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.
Most dendrite branches and a large fraction of dendritic spines in the adult rodent forebrain are stable for extended periods of time. Destabilization of these structures compromises brain function ...and is a major contributing factor to psychiatric and neurodegenerative diseases. Integrins are a class of transmembrane extracellular matrix receptors that function as αβ heterodimers and activate signaling cascades regulating the actin cytoskeleton. Here we identify integrin α3 as a key mediator of neuronal stability. Dendrites, dendritic spines, and synapses develop normally in mice with selective loss of integrin α3 in excitatory forebrain neurons, reaching their mature sizes and densities through postnatal day 21 (P21). However, by P42, integrin α3 mutant mice exhibit significant reductions in hippocampal dendrite arbor size and complexity, loss of dendritic spine and synapse densities, and impairments in hippocampal-dependent behavior. Furthermore, gene-dosage experiments demonstrate that integrin α3 interacts functionally with the Arg nonreceptor tyrosine kinase to activate p190RhoGAP, which inhibits RhoA GTPase and regulates hippocampal dendrite and synapse stability and mouse behavior. Together, our data support a fundamental role for integrin α3 in regulating dendrite arbor stability, synapse maintenance, and proper hippocampal function. In addition, these results provide a biochemical and structural explanation for the defects in long-term potentiation, learning, and memory reported previously in mice lacking integrin α3.
Most dendrite branches and a large fraction of dendritic spines in the adult rodent forebrain are stable for extended periods of time. Destabilization of these structures compromises brain function ...and is a major contributing factor to psychiatric and neurodegenerative diseases. Integrins are a class of transmembrane extracellular matrix receptors that function as alpha beta heterodimers and activate signaling cascades regulating the actin cytoskeleton. Here we identify integrin alpha 3 as a key mediator of neuronal stability. Dendrites, dendritic spines, and synapses develop normally in mice with selective loss of integrin alpha 3 in excitatory forebrain neurons, reaching their mature sizes and densities through postnatal day 21 (P21). However, by P42, integrin alpha 3 mutant mice exhibit significant reductions in hippocampal dendrite arbor size and complexity, loss of dendritic spine and synapse densities, and impairments in hippocampal-dependent behavior. Furthermore, gene-dosage experiments demonstrate that integrin alpha 3 interacts functionally with the Arg nonreceptor tyrosine kinase to activate p190RhoGAP, which inhibits RhoA GTPase and regulates hippocampal dendrite and synapse stability and mouse behavior. Together, our data support a fundamental role for integrin alpha 3 in regulating dendrite arbor stability, synapse maintenance, and proper hippocampal function. In addition, these results provide a biochemical and structural explanation for the defects in long-term potentiation, learning, and memory reported previously in mice lacking integrin alpha 3.
The Abl2/Arg nonreceptor tyrosine kinase is enriched in dendritic spines where it is essential for maintaining dendrite and synapse stability in the postnatal mouse brain. Arg is activated downstream ...of integrin α3β1 receptors and it regulates the neuronal actin cytoskeleton by directly binding F-actin and via phosphorylation of substrates including p190RhoGAP and cortactin. Neurons in mice lacking Arg or integrin α3β1 develop normally through postnatal day 21 (P21), however by P42 mice exhibit major reductions in dendrite arbor size and complexity, and lose dendritic spines and synapses. As a result, mice with loss of Arg and Arg-dependent signaling pathways have impairments in memory tasks, heightened sensitivity to cocaine, and vulnerability to corticosteroid-induced neuronal remodeling. Therefore, understanding the molecular mechanisms of Arg regulation may lead to therapeutic approaches to treat human psychiatric and neurodegenerative diseases in which neuronal structure is destabilized.
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.
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