Journal
ANNALS OF NEUROLOGY
Volume 77, Issue 6, Pages 953-971Publisher
WILEY
DOI: 10.1002/ana.24394
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Funding
- NIH National Center for Advancing Translation Sciences [UH2TR00967]
- NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director
- NIH National Institute on Aging [R01AG34924]
- BrightFocus Foundation
- Alzheimer's Association
- Falk Medical Research Trust
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ObjectiveCurrently no effective disease-modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathology triggered by amyloid-ss oligomers (A ss o) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD. MethodsThe pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of A ss o signaling to Fyn, Pyk2, and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild-type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, amyloid precursor protein (APP) metabolism, synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting. ResultsAZD0530 potently inhibits Fyn and prevents both A ss o-induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or A ss metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. InterpretationTargeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD. Ann Neurol 2015;77:953-971
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