Poster Topical Area: Neurobiology
Location: Hall D
Poster Board Number: 722
Objectives: Hypercholesterolemia is intricately associated with cognitive impairment and is considered a bona-fide risk factor for dementia and neurodegenerative disorders, including Alzheimer's disease (AD). The histone deacetylase SIRT1, is a master regulator of neuronal metabolism and molecular processes that govern aging, the primary risk factor for cognitive decline and AD. SIRT1 is essential for normal cognitive function and maintenance of synaptic plasticity and synaptic integrity, known deficits in cognitive dysfunction and AD. In this study, we determined the impact of hypercholesterolemia on SIRT1 expression levels in the brain and the underlying mechanisms involved.
Methods: Three-month old cohorts of male and female rabbits (n=6) were fed a high cholesterol diet (2% w/w cholesterol) for six months. The cortex and hippocampal homogenates were subjected to immunoblotting, qRT-PCR analysis, enzyme activity assays to determine changes in SIRT1 expression and enzymatic activity. Transcription factor activity assays and Chromatin Immunoprecipitation (ChIP) analysis were subsequently performed to determine the underlying molecular mechanisms involved in mediating the effects of hypercholesterolemia on SIRT1 expression.
Results: Our data demonstrates that diet-induced hypercholesterolemia causes a profound attenuation in SIRT1 expression and enzymatic activity in the cortical and hippocampal region of the brain. Delineation and dissection of underlying cellular and molecular mechanisms implicated the hypercholesterolemia-induced Endoplasmic Reticulum (ER) stress as a pathophysiological component and unveiled the complicit role of ER-stress induced transcription factor, C/EBP Homologous Protein (CHOP) in mitigating SIRT1 expression.
Conclusions: Our novel findings identify and highlight the deleterious effects of hypercholesterolemia on SIRT1 expression in the brain. Given the seminal importance and indispensability of SIRT1 in maintaining the homeostasis of all facets of neural function and physiology, our unprecedented study bears enormous implications in the identification of molecular entities that link hypercholesterolemia to the etiology of cognitive dysfunction and neurodegenerative disorders including Alzheimer's disease.
Post Doctoral Fellow
University of North Dakota School of Medicine & Health Sciences
Grand Forks, North Dakota