The overall goal of the proposed research is to develop orally active inhibitors of myeloperoxidase MPO as a treatment forAlzheimer's disease. MPO is an abundant enzyme in leukocytes but its expression can be induced in astrocytes in Alzheimer's disease. This abnormal expression of MPO can lead to the oxidation of lipids and proteins leading to tissue damage and cell death resulting in loss of memory. A potent and safe inhibitor of MPO could be helpful in the treatment of Alzheimer's disease. We have developed novel mouse model to evaluate the role of MPO in Alzheimer's disease. In Specific Aim 1 We propose to improve the potency of hits identified in a screen looking for inhibitors of MPO. In Specific Aim 2 we propose to test several of the MPO inhibitors in a mouse model of Alzheimer's disease. The mice will be evaluated using both biochemical and behavioral/cognitive tests.
Public Health Relevance Statement: Myeloperoxidase is recognized as an important causative contributory agent in inflammatory diseases including Alzheimer's disease. An inhibitor of myeloperoxidase would provide a novel therapeutic agent that could be used to lower the level of oxidative damage that occurs in Alzheimer's disease. The experiments outlined in this Phase I SBIR application will help set the stage for the development of a novel and safe myeloperoxidase inhibitor for clinical use.
NIH Spending Category: Aging; Alzheimer's Disease; Brain Disorders; Dementia; Genetics; Neurodegenerative; Neurosciences
Project Terms: Alu Elements; Alzheimer's Disease; Alzheimer's disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Astrocytes; Atherosclerosis; Autopsy; base; Behavioral; Binding Sites; Biochemical; Bone Marrow; Brain; cancer cell; Cell Death; chlorination; Clinical; Cognitive; Cognitive deficits; Deposition; Development; Disease; Disease Progression; Elements; Enzymes; Event; Foam Cells; Free Radicals; Gene Expression; Genes; Goals; high throughput screening; Human; Hypochlorous Acid; Immune system; improved; Infection; Inflammatory; inhibitor/antagonist; Iron; Lead; Leukocytes; Lipid Peroxidation; Lipids; macrophage; member; Memory Loss; mild cognitive impairment; Mitochondria; Modeling; monocyte; mouse model; Mus; Myelogenous; Neurons; neutrophil; Nitrates; Nitrogen Dioxide; Normal Cell; novel; novel therapeutics; Nuclear Receptors; Nucleic Acids; Oxidants; oxidation; oxidative damage; Oxygen Consumption; Pathology; Patients; Peroxidases; peroxidation; Pharmaceutical Preparations; Phase; Phospholipids; Primates; Promotor (Genetics); Property; Proteins; Reactive Oxygen Species; Research; research study; Role; Senile Plaques; Site; Small Business Innovation Research Grant; small molecule libraries; Source; Staging; Testing; Therapeutic Agents; Tissues; transcription factor; Transgenes; Transgenic Mice; Tyrosine; Unsaturated Fatty Acids
