Fyn kinase inhibition as a novel therapy for Alzheimer's disease.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder, afflicting more than one-third of people over the age of 85. While many therapies for AD are in late-stage clinical testing, rational drug design based on distinct signaling pathways in this disorder is only now emerging. Here we review the putative signaling pathway of amyloid-beta (Aβ), by which the tyrosine kinase Fyn is activated via cell surface binding of Aβ oligomers to cellular prion protein. Several lines of evidence implicate Fyn in the pathogenesis of AD, and its interaction with both Aβ and Tau renders Fyn a unique therapeutic target that addresses both of the major pathologic hallmarks of AD. We are currently enrolling patients in a phase Ib study of saracatinib (AZD0530), a small molecule inhibitor with high potency for Src and Fyn, for the treatment of AD. The results of this trial and a planned phase IIa multisite study will provide important data regarding the potential for this therapeutic strategy in AD.
Department of Neurology, Yale University School of Medicine, PO Box 208018, New Haven, CT 06520, USA ; Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, 295 Congress Avenue, BCMM 436, New Haven, CT 06536, USA.
Haakon B
HB
Nygaard
Alzheimer's Disease Research Unit, Yale University School of Medicine, 1 Church Street, Suite 600, New Haven, CT 06510, USA ; Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511, USA.
Christopher H
CH
van Dyck
Department of Neurology, Yale University School of Medicine, PO Box 208018, New Haven, CT 06520, USA ; Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, 295 Congress Avenue, BCMM 436, New Haven, CT 06536, USA.
Stephen M
SM
Strittmatter