SUMMARY Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer’s disease (AD) pathophysiology. Cellular Prion Protein (PrPC) selectively binds oligomeric Aβ and can mediate AD-related phenotypes. Here, we examined the specificity, distribution and signaling from Aβ/PrP complexes, seeking to explain how they might alter the function of NMDA receptors in neurons. PrPC is enriched in post-synaptic densities, and Aβ/PrPC interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from human AD brain interact with PrPC to activate Fyn. Aβ engagement of PrPC/Fyn signaling yields phosphorylation of the NR2B subunit of NMDA-receptors, which is coupled to an initial increase and then loss of surface NMDA-receptors. Aβ-induced LDH release and dendritic spine loss require both PrPC and Fyn, and human familial AD transgene-induced convulsive seizures do not occur in mice lacking PrPC. These results delineate an Aβ oligomer signal transduction pathway requiring PrPC and Fyn to alter synaptic function with relevance to AD.

SUMMARY Soluble Amyloid-β oligomers (Aβo) trigger Alzheimer’s disease (AD) pathophysiology and bind with high affinity to Cellular Prion Protein (PrPC). At the post-synaptic density (PSD), extracellular Aβo bound to lipid-anchored PrPC activates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple Aβo–PrPC with Fyn. Only co-expression of the metabotropic glutamate receptor, mGluR5, allowed PrPC-bound Aβo to activate Fyn. PrPC and mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. Aβo–PrPC generates mGluR5-mediated increases of intracellular calcium in Xenopus oocytes and in neurons, and the later is also driven by human AD brain extracts. In addition, signaling by Aβo–PrPC–mGluR5 complexes mediates eEF2 phosphorylation and dendritic spine loss. For mice expressing familial AD transgenes, mGluR5 antagonism reverses deficits in learning, memory and synapse density. Thus, Aβo–PrPC complexes at the neuronal surface activate mGluR5 to disrupt neuronal function.

Soluble oligomers of the amyloid-β (Aβ) peptide are thought to play a key role in the pathophysiology of Alzheimer’s disease (AD). Recently, we reported that synthetic Aβ oligomers bind to cellular prion protein (PrPC) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Aβ peptide. We hypothesized that PrPC is essential for the ability of brain-derived Aβ to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1ΔE9 into Prnp−/− mice to examine the necessity of PrPC for AD-related phenotypes. Neither APP expression nor Aβ level is altered by PrPC absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrPC expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1ΔE9 transgenic mice. The AD transgenic mice with intact PrPC expression exhibit deficits in spatial learning and memory. Mice lacking PrPC, but containing Aβ plaque derived from APPswe/PSen1ΔE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrPC expression dissociates Aβ accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrPC.

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.

Background: Amyloid-␤ (A␤) oligomers are key in Alzheimer disease (AD) but are diverse and poorly characterized. Results: Multiple A␤ forms were measured across the life span of AD model mice and human AD brain. Conclusion: A␤ species interacting with prion protein were tightly linked to behavioral impairment. Significance: An A␤ oligomer subset with defined biochemical properties is present in multiple AD-relevant samples.