This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR017699-07
Application #
7720885
Study Section
Special Emphasis Panel (ZRR1-RI-5 (01))
Project Start
2008-06-01
Project End
2009-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
7
Fiscal Year
2008
Total Cost
$231,239
Indirect Cost
Name
University of North Dakota
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
102280781
City
Grand Forks
State
ND
Country
United States
Zip Code
58202
Kulas, Joshua A; Puig, Kendra L; Combs, Colin K (2017) Amyloid precursor protein in pancreatic islets. J Endocrinol 235:49-67
Krout, Danielle; Pramod, Akula Bala; Dahal, Rejwi Acharya et al. (2017) Inhibitor mechanisms in the S1 binding site of the dopamine transporter defined by multi-site molecular tethering of photoactive cocaine analogs. Biochem Pharmacol 142:204-215
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
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
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
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

Showing the most recent 10 out of 178 publications