There is increasing evidence that oxidative damage may contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer's Disease (AD). A number of recent studies have suggested that oxidative damage may precede and be causally linked to the deposition of beta-amyloid. Conversely, beta-amyloid may induce oxidative damage. There are two major classes of oxidants and biological systems; reactive oxygen intermediates and reactive nitrogen intermediates. A number of studies have shown that there are increased reactive oxygen intermediates in AD postmortem brain tissue as assessed by oxidative damage markers. There also appears to be increased reactive nitrogen intermediates as assessed by biochemical and immunocytochemical measurements of 3-nitrotyrosine. Our data, which has been confirmed by others, shows that there is an increase in inducible nitric oxide synthase (NOS2) immunoreactivity within neurons in both AD postmortem brain tissue, as well as in transgenic mouse models. Genetic reduction of NOS2 activity markedly reduced beta-amyloid deposition in a transgenic mouse model of AD. The goals of the present application are to utilize two compounds, which can block reactive oxygen species and reactive nitrogen intermediates. We will utilize coenzyme Q10 and L-iminoethyl-L-lysine (L-NIL) in transgenic mouse models of AD. CoQ10 is a cofactor of the electron transport gene, which has strong antioxidant properties. It is extremely well tolerated in human subjects and is under clinical development for treatment of Parkinson's Disease, Huntington's Disease and amyotrophic lateral sclerosis. We will also look at the effects of L-iminoethyl-L-lysine, which is a relatively specific inhibitor of NOS2. We will determine whether treatment with either CoQ10 or L-NIL can exert neuroprotective effects against beta-amyloid deposition and oxidative damage, and improve memory in transgenic mouse models of AD. If we can demonstrate significant effects of CoQ10 and L-NIL, this could lead to rapid development of new therapies for slowing the progression of AD. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG027357-01
Application #
7020246
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (95))
Program Officer
Buckholtz, Neil
Project Start
2006-03-15
Project End
2008-01-31
Budget Start
2006-03-15
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$209,160
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Johri, Ashu; Beal, M Flint (2012) Antioxidants in Huntington's disease. Biochim Biophys Acta 1822:664-74
Dumont, Magali; Wille, Elizabeth; Calingasan, Noel Y et al. (2010) N-iminoethyl-L-lysine improves memory and reduces amyloid pathology in a transgenic mouse model of amyloid deposition. Neurochem Int 56:345-51