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Role of p38α MAP kinase in amyloid-β derived diffusible ligand (ADDL) induced dendritic spine loss in hippocampal neurons

Abstract ID: 35279

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Abstract:

Ladan Amin, PhD1; Nhat Le, PhD1; Robert C.C. Mercer, PhD1; Ursula Germann, PhD2; John Alam, MD2 and David A Harris, MD-PhD1, (1)Boston University School of Medicine, Boston, MA, USA, (2)EIP Pharma Inc., Cambridge, MA, USA

Background: We recently described a p38 MAP kinase-dependent synaptotoxic signaling pathway that is activated by prions (Fang et al. 2018, PLoS Pathog. 14:e1007283). Although there is evidence that p38 MAPK also plays a role in the toxicity of Aβ oligomers (Birnbaum et al, 2015, Cell Death Dis, 18;6:e1791), we reported previously that a non-selective chemical inhibitor of all four p38 isoforms (SB239063) did not prevent dendritic spine retraction caused by synthetic ADDLs (Fang et al. 2018). To further explore the relationship between p38 activation and ADDL-induced synaptotoxicity, we evaluated the effect of neflamapimod (VX-745), a selective inhibitor of the α isoform of p38 MAPK (p38α), on ADDL-induced spine degeneration in cultured hippocampal neurons. Method: Primary mouse hippocampal neurons were treated with 500 nM ADDLs and 0, 10, 50 or 100 nM concentrations of neflamapimod for 24 hrs, and were then fixed, and spine number was quantitated after staining with Alexa 488-labeled phalloidin to visualize F-actin (which is enriched in dendritic spines). We chose neflamapimod because it is a highly selective p38α inhibitor that improved Morris water maze performance in aged rats (Alam 2015, J. Alzheimers Dis. 48:219-227); and it demonstrated potential to improve episodic memory function in early AD patients (Scheltens et al. 2018 Ann. Clin. Transl. Neurol. 5:464-473). As a positive control, we conducted a dose-response analysis of neflamapimod for its ability to prevent spine retraction induced by purified PrPSc, the infectious form of the prion protein. Result: Neflamapimod reduced ADDL-induced spine retraction starting at the lowest concentration tested (10 nM) and fully blocked the effect at 50 nM (see Figure 1). Consistent with our previous report (Fang, et al. 2018), neflamapimod reduced dendritic spine retraction after exposure to PrPSc starting at 25 nM, and fully blocked spine retraction at 100 nM (EC50=30 nM). Conclusion: The results suggest that Aβ oligomers and PrPSc may trigger overlapping synaptotoxic signaling pathways that have in common activation of p38α MAP kinase. The results of an ongoing placebo-controlled clinical trial of neflamapimod in patients with early AD, which has episodic memory as a primary endpoint, may inform on the clinical translatability of our findings.