The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

Background: Spleen tyrosine kinase (Syk) mediates microglial activation and neurotoxicity elicited by Alzheimer A peptides. Results: Syk regulates A production via NFB-dependent mechanisms and Tau phosphorylation by controlling the activation of glycogen synthase 3. Conclusion: Inhibition of Syk can interrupt the neuroinflammation, pathological A accumulation, and Tau hyperphosphorylation in AD. Significance: Syk represents a therapeutic target for the key pathological lesions that define AD.We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain amyloid- (A) accumulation by affecting both A production and A 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 A production and improve the clearance of A 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 A by showing that pharmacological inhibition of Syk or down-regulation of Syk expression reduces A production and increases the clearance of A across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing A and transgenic Tau P301S mice with a selective Syk inhibitor respectively decreased brain A 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-3, a primary Tau kinase involved in Tau phosphorylation, by activating protein kinase A, providing a mechanism explaining the reduction of Tau phosphorylation at GSK3-dependent epitopes following Syk inhibition. Altogether our data highlight Syk as a promising target for preventing both A accumulation and Tau hyperphosphorylation in AD.