This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Alzheimer's disease (AD) is a neurodegenerative disorder with a complex pathogenesis and for which there is limited therapeutic intervention. The major pathological hallmarks of AD are the accumulations of B-amyloid (AB) peptide, the hyperphosphorylation of tau, and neuronal damage. Accumulation of AB may be particularly important because mutations in specific genes, as occur in familial AD, are associated with increased AB levels. While these genetic mutations are responsible for the accumulation of AB in familial AD, the causative factors for increased levels of AB in most cases of AD are not known. Hypercholesterolemia and caffeine are two factors that are capable of modulating AB levels and may affect the pathogenesis of AD. Our longterm objectives are to identify risks and mechanisms by which these factors contribute to the pathology of AD. The objective of this proposal is to determine the extent to which and the mechanisms by which cholesterol-enriched diet triggers and caffeine attenuates or exacerbates AD-like pathology in rabbit brain. The hypotheses to be tested in this proposal are (1) that cholesterol-enriched diets cause B-amyloid (AB) accumulation, tau hyperphosphorylation and neurodegeneration involving modulation of adenosine A2A receptors (A2AR), inositol-1,4,5-trisphosphate receptors (IP3R), and ryanodine receptors (RyR), and (2) that caffeine-induced blockage of A2AR or blockade of calcium release through IP3R will attenuate and caffeine-induced release of calcium from RyR-regulated calcium channels will exacerbate AB accumulation, tau hyperphosphorylation and neurodegeneration.
Our specific aims are as follows:
Aim 1 : Determine the extent to which the expression of A2AR, RyR and IP3R is altered in brain of rabbits fed a diet enriched in cholesterol;
Aim 2 : Determine the extent to which caffeine dose-dependently regulates cholesterol-induced AD-like pathology and modulates A2AR, RyR and IP3R in rabbit brain;
and Aim 3 : Determine the extent to which A2AR, RyR and IP3R are involved in cholesterol-induced AB accumulation, tau phosphorylation and oxidative damage. Successful completion of the work proposed here will increase our understanding of the cellular mechanisms by which two factors, cholesterol and caffeine, affect the pathogenesis of AD and may lead to newer and better therapeutics for the prevention or treatment of AD.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZRR1-RI-5 (01))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Dakota
Anatomy/Cell Biology
Schools of Medicine
Grand Forks
United States
Zip Code
Sukumaran, Pramod; Schaar, Anne; Sun, Yuyang et al. (2016) Functional role of TRP channels in modulating ER stress and Autophagy. Cell Calcium 60:123-32
Puig, Kendra L; Kulas, Joshua A; Franklin, Whitney et al. (2016) The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice. Neurobiol Aging 40:22-40
Liu, Qing Yan; Koukiekolo, Roger; Zhang, Dong Ling et al. (2016) Molecular events linking cholesterol to Alzheimer's disease and inclusion body myositis in a rabbit model. Am J Neurodegener Dis 5:74-84
Moritz, Amy E; Rastedt, Danielle E; Stanislowski, Daniel J et al. (2015) Reciprocal Phosphorylation and Palmitoylation Control Dopamine Transporter Kinetics. J Biol Chem 290:29095-105
Zhou, Xikun; Ye, Yan; Sun, Yuyang et al. (2015) Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase C? Signaling. Mol Cell Biol 35:2729-39
Puig, Kendra L; Lutz, Brianna M; Urquhart, Siri A et al. (2015) Overexpression of mutant amyloid-? protein precursor and presenilin 1 modulates enteric nervous system. J Alzheimers Dis 44:1263-78
Zhang, Shuang; Yu, Min; Guo, Qiang et al. (2015) Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway. Sci Rep 5:15859
Rojanathammanee, Lalida; Floden, Angela M; Manocha, Gunjan D et al. (2015) Attenuation of microglial activation in a mouse model of Alzheimer's disease via NFAT inhibition. J Neuroinflammation 12:42
Wallert, Mark A; Hammes, Daniel; Nguyen, Tony et al. (2015) RhoA Kinase (Rock) and p90 Ribosomal S6 Kinase (p90Rsk) phosphorylation of the sodium hydrogen exchanger (NHE1) is required for lysophosphatidic acid-induced transport, cytoskeletal organization and migration. Cell Signal 27:498-509
Cain, Jacob T; Berosik, Matthew A; Snyder, Stephanie D et al. (2014) Shifts in the vascular endothelial growth factor isoforms result in transcriptome changes correlated with early neural stem cell proliferation and differentiation in mouse forebrain. Dev Neurobiol 74:63-81

Showing the most recent 10 out of 175 publications