title: The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.
abstract: We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain amyloid-β (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 (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 Aβ by showing that pharmacological inhibition of Syk or down-regulation 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 transgenic 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 Ser-9 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.
authors.affiliation: From the Roskamp Institute, Sarasota, Florida 34243 dparis@rfdn.org.
authors.forename: Daniel
authors.initials: D
authors.lastname: Paris
authors.affiliation: From the Roskamp Institute, Sarasota, Florida 34243.
authors.forename: Ghania
authors.initials: G
authors.lastname: Ait-Ghezala
authors.affiliation: From the Roskamp Institute, Sarasota, Florida 34243.
authors.forename: Corbin
authors.initials: C
authors.lastname: Bachmeier
authors.affiliation: From the Roskamp Institute, Sarasota, Florida 34243.
authors.forename: Gary
authors.initials: G
authors.lastname: Laco
authors.affiliation: From the Roskamp Institute, Sarasota, Florida 34243.
authors.forename: David
authors.initials: D
authors.lastname: Beaulieu-Abdelahad
authors.affiliation: From the Roskamp Institute, Sarasota, Florida 34243.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: From the Roskamp Institute, Sarasota, Florida 34243.
authors.forename: Chao
authors.initials: C
authors.lastname: Jin
authors.affiliation: From the Roskamp Institute, Sarasota, Florida 34243.
authors.forename: Fiona
authors.initials: F
authors.lastname: Crawford
authors.affiliation: From the Roskamp Institute, Sarasota, Florida 34243.
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology; D045744:Cell Line, Tumor; D003412:Cricetulus; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D016875:tau Proteins; C035100:nilvadipine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D009543:Nifedipine
keywords: Alzheimer Disease; Amyloid β (AB); Glycogen Synthase Kinase 3 (GSK-3); Hyperphosphorylation; Mechanism of Action; Neuroinflammation; Nilvadipine; Protein Kinase A (PKA); Tau Protein (Tau); Therapeutic Target