For drivers of Alzheimer’s disease, check the roadmap

Recently, the BroadMinded blog highlighted the exciting science emerging from the Roadmap Epigenomics program, resulting in the most comprehensive map of the human epigenome — the collection of chemical changes to DNA and its supporting proteins that help control how genes are turned on or off. Described in a suite of Nature papers, the Epigenome Roadmap aims to help enable basic biology and disease research, and it is already shedding light on a question debated by neurobiologists for years: Is Alzheimer’s disease rooted more in neuronal dysregulation or immune dysregulation?

In Alzheimer’s disease (AD), the brain is marked by accumulations of misfolded beta-amyloid protein around cells and tangles of misfolded tau protein within cells, causing neuronal damage and dysfunction, and presumably contributing to cognitive impairments. However, AD brains also show signs of inflammation, including activated microglial cells and macrophages. Scientists don’t fully understand the interplay of these neuronal and immune factors in the initiation and progression of AD, but clues may lie in the human genome and epigenome.

Lifestyle and environmental factors like age, diet, education, and exercise contribute to AD risk, but the disease also has a hereditary component. The late-onset form of AD is 60% to 80% genetic, and recent genome-wide association studies have identified several DNA variants that contribute to risk. Understanding the genetic alterations that predispose individuals to AD, and the functional effects of those variants, could shed light on what happens in the brain before patients even show symptoms, and could potentially uncover new therapeutic avenues.

The majority of AD risk factors are found in so-called “non-coding” regions of the genome — areas that fall outside of the protein-coding segments of DNA and often are involved in turning genes on or off by adding or removing epigenetic marks on DNA or its associated chromatin protein. The abundance of non-coding variants associated with AD suggests that the regulation of genes may be key to the initiation of the disease. To understand the impact of gene regulation in AD, a team of researchers led by Manolis Kellis, institute member of the Broad and professor in MIT’s Computer Science and Artificial Intelligence Laboratory, and Li-Huei Tsai, senior associate member of the Broad and director of the Picower Institute for Learning and Memory at MIT, set out to map the epigenetic landscape during neurodegeneration.

They began by observing changes in the activity and epigenetic state of genes in brain tissue from a mouse model of AD, during early and late stages of neurodegeneration. As the disease progressed, they observed increased activity in cell-cycle and immune response genes, and decreased activity in synaptic and learning function genes, a pattern consistent with what’s seen in human cases of AD. The patterns of epigenetic marks in the AD mice mirrored those found in human brain tissues, and genomic regions of increased and decreased activity mapped to segments of human DNA with immune and neural function in the human genome, respectively.

“The conservation of function between human and mouse underscores the power of using model systems to study the epigenomics of human disease,” said Andreas Pfenning, co-first author and a postdoctoral researcher in the Kellis lab.

To understand whether immune activation was simply a consequence of neuronal loss, the researchers investigated the genetic factors known to predispose individuals to AD based on genome-wide association studies. They found that AD-associated variants were only found in immune-related regions that were activated during AD progression, and were surprisingly lacking in neuron-related regions that were shut off. They found the same results by studying AD variant activity across the 127 reference epigenomes of the Epigenome Roadmap: AD-associated variants were only active in immune cell types, not in neuronal cells or brain tissues, suggesting that genetic predisposition is rooted in the immune system, rather than in neuronal cells.

The work implicates immune function as a major player in the initial development of AD, and supports a model in which genetic risk factors dysregulate immune cells and environmental factors epigenomically alter neuronal cells, possibly driving increased immune susceptibility to environmental factors during aging and cognitive decline.

“Our work also identified a number of regulators, among them the transcription factor PU.1, which binds many of the regulatory regions implicated in AD and is likely to act as a ‘master regulator’ of the immune response, thereby providing a novel target for future therapeutic interventions,” said Elizabeta Gjoneska, co-first author and postdoctoral researcher in the Tsai lab.

More research is needed to fully explain the role of the immune system during neurodegeneration, but this work demonstrates the power of model organisms to study disease progression and the effects of therapeutic interventions.

Other scientists on the work include co-first author Elizabeta Gjoneska, Hansruedi Mathys, Gerald Quon, and Anshul Kundaje.

Gjoneska E, et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature. 518, 365-369 (19 February 2015). DOI: 10.1038/nature14252