P3‐036: Aß inhibition of kinesin 5 induces neurotransmitter and neurotrophin receptor mislocalization and dysfunction

Abstract

second biosimulation test used a combination of 25 mM brain derived neurotrophic factor (BDNF) and 10 m M NGF as a continuous exposure for 60 min duration; this approach evaluated stimulation of p75 NTR, TrkA, and TrkB. Based on the human microarray results demonstrating downregulation of TrkA (50%) and TrkB (60%), the corresponding parameters in the TTR biosimulation were decreased by the same amount. Results: Baseline results were validated from published literature on neuronal calcium levels mediated via the phospholipase C-g and inositol-3-phosphate pathway at both bolus doses of NGF alone. With the corresponding parameters decreased in the TTR biosimulation, Figure 1: A) The reaction flux for c-RAF1 phosphorylation of MEK1 was delayed to peak value by 1.5 min from exposure, but the peak value was increased to 5 times the baseline value; B) Moreover, a slight shift to the right of the flux over time was observed with the B-RAF phosphorylation of MEK1. Conclusions: These biosimulation results indicate that the transient response to neurotrophins is accentuated, whereas the sustained MEK activating pathway is blunted in AD, and may be potential mechanisms for the failure of pro-survival pathways in AD.