Soluble amyloid-β oligomers (Aβo) trigger Alzheimer’s disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrPC). At the postsynaptic 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 coexpression 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 latter 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.
•Among transmembrane PSD proteins, only mGluR5 couples Aβo-PrPC to Fyn kinase•mGluR5 also links Aβo-PrPC to calcium signaling and protein translation control•AD brain extract-induced dysregulation of neuronal calcium requires PrPC-mGluR5•Transgenic mouse memory deficits and synapse loss are reversed by mGluR5 antagonist
Amyloid-β oligomers trigger Alzheimer’s pathophysiology by binding to PrPC and disrupting synapses. Um et al. show that the mGluR5 metabotropic glutamate receptor links Aβo-PrPC to intracellular signaling. For AD mice, mGluR5 antagonism reverses deficits in learning, memory, and synapse density.
Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrP(C)) selectively binds oligomeric Aβ and can mediate Alzheimer's disease-related ...phenotypes. We examined the specificity, distribution and signaling of Aβ-PrP(C) complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons. PrP(C) is enriched in postsynaptic densities, and Aβ-PrP(C) interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrP(C) to activate Fyn. Aβ engagement of PrP(C)-Fyn signaling yielded phosphorylation of the NR2B subunit of NMDARs, which was coupled to an initial increase and then a loss of surface NMDARs. Aβ-induced dendritic spine loss and lactate dehydrogenase release required both PrP(C) and Fyn, and human familial Alzheimer's disease transgene-induced convulsive seizures did not occur in mice lacking PrP(C). These results delineate an Aβ oligomer signal transduction pathway that requires PrP(C) and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease.
Synaptic loss is critical in Alzheimer's disease (AD), but the dynamics of synapse turnover are poorly defined. We imaged dendritic spines in transgenic APPswe/PSen1∆E9 (APP/PS1) cerebral cortex. ...Dendritic spine turnover is increased far from plaque in aged APP/PS1 mice, and in young APP/PS1 mice prior to plaque formation. Dysregulation occurs in the presence of soluble Aβ oligomer and requires cellular prion protein (PrPC). APP/PS1 mice lack responsiveness of spine turnover to sensory stimulation. Critically, enhanced spine turnover is coupled with the loss of persistent spines starting early and continuing with age. To evaluate mechanisms of experience-independent supranormal spine turnover, we analyzed the transcriptome of young APP/PS1 mouse brain when turnover is altered but synapse density and memory are normal, and plaque and inflammation are absent. Early PrPC-dependent expression changes occur in synaptic and lipid-metabolizing genes. Thus, pathologic synaptic dysregulation underlying AD begins at a young age prior to Aβ plaque.
Cellular prion protein (PrPC) binds the scrapie conformation of PrP (PrPSc) and oligomeric β-amyloid peptide (Aβo) to mediate transmissible spongiform encephalopathy (TSE) and Alzheimer’s disease ...(AD), respectively. We conducted cellular and biochemical screens for compounds blocking PrPC interaction with Aβo. A polymeric degradant of an antibiotic targets Aβo binding sites on PrPC with low nanomolar affinity and prevents Aβo-induced pathophysiology. We then identified a range of negatively charged polymers with specific PrPC affinity in the low to sub-nanomolar range, from both biological (melanin) and synthetic (poly 4-styrenesulfonic acid-co-maleic acid, PSCMA) origin. Association of PSCMA with PrPC prevents Aβo/PrPC-hydrogel formation, blocks Aβo binding to neurons, and abrogates PrPSc production by ScN2a cells. We show that oral PSCMA yields effective brain concentrations and rescues APPswe/PS1ΔE9 transgenic mice from AD-related synapse loss and memory deficits. Thus, an orally active PrPC-directed polymeric agent provides a potential therapeutic approach to address neurodegeneration in AD and TSE.
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•Screen for antagonist of PrPC binding to Aβo identifies polymeric antibiotic degradant•Class of polymeric nM-potent PrPC antagonists rescue Aβo-induced phenotypes in vitro•PrPC antagonists also clear neuroblastoma cells of PrPSc replication•Oral PrPC antagonist rescues transgenic AD mouse synapse loss and memory deficits
Gunther et al. search for antagonists for Aβ oligomer binding to PrPC and identify a class of potent polymeric compounds. These molecules bind PrPC and competitively antagonize Aβo action at synapses, while also clearing PrPSc replication from neuroblastoma cells. An orally available PrPC antagonist rescues transgenic mouse Alzheimer phenotypes.
Soluble amyloid-? oligomers (A?o) trigger Alzheimer's disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrPC). At the postsynaptic density (PSD), extracellular A?o ...bound to lipid-anchored PrPCactivates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple A?o-PrPCwith Fyn. Only coexpression of the metabotropic glutamate receptor, mGluR5, allowed PrPC-bound A?o to activate Fyn. PrPCand mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. A?o-PrPCgenerates mGluR5-mediated increases of intracellular calcium inXenopusoocytes and in neurons, and the latter is also driven by human AD brain extracts. In addition, signaling by A?o-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, A?o-PrPCcomplexes at the neuronal surface activate mGluR5 to disrupt neuronal function.
Soluble Amyloid-β oligomers (Aβo) trigger Alzheimer’s disease (AD) pathophysiology and bind with high affinity to Cellular Prion Protein (PrP
C
). At the post-synaptic density (PSD), extracellular ...Aβo bound to lipid-anchored PrP
C
activates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple Aβo–PrP
C
with Fyn. Only co-expression of the metabotropic glutamate receptor, mGluR5, allowed PrP
C
-bound Aβo to activate Fyn. PrP
C
and mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. Aβo–PrP
C
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–PrP
C
–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–PrP
C
complexes at the neuronal surface activate mGluR5 to disrupt neuronal function.
Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer’s disease (AD) pathophysiology. Cellular Prion Protein (PrP
C
) 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. PrP
C
is enriched in post-synaptic densities, and Aβ/PrP
C
interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from human AD brain interact with PrP
C
to activate Fyn. Aβ engagement of PrP
C
/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 PrP
C
and Fyn, and human familial AD transgene-induced convulsive seizures do not occur in mice lacking PrP
C
. These results delineate an Aβ oligomer signal transduction pathway requiring PrP
C
and Fyn to alter synaptic function with relevance to AD.
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