Gene Regulatory-Network Maps Guide Alzheimer's Disease Researchers

Researchers studying the molecular basis for development of neurological disorders have constructed a map of the gene-regulatory networks associated with late-onset Alzheimer’s disease (LOAD).

LOAD is the most common form of Alzheimer's disease. Nonetheless, the molecular mechanisms that underlie LOAD have not been defined. At present, no effective disease modifying or preventive therapies exist and the number of individuals suffering from the disease is expected to double within the next forty years.

Investigators at the Icahn School of Medicine at Mount Sinai (New York, NY, USA) and numerous collaborators including researchers at the Icelandic Heart Association (Kopavogur, Iceland) applied a systems approach based on large-scale human brain-tissue sampling to study LOAD. Specifically, they constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and healthy subjects.

The networks were based on integrated analysis of patient DNA combined with gene expression data. The networks provided a unified map that integrated not only the key genes involved in the disease but also the biological pathways that those genes control.

Results published in the April 25, 2013, online edition of the journal Cell revealed that evaluation of network interactions pointed to the gene TYROBP (TYRO protein tyrosine kinase-binding protein) as a key regulator, which was upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP showed expression changes that significantly overlapped the human brain TYROBP network.

TYROBP is known to interact with the gene TREM2 (triggering receptor expressed on myeloid cells 2). A rare missense mutation in the TREM2 gene confers a significant risk of Alzheimer's disease. Given the reported anti-inflammatory role of TREM2 in the brain, it is suspected of interfering with the brain’s ability to prevent the buildup of plaque.

Senior author Dr. Valur Emilsson, head of systems medicine at the Icelandic Heart Association, said, “Currently, we see a long lag time between appearance of amyloid on brain scans of patients and the appearance of clinical symptoms. An individual's inflammatory response could well play a role in the disease progression, and an appropriate anti-inflammatory drug, given after amyloid is detected but before symptoms begin, could be an important part of dementia prevention.”

Related Links:
Icahn School of Medicine at Mount Sinai
Icelandic Heart Association