Brain-immune Interactions in Neurodegenerative Disease (2016-2017)

Alzheimer’s disease is a complex chronic disease of the brain that significantly decreases memory and learning, and is ultimately fatal. The mechanism behind the onset or progression of Alzheimer’s remains unknown. Although the common view is that A-beta peptide is the principal causative factor, multiple unsuccessful clinical trials have lessened the enthusiasm for this concept and have stimulated the search for alternative pathways. Understanding these pathways may increase our ability to offset this devastating disease process.

Experiments in the Colton, Gottshalk and Chiba-Falek Labs in the Department of Neurology are designed to understand basic pathophysiological mechanisms of brain disease. This project team focused on the study of neurodegeneration and, in particular, Alzheimer’s disease.

Late-onset Alzheimer’s Disease (LOAD) accounts for roughly 99% of Alzheimer’s cases and is the most common cause of dementia. Age is the greatest known risk factor for LOAD. The next strongest risk factor is genetic background, which accounts for 58-79% of the predisposition to LOAD. In 2010, the structural variant TOMM40’523 was associated with the age-of-onset of LOAD. One of this year’s sub-projects aimed to further characterize the TOMM40 gene and investigate the functional role of TOMM40’523. To examine the regulatory role of TOMM40’523 on gene expression, team members attempted to detect the presence of a rare alternative splice variant within human brain tissue. They developed an assay to analyze TOMM40 splicing, and examined the stability of the TOMM40’523 genomic locus using two systems to genotype for potential poly-T variations.

Using the splice analysis assay, the team was able to detect a novel TOMM40 alternative splice variant. Poly-T instability was not detected in either system. Researchers will continue to investigate the role of the TOMM40’523 structural variant in neurodegeneration.

Timing

Summer 2016 – Spring 2017

Team Outcomes

Genomic Instability in Alzheimer’s Disease: TOMM40 Poly-T Variations (Kathy Z. Dai, Omolara-Chinue Glenn, Julio A. Barrera, Ornit Chiba-Falek)

Family-oriented activities at Duke Institute for Brain Sciences (DIBS) Discovery Day (April 9, 2017)

Genomic Instability in Alzheimer’s Disease: TOMM40 Poly-T Variations (honors thesis by Kathy Dai, Neuroscience)

Reflections

Kathy Dai

See earlier related team, Brain-immune Interactions in Neurodegenerative Disease (2015-2016).

Faculty/Staff Team Members

Ornit Chiba-Falek, School of Medicine - Neurology*
Carol Colton, School of Medicine - Neurology
William Gottschalk, School of Medicine - Neurology*

Undergraduate Team Members

Kathy Dai, Chemistry (AB), Neuroscience (AB2)
Ryan Kramer, Evolutionary Anthropology (BS)
Christine O'Connell, Neuroscience (AB)
Rema Shah, Neuroscience (AB)

* denotes team leader

Status

Completed, Archived