Selective neuronal vulnerability, protease‐activated receptors (PARS) and thrombin signalling

Abstract

In order to investigate the roles of thrombin and its signalling via PARs in defining selective neuronal vulnerability we compared two different murine clonal neuronal lines: NSC34 motor and HT22 hippocampal neurons. RT‐PCR revealed mRNA expression all four PARS. Responses of both cell lines for thrombin effects on neurite outgrowth, cell survival and signalling changes through mitogen activated protein kinases (MAPKs) were evaluated. Ability of thrombin and PAR‐specific active peptides (agonists): PAR1 (SFLLRN) and PAR4 (GYPGQV), were compared for these parameters and for the presence of aggregated microtubule‐associated protein (MAP) tau neurofibrillary tangles (NFTs). Motor neuronal PAR1 or PAR4 activation induced rapid neurite retraction and neuronal apoptosis. This was accompanied by tau degradation. In contrast, hippocampal neuronal PAR1 or PAR4 activation resulted in mild effects on neurite outgrowth but rapid tau aggregation, which was dependent on phosphorylation and positive for NFT‐specific antibody. Delayed reduction in cell viability occurred 24–48 h after tau aggregation. Evaluation of signalling pathways revealed p38 MAPK in NSC‐34 and p44/42 MAPK activation in HT22 cells were closely related to observed differential neuronal morphology in response to thrombin. We conclude that different intracellular signalling pathways coupled to PARs in different neuronal sub‐populations mediate selective thrombin vulnerability.Acknowledgements: Supported by the DVA, Christopher Reeve Paralysis Foundation, Missouri Alzheimer's Res. Fund, ALS Association, Lied Endowment, KUMCRI and Midwest Biomedical Research Foundation.