Metabotropic Glutamate Receptor 5 Is a Coreceptor for Alzheimer Aβ Oligomer Bound to Cellular Prion Protein

Um, Ji Won; Kaufman, A; Kostylev, Mikhail A.; Heiss, Jacqueline K.; Stagi, Massimiliano; Takahashi, Hideyuki; Kerrisk, Meghan E.; Vortmeyer, Alexander O.; Wısnıewskı, Thomas; Koleske, Anthony J.; Gunther, Erik C.; Nygaard, Haakon B.; Strittmatter, Stephen M.

doi:10.1016/j.neuron.2013.06.036

Cited by 499 publications

(571 citation statements)

References 64 publications

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“…The second model is also supported by reports of oligomer receptor candidates that have appeared in the literature [9]–[11],[13],[27]–[29]. For several of these candidate receptors, oligomer binding to neurons (visualized via immunohistochemistry) is reduced by at most 50% when the receptor levels are eliminated by genetic knock-out [27],[29].…”

Section: Discussionmentioning

confidence: 61%

Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

et al. 2014

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Amyloid beta (Abeta) 1–42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.

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Section: Discussionmentioning

confidence: 61%

Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

et al. 2014

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“…Aβ has been shown to activate mGluR5 (a group 1 mGluR), and affect downstream activity of an ionotropic glutamate receptor (Um et al, 2012; Um et al, 2013). Other studies have implicated group 1 mGluRs (mGluR1 and 5) and downstream activation of PKC via a canonical G-protein coupled receptor (GPCR) pathway in modulation of KAR activity and surface expression (Cho et al, 2003; Nasu-Nishimura et al, 2010; Rojas et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

“…The biphasic effect of Aβ 42 we observed on KA-induced Ca 2+ influx mimics previously demonstrated modulation of KAR by group 1 mGluRs and protein kinase C (PKC) (Cho et al, 2003; Nasu-Nishimura et al, 2010; Rojas et al, 2013). In addition, Aβ has previously been shown to activate group 1 mGluRs and elicit downstream effects on glutamate receptor activity (Um et al, 2012; Um et al, 2013). Therefore, we investigated whether Aβ 42 was modulating KAR by activating group 1 mGluRs.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of tau and Aβ-induced excitotoxicity

et al. 2016

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Excitotoxicity was originally postulated to be a late stage side effect of Alzheimer’s disease (AD)-related neurodegeneration, however more recent studies indicate that it may occur early in AD and contribute to the neurodegenerative process. Tau and amyloid beta (Aβ), the main components of neurofibrillary tangles (NFTs) and amyloid plaques, have been implicated in cooperatively and independently facilitating excitotoxicity. Our study investigated the roles of tau and Aβ in AD-related excitotoxicity. In vivo studies showed that tau knockout (tau−/−) mice were significantly protected from seizures and hippocampal superoxide production induced with the glutamate analog, kainic acid (KA). We hypothesized that tau accomplished this by facilitating KA-induced Ca2+ influx into neurons, however lentiviral tau knockdown failed to ameliorate KA-induced Ca2+ influx into primary rat cortical neurons. We further investigated if tau cooperated with Aβ to facilitate KA-induced Ca2+ influx. While Aβ biphasically modulated the KA-induced Ca2+cyt responses, tau knockdown continued to have no effect. Therefore, tau facilitates KA-induced seizures and superoxide production in a manner that does not involve facilitation of Ca2+ influx through KA receptors (KAR). On the other hand, acute pretreatment with Aβ (10 minutes) enhanced KA-induced Ca2+ influx, while chronic Aβ (24 hours) significantly reduced it, regardless of tau knockdown. Given previously published connections between Aβ, group 1 metabotropic glutamate receptors (mGluRs), and KAR regulation, we hypothesized that Aβ modulates KAR via a G-protein coupled receptor pathway mediated by group 1 mGluRs. We found that Aβ did not activate group 1 mGluRs and inhibition of these receptors did not reverse Aβ modulation of KA-induced Ca2+ influx. Therefore, Aβ biphasically regulates KAR via a mechanism that does not involve group 1 mGluR activation.

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“…More recent studies have however confirmed that antibodies targeting a specific domain of PrP C (amino acids 94–104) can prevent the oligomeric Aβ–induced inhibition of LTP (Barry et al, 2011; Freir et al, 2011), and Larson et al observed that soluble Aβ binding to PrP C in dendritic spines forms a complex with Fyn causing Fyn activation and tau phosphorylation (Larson et al, 2012). The interaction of Aβ and PrP C appears to depend on mGluR5 (Um et al, 2013). These last two studies are intriguing as they link Aβ to tau pathology via Fyn, which has been seen to be an important interacting partner of tau at the PSD; however the molecules that link PrP to Fyn remain unknown (Chen et al, 2013).…”

Section: Mechanisms Of Synaptic Dysfunction and Lossmentioning

confidence: 99%

The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease

Spires‐Jones

Hyman

2014

Neuron

937

745

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Summary The collapse of neural networks important for memory and cognition, including death of neurons and degeneration of synapses, causes the debilitating dementia associated with Alzheimer’s disease (AD). We suggest that synaptic changes are central to the disease process. Amyloid beta and tau form fibrillar lesions that are the classical hallmarks of AD. Recent data indicate that both molecules may have normal roles at the synapse, and that the accumulation of soluble toxic forms of the proteins at the synapse may be on the critical path to neurodegeneration. Further, the march of neurofibrillary tangles through brain circuits appears to take advantage of recently described mechanisms of trans-synaptic spread of pathological forms of tau. These two key phenomena, synapse loss and the spread of pathology through the brain via synapses, make it critical to understand the physiological and pathological roles of amyloid beta and tau at the synapse.

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Metabotropic Glutamate Receptor 5 Is a Coreceptor for Alzheimer Aβ Oligomer Bound to Cellular Prion Protein

Cited by 499 publications

References 64 publications

Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

Mechanisms of tau and Aβ-induced excitotoxicity

The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease

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