Alzheimer's disease (AD) is a neurodegenerative disorder affecting 4 million older Americans. Our hypothesis is that brain microvessels contribute to the pathogenesis of AD by producing soluble factors that injure or kill neurons. Recent data from our group strongly support this hypothesis and demonstrate that both brain microvessels isolated from AD patients and rat brain endothelial cells injured in culture secrete factors that cause lethal injury specifically to neurons. We have generated monoclonal antibodies that recognize and immunoprecipitate the rat endothelial cell-derived toxin. Preliminary experiments show that at least one of these antibodies also immunoprecipitates the neurotoxic factor secreted by human AD microvessels, suggesting that the endothelial and microvessel neurotoxins are identical or closely related. These novel findings are exciting and implicate the vasculature as a source of neurotoxins in the brain. The feasibility of achieving the goals of this project, to purify and identify these vascular- derived neurotoxic factors, is strongly supported by our initial data and the availability of monoclonal antibodies. In this project, our specific aims are: 1) to purify and characterize the rat endothelial cell-derived toxic factor (EDTF); 2) to clone the cDNA for EDTF and determine the structural basis for neuronal killing; 3) to characterize multi-functional monoclonal antibodies to the human AD microvessel-derived neurotoxic factor(s); and 4) to determine the localization of neurotoxin(s) in normal and AD tissues. Our experiments are the first to identify the vasculature as a source of neurotoxic molecules in AD. Whether the neurotoxic factor is known or unique, as will be assessed in this project, the demonstration that AD brain microvessels produce soluble factors that injure or kill neurons shows that the cerebral microcirculation is a novel, unexplored source of neurotoxic factors in AD, and a heretofore unrecognized target for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG015964-01A1
Application #
6045298
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Oliver, Eugene J
Project Start
1999-09-30
Project End
2003-08-31
Budget Start
1999-09-30
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Pathology
Type
Schools of Medicine
DUNS #
937727907
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Sanchez, Alma; Tripathy, Debjani; Luo, Jinau et al. (2013) Neurovascular unit and the effects of dosage in VEGF toxicity: role for oxidative stress and thrombin. J Alzheimers Dis 34:281-91
Luo, J; Martinez, J; Yin, X et al. (2012) Hypoxia induces angiogenic factors in brain microvascular endothelial cells. Microvasc Res 83:138-45
Sanchez, A; Tripathy, D; Yin, X et al. (2012) Pigment epithelium-derived factor (PEDF) protects cortical neurons in vitro from oxidant injury by activation of extracellular signal-regulated kinase (ERK) 1/2 and induction of Bcl-2. Neurosci Res 72:1-8
Wang, Shu; Qaisar, Uzma; Yin, Xiangling et al. (2012) Gene expression profiling in Alzheimer's disease brain microvessels. J Alzheimers Dis 31:193-205
Grammas, Paula; Martinez, Joseph; Miller, Bradley (2011) Cerebral microvascular endothelium and the pathogenesis of neurodegenerative diseases. Expert Rev Mol Med 13:e19
Grammas, Paula (2011) Neurovascular dysfunction, inflammation and endothelial activation: implications for the pathogenesis of Alzheimer's disease. J Neuroinflammation 8:26
Grammas, Paula; Sanchez, Alma; Tripathy, Debjani et al. (2011) Vascular signaling abnormalities in Alzheimer disease. Cleve Clin J Med 78 Suppl 1:S50-3
Sanchez, Alma; Wadhwani, Suchin; Grammas, Paula (2010) Multiple neurotrophic effects of VEGF on cultured neurons. Neuropeptides 44:323-31
Tripathy, Debjani; Yin, Xiangling; Sanchez, Alma et al. (2010) Cerebrovascular expression of proteins related to inflammation, oxidative stress and neurotoxicity is altered with aging. J Neuroinflammation 7:63
Tripathy, Debjani; Thirumangalakudi, Lakshmi; Grammas, Paula (2010) RANTES upregulation in the Alzheimer's disease brain: a possible neuroprotective role. Neurobiol Aging 31:8-16

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