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Ann Neurol. 2015 Jun;77(6):953-71. doi: 10.1002/ana.24394. Epub 2015 Mar 21.

Fyn inhibition rescues established memory and synapse loss in Alzheimer mice.

Author information

1
Department of Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT.
2
Department of Neurology, Yale University School of Medicine, New Haven, CT.
3
Department of Psychiatry, Yale University School of Medicine, New Haven, CT.

Abstract

OBJECTIVE:

Currently 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 (Aßo) 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.

METHODS:

The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aßo 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.

RESULTS:

AZD0530 potently inhibits Fyn and prevents both Aßo-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 Aß 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.

INTERPRETATION:

Targeting 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.

PMID:
25707991
PMCID:
PMC4447598
DOI:
10.1002/ana.24394
[Indexed for MEDLINE]
Free PMC Article

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