Alzheimer's disease (AD) is a complex neurodegenerative disorder for which there is presently no effective therapy. While some genetic mutations are responsible for the familial AD forms, the causative factors for the non-familial forms, which represent the majority of cases, are not known. Identification of risk factors and mechanisms by which these factors contribute to the pathology of AD may therefore aid in better understanding the disease and may ultimately lead to designing an efficient therapeutic strategy to prevent the onset or stop the progression of this devastating disorder. Our longterm objectives are to identify risk factors and mechanisms by which these factors trigger the pathogenesis of AD. Hypercholesterolemia is a potential risk factors for AD. However, the mechanisms by which high blood cholesterol levels affect the brain and increase the risk of AD are not known. The objective of this application is to determine the extent to which cholesterol-enriched diets cause cellular damage in the brain with AD features. We will be using a long-term cholesterol-enriched diet in the rabbits a model system that we have found to demonstrate iron deposition, beta-amyloid (Abeta) accumulation, and oxidative stress, all hallmarks of AD. Our hypothesis is that cholesterol diets increase levels of the cholesterol metabolite, 27-hydroxy-cholesterol, which crosses a disrupted blood brain barrier (BBB) and activates the endoplasmic reticulum stress response, thereby activating the growth arrest-and DNA damage-inducible gene 153 (gadd153) and the cytokine, TNF-alpha. While activation of gadd153 triggers the generation of reactive oxygen species and the overproduction of Abeta, the activation of TNF-alpha alters iron metabolism, induces apoptosis and exacerbates oxidative stress. To test our hypothesis, our specific aims are as follows:
Aim I. Identify mechanisms that underlie hypercholesterolemia-induced oxidative stress, Abeta accumulation and iron dyshomeostasis. We will determine the role of gadd153 and TNF-alpha in iron dyshomeostasis, oxidative stress induction and Abeta accumulation.
Aim II. Determine the extent to which chelation of iron protects against the deleterious effects of hypercholesterolemia. We will determine the effect of the iron chelator, deferiprone, on hypercholesterolemia-induced iron dyshomeostasis, oxidative stress and Abeta generation.
Aim III. Determine the extent to which lowering blood cholesterol levels reduces the entrance of 27- hydroxycholesterol into the brain, thereby inhibiting oxidative stress, iron dyshomeostasis, and Abeta accumulation. We will compare the effects of pravastatin (a hydrophilic statin that has a low propensity to cross the BBB) and simvastatin (a lipophilic statin that readily cross the BBB) on oxidative stress, iron dyshomeostasis, and Abeta accumulation. Successful completion of the present proposal may reveal the missing link between high blood cholesterol levels and AD-like pathology in the brain.

Public Health Relevance

Hypercholesterolemia is a serious health issue in the U.S.A. which, in addition to cardiovascular problems, may also increase the risk for Alzheimer's disease. However, the mechanisms by which high blood cholesterol levels cause AD pathology are not known. The outcome of this proposal may aid in a better understanding of the mechanisms by which high cholesterol levels in blood cause degeneration characteristic of AD, and may ultimately help in designing strategies that prevent or slow the progression of hypercholesterolemia-related forms of this devastating neurodegenerative disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES014826-04
Application #
8016689
Study Section
Special Emphasis Panel (ZRG1-IFCN-K (03))
Program Officer
Kirshner, Annette G
Project Start
2008-03-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
4
Fiscal Year
2011
Total Cost
$282,821
Indirect Cost
Name
University of North Dakota
Department
Pharmacology
Type
Schools of Medicine
DUNS #
102280781
City
Grand Forks
State
ND
Country
United States
Zip Code
58202
Marwarha, Gurdeep; Ghribi, Othman (2015) Does the oxysterol 27-hydroxycholesterol underlie Alzheimer's disease-Parkinson's disease overlap? Exp Gerontol 68:13-8
Marwarha, Gurdeep; Raza, Shaneabbas; Meiers, Craig et al. (2014) Leptin attenuates BACE1 expression and amyloid-? genesis via the activation of SIRT1 signaling pathway. Biochim Biophys Acta 1842:1587-95
Marwarha, Gurdeep; Raza, Shaneabbas; Prasanthi, Jaya R P et al. (2013) Gadd153 and NF-?B crosstalk regulates 27-hydroxycholesterol-induced increase in BACE1 and ?-amyloid production in human neuroblastoma SH-SY5Y cells. PLoS One 8:e70773
Dasari, Bhanu; Prasanthi, Jaya R P; Meiers, Craig et al. (2013) Differential effects of the estrogen receptor agonist estradiol on toxicity induced by enzymatically-derived or autoxidation-derived oxysterols in human ARPE-19 cells. Curr Eye Res 38:1159-71
Prasanthi, Jaya R P; Schrag, Matthew; Dasari, Bhanu et al. (2012) Deferiprone reduces amyloid-? and tau phosphorylation levels but not reactive oxygen species generation in hippocampus of rabbits fed a cholesterol-enriched diet. J Alzheimers Dis 30:167-82
Marwarha, Gurdeep; Dasari, Bhanu; Ghribi, Othman (2012) Endoplasmic reticulum stress-induced CHOP activation mediates the down-regulation of leptin in human neuroblastoma SH-SY5Y cells treated with the oxysterol 27-hydroxycholesterol. Cell Signal 24:484-92
Marwarha, Gurdeep; Ghribi, Othman (2012) Cellular model of Alzheimer's disease--relevance to therapeutic testing. Exp Neurol 233:733-9
Marwarha, Gurdeep; Prasanthi, Jaya Rp; Schommer, Jared et al. (2011) Molecular interplay between leptin, insulin-like growth factor-1, and ?-amyloid in organotypic slices from rabbit hippocampus. Mol Neurodegener 6:41
Dasari, Bhanu; Prasanthi, Jaya Rp; Marwarha, Gurdeep et al. (2011) Cholesterol-enriched diet causes age-related macular degeneration-like pathology in rabbit retina. BMC Ophthalmol 11:22
Marwarha, Gurdeep; Rhen, Turk; Schommer, Trevor et al. (2011) The oxysterol 27-hydroxycholesterol regulates ?-synuclein and tyrosine hydroxylase expression levels in human neuroblastoma cells through modulation of liver X receptors and estrogen receptors--relevance to Parkinson's disease. J Neurochem 119:1119-36

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