2011-2012 ARDRAF Final Project Report

Functional Characterization of Promoter Polymorphisms of the Human GRIN2B Glutamate Receptor Gene Associated with Altered Memory Functioning in Older Adults

Functional Characterization of Promoter Polymorphisms of the Human GRIN2B Glutamate Receptor Gene Associated with Altered Memory Functioning in Older Adults

Robert H. Lipsky, PhD 

George Mason University

Mild cognitive impairment (MCI) is a clinical diagnosis that describes a small but measurable decline in an individual’s cognitive abilities, including memory.  A person with MCI is at greater risk of developing Alzheimer’s disease. Currently, there are no methods for early detection of MCI or to predict the outcome of MCI or its progression to Alzheimer’s disease.  FDA-approved drugs for treating symptoms of Alzheimer’s do not seem to benefit MCI patients, underscoring a need to understandthe underlying mechanisms leading to MCI.  Using a method that combines an understanding of human geneticsandbrain imaging, the investigators discovered a variant of the GRIN2B gene, a gene critical for learning and memory that may be a marker for MCI.  The funded study determined how this genetic variant controls the GRIN2B gene at the biochemicalandcellular level.  They found a protein, Elk-1, that binds the DNA of the GRIN2B gene variant, called the A allele.  The A allele also activates genes introduced into neuron-like cells maintained in the laboratory.  These results support their previous observation that the A allele of the GRIN2B gene is linked to a specific pattern of brain activity seen when older adults (who were otherwise matched for age, gender,andcognitive ability) performed certain memory tasks.  Taken together, these results are the first to support the role of a GRIN2B gene variant associated with human memory performance based on molecularandcellular function.  They constitute the first genetic association between a functional NR2B gene variantandan endophenotype, a characteristic that is more closely related to pathophysiology of AD than diagnostic markers.

 (Dr. Lipsky may be contacted at 703/993-5140;robert.lipsky@nova.org)

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