Fyn inhibition rescues established memory and synapse loss in Alzheimer mice

Abstract

Objective Currently no effective disease modifying agents exist for the treatment of AD. The Fyn tyrosine kinase is implicated in Alzheimer’s disease (AD) pathology triggered by amyloid-β oligomers (Aβo) 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 Aβo 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, 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 Aβo-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 Aβ 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.

Oligomers of Amyloid β Prevent Physiological Activation of the Cellular Prion Protein-Metabotropic Glutamate Receptor 5 Complex by Glutamate in Alzheimer Disease

“…Pyk2 and CamKII are two kinases associated with the PrP C -mGluR5 complex that are activated by acute A␤o stimulation in a PrP C -and mGluR5-dependent manner (16,18). Here we determined that DHPG as well as ionomycin treatments activate both kinases similarly to A␤o-triggered phosphorylation of Pyk2 and CamKII (Fig.…”

“…A␤o binding to PrP C triggers intracellular signaling via metabotropic glutamate receptor 5 (mGluR5) (12,16,17), which includes downstream Fyn activation and synapse loss (12,13,18). We recently demonstrated that PrP C is linked to intracellular proteins via mGluR5 and that this coupling is modulated by extracellular A␤o (16).…”

Synthesis and Preclinical Evaluation of11C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain

“…Figure 2 depicts a brief synthesis scheme for the preparation of the unlabeled UCB-J reference standard (3), the trifluoroborate radiolabeling precursor (6), and the radiolabeled tracer (7). Both the precursor and the reference standard were prepared from commercially available or custom-synthesized starting materials.…”

“…Mice deficient in SV2A develop seizures and die within 3 wk of birth (4). In addition to its well-established role as the target for the antiepileptic drug levetiracetam (5,6), dysfunction of SV2A has been implicated in other neurologic disorders such as Alzheimer's disease (7)(8)(9).…”

Academic drug discovery: current status and prospects

“…AstraZeneca are also collaborating with Yale University to repurpose saracatinib (AZD0530), a Src tyrosine kinase inhibitor, as a treatment for AD, on the basis of its Fyn kinase inhibitory properties [50]. A phase 1b trial in AD patients has been successful and a phase IIa study is underway [51].…”