Developing an Alzheimer’s Disease Therapeutic: Identification and Validation of Signaling Pathways Involved in Small Molecule Induction of Nerve Growth Factor
Date
2016
Authors
Davis, Justin Bradford
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Abstract
Nerve growth factor (NGF) has been identified as a key protein involved in preventing neuronal cell death, a hallmark of neurodegeneration due to age and Alzheimer’s Disease. Recent preclinical and clinical Alzheimer’s Disease studies have noted a reduction in the rate of cognitive decline upon treatment with NGF. However, because NGF is unable to penetrate the blood-brain barrier, current means of delivering NGF to the brain are highly invasive and cost-prohibitive. An orally administered small molecule, capable of stimulating the upregulation of NGF in the brain, is preferred. Several small molecules that cause the upregulation of NGF have been discovered through serendipity, but their mechanisms of action are still poorly understood. A thorough investigation into the mechanisms of known inducers of NGF identified Protein Kinase C and the Mitogen Activated Protein Kinase pathway as critical to the upregulation of NGF protein. A series of protein specific agonists and antagonists was employed to validate select members of this signaling pathway, revealing promising targets for the development of neuroprotective therapeutics.
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Keywords
Biochemistry, Microbiology, Chemistry, MAPK pathway, Nerve growth factor, Phorbol 12-myristate 13-acetate, Protein kinase c