Poster Topical Area: Neurobiology
Location: Hall D
Poster Board Number: 721
Objectives: A multitude of epidemiological and clinical studies have ascribed a deleterious role of high cholesterol diets in precipitating cognitive decline as well as evoking deficits in learning and memory. However, the molecular mechanisms that underlie and effectuate the detrimental effects of a high cholesterol diet in the initiation and fostering of pathophysiological cascades that induce cognitive dysfunction remain elusive and egregiously characterized. In this study, we determined the effects of a cholesterol-enriched diet (2% w/w cholesterol in diet for six months) on the expression of the Brain-derived Neurotrophic Factor (BDNF), the most abundant neurotrophic factor that plays a seminal role in learning, memory, and cognition.
Methods: Three-month old cohorts of male and female rabbits (n=8) were fed a high cholesterol diet (2% w/w cholesterol) for six months. The cortex and hippocampal homogenates were subjected to immunoblotting, kinase activity assays, transcription factor activity assays, and Chromatin Immunoprecipitation (ChIP) analysis to determine the effects of high cholesterol diet on BDNF expression and delineate the underlying molecular mechanisms.
Results: Herein, we demonstrate that a high cholesterol diet decreases BDNF expression in the cortex and hippocampi of male and female rabbits. We further elucidated and delineated the upstream molecular mechanisms and found that the cholesterol-enriched diet causes an attenuation in cyclic AMP levels and the ensuing Protein Kinase A (PKA) activation that results in a mitigation of basal CREB transcriptional activity. Further delving into the underlying molecular basis characterized a reduced CREB-driven trans-activation of the BDNF promoter that culminates in a decrease in BDNF expression. This decrease in BDNF expression translated and manifested into a commensurate decrease in downstream BDNF signaling through its cognate receptor, Tropomyosin Receptor Kinase B (TrkB).
Conclusions: Our study highlights the dysregulation in BDNF expression and signaling as a seminal event that underlies the high cholesterol diet-induced cognitive impairment and deficits in learning and memory.
Post Doctoral Fellow
University of North Dakota School of Medicine & Health Sciences
Grand Forks, North Dakota