We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain Aβ accumulation by affecting both Aβ production and Aβ 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 Aβ production and improve the clearance of Aβ across the BBB showing that these effects are not related to LCC inhibition. In addition, treatment of P301S mutant human Tau transgenic mice (Tg Tau P301S) with (-)-nilv... More
We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain Aβ accumulation by affecting both Aβ production and Aβ 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 Aβ production and improve the clearance of Aβ across the BBB showing that these effects are not related to LCC inhibition. In addition, treatment of P301S mutant human Tau transgenic mice (Tg Tau P301S) with (-)-nilvadipine reduces tau hyperphosphorylation at several 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 Aβ by showing that pharmacological inhibition of syk or downregulation of syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and Tg Tau P301S mice with a selective syk inhibitor respectively decreased brain Aβ accumulation and tau hyperphosphorylation at multiple AD relevant epitopes. We show that syk inhibition induces an increased phosphorylation of the inhibitory Ser9 residue of glycogen synthase kinase-3β, a primary tau kinase involved in tau phosphorylation, by activating protein kinase A, providing a mechanism explaining the reduction of tau phosphorylation at GSK3β dependent epitopes following syk inhibition. Altogether our data highlight syk as a promising target for preventing both Aβ accumulation and tau hyperphosphorylation in AD.
