Alzheimer's disease (AD) is most commonly associated with deposition of amyloid-beta (Abeta) peptide in the brain. The presence of Abeta peptide in the brain plays an important role in the development of aggregates that may result in neuronal damage, dysfunction, microglial activation and neuropathological features of AD. Abeta [with or without tau/neurofibrillary tangles (NFTs)] perturbs cellular properties mainly by oxidant stress, which overwhelms the cellular antioxidant defense mechanisms. Recent studies suggest that environmental toxins (ETs) may contribute to the pathogenic process of AD and neurodegenerative diseases, disrupting neuronal function resulting in oxidative stress (OS), inflammation and cell death. We and others have shown that paraoxonase-1 (PON-1) activity is reduced in the plasma of individuals with AD, and that ETs (organophosphates) exacerbate AD pathogenesis in APP transgenic mice. We hypothesize that AD partially results from early (embryonic/neonatal) or chronic low level exposure to ETs or a defect in paraoxonase activity that gives rise to increased ET levels in plasma and brain triggering oxidative stress, inflammation and Abeta production. This paradigm facilitates Abeta aggregation and exacerbates cellular perturbation and AD pathogenesis. The focus of this proposal is to understand the function of organophosphates (OPs as symbolic ETs) and interrelationship between ETs and paraoxonase (PON-1) in oxidative stress and inflammation associated with AD. The long-term goal of this proposal is to understand the role of ETs and PON-1 in oxidative stress in order to determine if alteration in the level of toxins is a potential therapeutic strategy for individuals with AD. To this end, the following specific aims will be tested:
Specific Aim 1 : To determine the effect of organophosphates (OPs) on AD pathogenesis in APP transgenic mice.
Specific Aim 2 : To determine the effect of paraoxonase 1 deficiency on organophosphate induced AD pathogenesis in APP transgenic mice.
Specific Aim 3 : To study the therapeutic effects of galantamine and adenoviral delivered PON1 on organophosphate provoked AD.
Specific Aim 4 : To determine if PON1 allotype or functional deficits in PON1 activity predict the development and progression of AD that may be stimulated by environmental toxins. These studies will help to define the role of environmental factors in the pathogenesis of AD.

Public Health Relevance

The overall goal of this project is to determine the role of environmental toxins (ETs) in their contribution to the pathogenic process of AD and neurodegenerative diseases. We hypothesize that AD partially results from early (embryonic/neonatal) or chronic low level exposure to ETs or a defect in paraoxonase activity that gives rise to increased ET levels in plasma and brain triggering oxidative stress, inflammation and Abeta production. The focus of this proposal is to understand the function of organophosphates (OPs as symbolic ETs) and interrelationship between ETs and paraoxonase (PON- 1) in oxidative stress and inflammation associated with AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016774-02
Application #
7933938
Study Section
Special Emphasis Panel (ZRG1-BDCN-Y (04))
Program Officer
Kirshner, Annette G
Project Start
2009-09-17
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$405,625
Indirect Cost
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Hook, Gregory; Yu, Jin; Toneff, Thomas et al. (2014) Brain pyroglutamate amyloid-? is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic. J Alzheimers Dis 41:129-49
Krishna, Vibhor; Andrews, Hampton; Varma, Abhay et al. (2014) Spinal cord injury: how can we improve the classification and quantification of its severity and prognosis? J Neurotrauma 31:215-27
Yun, Xiang; Maximov, Victor D; Yu, Jin et al. (2013) Nanoparticles for targeted delivery of antioxidant enzymes to the brain after cerebral ischemia and reperfusion injury. J Cereb Blood Flow Metab 33:583-92
Krishna, Vibhor; Lazaridis, Christos; Ellegala, Dilantha et al. (2012) Spinal cord infarction associated with subarachnoid hemorrhage. Clin Neurol Neurosurg 114:1030-2

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