Rock Creek Pharmaceuticals Inc. (fka RCPIQ)

[Buddhahead]

The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-ß production and Tau hyperphosphorylation in PubMed,
Paris D1, Ait-Ghezala G2, Bachmeier C2, Laco G2, Beaulieu-Abdelahad D2, Lin Y2, Jin C2, Crawford F2, Mullan M2.

Abstract:
"We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain amyloid-ß (Aß) accumulation by affecting both Aß production and Aß clearance across the blood-brain barrier (BBB). Nilvadipine consists of a mixture of two enantiomers, (+)-nilvadipine and (-)-nilvadipine, in equal proportion. (+)-Nilvadipine is the active enantiomer responsible for the inhibition of LCC, whereas (-)-nilvadipine is considered inactive. Both nilvadipine enantiomers inhibit Aß production and improve the clearance of Aß across the BBB showing that these effects are not related to LCC inhibition. In addition, treatment of P301S mutant human Tau transgenic mice (transgenic Tau P301S) with (-)-nilvadipine reduces Tau hyperphosphorylation at several Alzheimer disease (AD) pertinent epitopes. A search for the mechanism of action of (-)-nilvadipine revealed that this compound inhibits the spleen tyrosine kinase (Syk). We further validated Syk as a target-regulating Aß by showing that pharmacological inhibition of Syk or down-regulation of Syk expression reduces Aß production and increases the clearance of Aß across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aß and transgenic Tau P301S mice with a selective Syk inhibitor respectively decreased brain Aß accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes. We show that Syk inhibition induces an increased phosphorylation of the inhibitory Ser-9 residue of glycogen synthase kinase-3ß, a primary Tau kinase involved in Tau phosphorylation, by activating protein kinase A, providing a mechanism explaining the reduction of Tau phosphorylation at GSK3ß-dependent epitopes following Syk inhibition. Altogether our data highlight Syk as a promising target for preventing both Aß accumulation and Tau hyperphosphorylation in AD.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Article at:
http://www.ncbi.nlm.nih.gov/pubmed/25331948