Poster Topical Area: Neurobiology

Location: Hall D

Poster Board Number: 704

P16-002 - Effects of δ-tocotrienols and lovastatin on GluA1 and the accumulation of amyloid β protein: role of the mevalonate pathway

Monday, Jun 11
8:00 AM – 3:00 PM

Objectives: Alzheimer's Disease (AD) is a progressive neurodegenerative condition characterized by a loss of memory, destruction of the ability to learn and a decreased ability to make judgements, communicate in a social environment, or perform daily tasks. Due to the increase in life expectancy, it is estimated the number of AD patients will be over 100 million by 2050. Accumulation of neurotic plaques containing amyloid beta protein (Aβ) is one of the hallmarks of AD. Statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, reduce the levels of two mevalonate-derived intermediates, farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP), and consequently reduce Aβ. Mevalonate metabolites may also play a role in synaptic function. We hypothesize that δ-tocotrienol, which enhances the degradation of HMG CoA reductase, and lovastatin increase the expression of the GluA1 subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) through its regulatory effects on Arc protein, a known regulator of AMPAR trafficking.
Methods:
To test the effects of δ-tocotrienol and lovastatin on AD, neuroblastoma cells (Neuro-2a) were incubated with increasing concentrations of δ-tocotrienol and Arc expression and ERK 1/2 phosphorylation were analyzed by western blot. Additionally, surface levels of GluA1 were measured in primary hippocampal neurons isolated from postnatal mice using an on-cell western blot and Aβ levels in media were quantified using an ELISA-based assay. Results: Arc protein expression was significantly decreased with addition of low doses (1 uM) but not higher doses (10 uM) of δ-tocotrienol in Neuro-2a cells. Moreover, an increase in the expression of the GluA1 AMPAR subunit was observed with addition of δ-tocotrienol (1 uM) in primary hippocampal neurons. Neurons exposed to lovastatin (1 uM) had a decrease in the levels of Aβ but did not alter the expression of the GluA1 AMPAR subunit.
Conclusion:
Suppressors of HMG-CoA reductase, a component of the mevalonate pathway, may provide unique therapeutic approaches for the treatment of AD and age-related cognitive decline.




Funding Source: American River Nutrition, Inc

CoAuthors: Sophie Yount – Georgia State University; Shea Sparks – Georgia State University; Zack Allen – Georgia State University; Angela Mabb, PhD – Georgia State University; Weiming Xia, PhD – Bedford VA hospital, Boston University School of Medicine; Huanbiao Mo, PhD – Georgia State University

Katherine Bechdol

Graduate Research Assistant
Georgia State University
Stone Mountain, Georgia