromatin in space and time is essential for context-dependent regulation of gene expression in post-mitotic neurons. Dysregulation of epigenetic processes have been observed in the aging brain and in patients with AD, though there is not yet agreement on the impact of these changes on transcription. New evidence shows that proteins involved in genome organization have altered expression and localization in the AD brain, suggesting that the genomic landscape may play a critical role in the development of AD. This review discusses the role of the chromatin organizers and epigenetic modifiers in post-mitotic cells, the aging brain, and in the development and progression of AD. How these new insights can be used to help determine disease risk and inform treatment strategies will also be discussed.
Highlights
Non-dividing post-mitotic cells present a unique challenge in biology—how can cells survive, in some cases for the entire lifespan of an organism, while dealing with environmental challenges such as oxidative or endoplasmic reticulum stress, DNA damage, or changes in metabolic state? Many cellular homeostatic changes require a DNA response to either activate or repressGenome Architecture in Aging and Alzheimer’s Disease transcription of response genes, which implies state-dependent dynamic regulation of gene access
By considering Alzheimer’s disease (AD) as a disease that involves the dysregulation of chromatin organizers and topology, we can begin to untangle the complex epigenetic changes that occur to better target the core genome architecture changes that lead to synaptic dysfunction and neurodegeneration
Studies are needed to address what topological chromatin changes are directly relevant to disease progression, as the four-dimensional structure of chromatin is critical for context-dependent regulation of gene expression
Summary
Non-dividing post-mitotic cells present a unique challenge in biology—how can cells survive, in some cases for the entire lifespan of an organism, while dealing with environmental challenges such as oxidative or endoplasmic reticulum stress, DNA damage, or changes in metabolic state? Many cellular homeostatic changes require a DNA response to either activate or repressGenome Architecture in Aging and Alzheimer’s Disease transcription of response genes, which implies state-dependent dynamic regulation of gene access. This review addresses how chromatin is organized in post-mitotic cells, and the disruptions in genome architecture observed in aging and neurodegenerative disease.
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