Pro-Nerve Growth Factor Induced RhoA Kinase Activation in PC12 Cells
Type of DegreeMaster's Thesis
Nutrition, Dietetics and Hospitality Management
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Alzheimer’s Disease (AD) is characterized by neurodegeneration and progressive decline in memory, cognition and independence. Nerve Growth Factor (NGF) is the neurotrophin responsible for mediating neuronal survival and differentiation by binding transmembrane receptors, tropomyosin receptor kinase A (TrkA) and p75 neurotrophin receptor (p75NTR). Active NGF is cleaved from its precursor, pro-nerve growth factor (proNGF), by the extracellular enzyme matrix metalloproteinase 7 (MMP-7). ProNGF favorably binds p75NTR receptor to induce neuronal apoptosis through RhoA Kinase activation. RhoA is a key GTP-binding protein that functions as a molecular switch between pro-survival and pro-apoptotic responses in the nervous system. RhoA activation by proNGF directly induces phosphorylation of c-Jun N-terminal kinase (JNK) and protein 38 mitogen-activated protein kinase (p38 MAPK) for apoptosis. Interestingly, Rho kinase inhibitor Y-27632 has been shown to mitigate proNGF induced activation of the JNK/p38 MAPK pathway and promote neurite outgrowth in rat pheochromocytoma (PC12) cells. Previously, our lab showed hippocampal brain tissue of AD patients expressed higher levels of proNGF and the receptor p75NTR as compared to age-matched control brain samples. Following these findings, investigation of p75NTR activity in proNGF enriched PC12 cells has revealed significant elevation in p75NTR receptor expression, RhoA kinase activity, and JNK/p38 MAPK phosphorylation. The addition of Rho kinase inhibitor Y27632 resulted in the reduction of p75NTR expression and subsequent RhoA activation of JNK/p38 MAPK apoptosis. These results suggest that overexpressed proNGF in AD promotes neuronal death through p75NTR mediated RhoA activation.