Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer’s disease

Haas, Laura T.; Salazar, Santiago V.; Kostylev, Mikhail A.; Um, Ji Won; Kaufman, A; Strittmatter, Stephen M.

doi:10.1093/brain/awv356

Cited by 117 publications

(135 citation statements)

References 77 publications

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“…1). We have previously characterized these phenomena to be fully dependent on mGluR5 and PrP C using genetic null brain preparations as well as a HEK cell overexpression system (16). Here we further show that DHPG and A␤o both cause increased mGluR5 but reduced Pyk2 signals in the anti-PrP C precipitates, similar to our previous results showing parallel actions of DHPG and A␤o for Fyn activation and Ca 2ϩ signaling (12).…”

Section: Resultssupporting

confidence: 89%

“…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.…”

Section: Resultsmentioning

confidence: 65%

“…1A and Ref. 16). We found that DHPG triggers an enhanced association between PrP C and Homer1b/c but a reduced association between PrP C and Pyk2 as well as between PrP C and CamKII (Fig.…”

Section: Resultsmentioning

confidence: 89%

“…We recently demonstrated that PrP C is linked to intracellular proteins via mGluR5 and that this coupling is modulated by extracellular A␤o (16). Critically, our work further revealed that the interaction between PrP C and intracellular protein mediators is perturbed in Alzheimer disease (16). Here we focus on comparing how the physiological glutamate analog 3,5-dihydroxyphenylglycine (DHPG) affects the PrP CmGluR5 complex in the absence and presence of A␤o.…”

mentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

Haas

Strittmatter

2016

Journal of Biological Chemistry

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The dysfunction and loss of synapses in Alzheimer disease are central to dementia symptoms. We have recently demonstrated that pathological Amyloid ␤ oligomer (A␤o) regulates the association between intracellular protein mediators and the synaptic receptor complex composed of cellular prion protein (PrP C ) and metabotropic glutamate receptor 5 (mGluR5). Here we sought to determine whether A␤o alters the physiological signaling of the PrP C -mGluR5 complex upon glutamate activation. We provide evidence that acute exposure to A␤o as well as chronic expression of familial Alzheimer disease mutant transgenes in model mice prevents protein-protein interaction changes of the complex induced by the glutamate analog 3,5-dihydroxyphenylglycine. We further show that 3,5-dihydroxyphenylglycine triggers the phosphorylation and activation of protein-tyrosine kinase 2-␤ (PTK2B, also referred to as Pyk2) and of calcium/calmodulin-dependent protein kinase II in wildtype brain slices but not in Alzheimer disease transgenic brain slices or wild-type slices incubated with A␤o. This study further distinguishes two separate A␤o-dependent signaling cascades, one dependent on extracellular Ca 2؉ and Fyn kinase activation and the other dependent on the release of Ca 2؉ from intracellular stores. Thus, A␤o triggers multiple distinct PrP C -mGluR5-dependent events implicated in neurodegeneration and dementia. We propose that targeting the PrP C -mGluR5 complex will reverse aberrant A␤o-triggered states of the complex to allow physiological fluctuations of glutamate signaling.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 65%

“…1A and Ref. 16). We found that DHPG triggers an enhanced association between PrP C and Homer1b/c but a reduced association between PrP C and Pyk2 as well as between PrP C and CamKII (Fig.…”

Section: Resultsmentioning

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Haas

Strittmatter

2016

Journal of Biological Chemistry

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Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease

et al. 2019

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IMPORTANCE Oligomeric amyloid-β peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease. OBJECTIVE To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated. DESIGN, SETTING, AND PARTICIPANTS This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n = 159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-β peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018. INTERVENTIONS AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks. MAIN OUTCOMES AND MEASURES Primary outcome was the reduction in relative CMRgl, as measured by 18 F-fluorodeoxyglucose (18 F-FDG) PET, at 52 weeks in an Alzheimer disease-associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers. RESULTS Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target = 180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: −0.006 units/y; 95% CI, −0.017 to 0.006; P = .34). The treatment groups also did not differ in the rate of change in Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness. CONCLUSIONS AND RELEVANCE Statistically significant effects of AZD0530 treatment were not found on relative CMRgl reduction in an Alzheimer disease-associated region of interest or on secondary clinical or biomarker measures.

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Advancements of the sFIDA method for oligomer‐based diagnostics of neurodegenerative diseases

et al. 2018

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Early diagnosis of Alzheimer's disease (AD) is of great importance for the development of therapeutics and their application in the clinical environment. Amyloid β (Aβ) oligomers are crucial for the onset and progression of AD and represent a popular drug target, being presumably the most direct biomarker. Efforts to measure Aβ oligomers in body fluids are hampered by the low analyte concentration and presence of Aβ monomers. The surface‐based fluorescence intensity distribution analysis (sFIDA) features both highly specific and sensitive oligomer quantitation as well as total insensitivity towards monomers. In this Review, we highlight structural features of oligomeric and fibrillar Aβ. Recent advancements in sFIDA assay development have been the successful automation, adaption for additional biomarkers such as α‐synuclein oligomers, and significant improvement of essential assay parameters.

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Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer’s disease

Cited by 117 publications

References 77 publications

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

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

Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease

Advancements of the sFIDA method for oligomer‐based diagnostics of neurodegenerative diseases

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