Data are emerging to support the idea that factors and processes characteristic of angiogenesis are found in the Alzheimer disease (AD) brain. We have shown that in AD microvessels express or release many inflammatory, proangiogenic proteins. Despite increases in proangiogenic factors in the AD brain, evidence for increased vascularity is lacking. In our model we hypothesize that the angiogenic process does not progress to new vessel growth because an imbalance of pro- and anti-angiogenic factors results in aborted angiogenic signaling. In this project we test the hypothesis that AD microvessels express an anqiogenic phenotype and that this abnormal activation of brain endothelial cells is important for the development of AD pathology.
Aim 1 : To test the hypothesis that in AD brain microvessels become activated but fail to complete angiogenesis because an imbalance of pro- and anti-angiogenic factors results in aborted angiogenic signaling. Brain microvessels are isolated from AD patients, age-matched non-demented controls, and patients with inflammatory and non-inflammatory CMS disease. Isolated vessels are compared for expression of pro- and anti-angiogenic factors including thrombin, VEGF, endothelin-1 TGF-/0, nitric oxide, thrombospondin, and amyloid beta (A?). The activities of signaling kinases phosphatidylinositol-3 kinase (PI3K)/Akt, p38 kinase, extracellular signal-regulated kinase (ERK), and c-Jun NH2-terminal kinase (JNK) are measured. Immunohistochemistry of brain sections is used to assess the spatial correlation of pro- and anti-angiogenic proteins with A/? deposition and AD pathology.
Aim 2 : To test the hypothesis that acquisition of the angiogenic phenotype contributes to the pathogenesis of AD pathology and cognitive impairment in animal models of AD. To determine the temporal association between acquisition of the angiogenic phenotype and the onset of disease, markers of angiogenesis are measured in isolated brain microvessels obtained from AD transgenic mice before the onset of cognitive changes and AD pathology and at several ages during disease progression. A causal link between the angiogenic phenotype and disease progression is evaluated using antiangiogenic drugs. Administration of these drugs to animals prior to the onset of behavioral changes and AD pathology will determine whether inhibiting the angiogenic phenotype affects the course of disease. Taken together, data from Aim 1 showing the clinical relevance of angiogenic changes in AD and results from Aim 2 demonstrating a causal link between the angiogenic phenotype and disease progression would argue strongly for a new therapeutic approach in AD. These results could be very exciting because the angiogenic brain endothelial cell is a novel, unexplored therapeutic target, and several antiangiogenic drugs are currently in use in Phase III clinical trials. Thus, clinical studies with angiogenesis inhibitors could be rapidly designed and implemented in AD patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG015964-09
Application #
7822712
Study Section
Special Emphasis Panel (ZRG1-BINP-L (01))
Program Officer
Petanceska, Suzana
Project Start
1999-09-30
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
9
Fiscal Year
2010
Total Cost
$295,353
Indirect Cost
Name
Texas Tech University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
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 (2011) Neurovascular dysfunction, inflammation and endothelial activation: implications for the pathogenesis of Alzheimer's disease. J Neuroinflammation 8:26
Grammas, Paula; Martinez, Joseph; Miller, Bradley (2011) Cerebral microvascular endothelium and the pathogenesis of neurodegenerative diseases. Expert Rev Mol Med 13:e19
Grammas, Paula; Sanchez, Alma; Tripathy, Debjani et al. (2011) Vascular signaling abnormalities in Alzheimer disease. Cleve Clin J Med 78 Suppl 1:S50-3
Evola, Marianne; Hall, Allyson; Wall, Trevor et al. (2010) Oxidative stress impairs learning and memory in apoE knockout mice. Pharmacol Biochem Behav 96:181-6
Luo, Jinhua; Grammas, Paula (2010) Endothelin-1 is elevated in Alzheimer's disease brain microvessels and is neuroprotective. J Alzheimers Dis 21:887-96
Sanchez, Alma; Wadhwani, Suchin; Grammas, Paula (2010) Multiple neurotrophic effects of VEGF on cultured neurons. Neuropeptides 44:323-31

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