P4‐033: Regulation of Ab Production and TAU Phosphorylation Via SYK‐Dependent Mechanisms

We have shown previously that the antihypertensive nilvadipine reduces Aβ accumulation, neuroinflammation and improves cognition in transgenic mouse models of Alzheimer's disease (AD). We have identified that the spleen tyrosine kinase (Syk) is the molecular target responsible for the Aβ lowering and anti-inflammatory properties of nilvadipine which is currently in a phase III clinical trial for AD. Syk plays essential functions for immunoreceptor signaling. Interestingly, Aβ oligomers have been shown to activate Syk in microglia resulting in microglial activation and in the promotion of Aβ induced neurotoxicity. We have therefore explored the possible impact of Syk inhibition on the pathological hallmarks (neuroinflammation, Aβ deposition and tau hyperphosphorylation) of AD using transgenic mice and cellular models of the disorder. Our data show that Syk inhibition antagonizes STAT3 and NFκB signaling resulting in decreased neuroinflammation and generation of Aβ peptides. In addition, we show that Syk inhibition affects tau phosphorylation not only at the expected Y18 epitope but also at GSK3β dependant epitopes in vitro in differentiated human neuronal like cells and in vivo in transgenic Tau P301S mice. Mechanistic data explaining the reduction of tau phosphorylation observed following Syk inhibition will be presented. In particular, we will show the impact of Syk inhibition on tau phosphorylation using differentiated human neuronal like cells. In addition, we will present some data regarding the impact of microglial conditioned medium from resting, activated and Syk inhibited human microglia on tau phosphorylation in human neuronal like cells. Finally, we will show some confocal microscopy data revealing an increased activation of Syk in the CNS of transgenic mice overexpressing Aβ peptides compared to wild-type littermates. Altogether, our data support a role of Syk in the development of Aβ deposition and tau hyperphosphorylation supporting Syk as a possible target for regulating the pathological events associated with AD.