Alzheimer's disease (AD) is the most common form of dementia for which there is no effective therapy. Although the causative events(s) responsible for the disease is not known, it is evident that some environmental elements by interacting with endogenous factors could play a role in its pathogenesis. Epidemiological studies have shown that high blood levels of homocysteine (Hcy), a condition known as hyperhomocysteinemia (HHcy) is a risk factor for developing AD. Hcy derives from the conversion of methionine through reactions that are dependent on the presence of necessary vitamins (i.e., B6, B12 and folate). Since cellular exposure in vitro to Hcy induces oxidative stress and inflammatory reactions, we want to test the hypothesis that these mechanisms mediate in vivo the link between AD and HHcy. Previously, we have shown that lipid peroxidation is increased in selective areas of AD brains, and in AD patients where it correlates with disease severity. Inflammation also occurs in AD, and it does do with the full complexity of local and peripheral inflammatory responses. Transgenic mice over-expressing the Swedish mutation of the amyloid precursor protein (Tg2576) manifest signs of brain lipid peroxidation and inflammation. Our longterm goal is to define the effects of long-term exposure to HHcy in two different models of AD-like amyloidosis (Tg2576 and the APP/YAC Tg mice). First, we will test the hypothesis that diet-induced HHcy exacerbates brain oxidative stress and inflammation, accelerates behavioral impairments and brain amyloid/3 peptide deposition in these mice. Second, by cross-breeding AD Tg mice with Tg mice that are deficient for a key enzyme in Hcy metabolism, we will investigate whether genetic-induced HHcy exacerbates brain oxidative stress, inflammatory responses, behavioral impairments, and amyloid beta peptide levels and deposition. In summary, this proposal tests the hypothesis that long-term exposure to high Hcy levels exacerbates ADlike phenotype in two different mouse models of AD-like amyloidosis, and investigates some of the molecular and cellular mechanisms that could account for this effect. These studies will be a necessary basis before prevention studies aimed to reduce Hcy levels are initiated in patients at risk for AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG022512-05
Application #
7530057
Study Section
Special Emphasis Panel (ZRG1-CNNT (03))
Program Officer
Snyder, Stephen D
Project Start
2004-04-15
Project End
2009-03-31
Budget Start
2007-12-15
Budget End
2008-03-31
Support Year
5
Fiscal Year
2007
Total Cost
$165,301
Indirect Cost
Name
Temple University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Zhuo, Jia-Min; Wang, Hong; Pratico, Domenico (2011) Is hyperhomocysteinemia an Alzheimer's disease (AD) risk factor, an AD marker, or neither? Trends Pharmacol Sci 32:562-71
Chu, Jin; Pratico, Domenico (2011) 5-lipoxygenase as an endogenous modulator of amyloid ýý formation in vivo. Ann Neurol 69:34-46
Zhuo, J-M; Portugal, G S; Kruger, W D et al. (2010) Diet-induced hyperhomocysteinemia increases amyloid-beta formation and deposition in a mouse model of Alzheimer's disease. Curr Alzheimer Res 7:140-9
Zhuo, Jia-Min; Pratico, Domenico (2010) Normalization of hyperhomocysteinemia improves cognitive deficits and ameliorates brain amyloidosis of a transgenic mouse model of Alzheimer's disease. FASEB J 24:3895-902
Zhuo, Jia-Min; Pratico, Domenico (2010) Acceleration of brain amyloidosis in an Alzheimer's disease mouse model by a folate, vitamin B6 and B12-deficient diet. Exp Gerontol 45:195-201
Zhuo, Jia-Min; Kruger, Warren D; Praticò, Domenico (2010) The Herp protein pathway is not involved in the pro-amyloidogenic effect of hyperhomocysteinemia. J Alzheimers Dis 20:569-76
Zhuo, Jia-Min; Praticò, Domenico (2010) Severe In vivo hyper-homocysteinemia is not associatedwith elevation of amyloid-beta peptides in the Tg2576 mice. J Alzheimers Dis 21:133-40
Cyrus, Tillmann; Yao, Yuemang; Ding, Tao et al. (2007) Thromboxane receptor blockade improves the antiatherogenic effect of thromboxane A2 suppression in LDLR KO mice. Blood 109:3291-6
Dentchev, Tzvete; Yao, Yuemang; Pratico, Domenico et al. (2007) Isoprostane F2alpha-VI, a new marker of oxidative stress, increases following light damage to the mouse retina. Mol Vis 13:190-5
Zhao, Lei; Pratico, Domenico; Rader, Daniel J et al. (2005) 12/15-Lipoxygenase gene disruption and vitamin E administration diminish atherosclerosis and oxidative stress in apolipoprotein E deficient mice through a final common pathway. Prostaglandins Other Lipid Mediat 78:185-93

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