The Experts below are selected from a list of 1563 Experts worldwide ranked by ideXlab platform
Kaj Blennow - One of the best experts on this subject based on the ideXlab platform.
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cerebrospinal fluid ykl 40 and Neurogranin in familial alzheimer s disease a pilot study
Journal of Alzheimer's Disease, 2020Co-Authors: Kaj Blennow, Henrik Zetterberg, Steinunn Thordardottir, Ove Almkvist, Charlotte Johansson, Caroline GraffAbstract:BACKGROUND YKL-40 and Neurogranin are promising additional cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) which reflect different underlying disease mechanisms. OBJECTIVE To compare the levels of CSF YKL-40 and Neurogranin between asymptomatic carriers of familial AD (FAD) mutations (MC) and non-carriers (NC) from the same families. Another objective was to assess changes in YKL-40 and Neurogranin, from the presymptomatic to clinical phase of FAD. METHODS YKL-40 and Neurogranin, as well as Aβ42, total tau-protein, and phospho-tau, were measured in the CSF of 14 individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G), and PSEN1 (p.H163Y), as well as in 17 NC from the same families. Five of the MC developed mild cognitive impairment (MCI) during follow-up. RESULTS In this pilot study, there was no difference in either CSF YKL-40 or Neurogranin when comparing the presymptomatic MC to the NC. YKL-40 correlated positively with expected years to symptom onset and to age in both the MC and the NC, while Neurogranin had no correlation to either variable in either of the groups. A subgroup of the participants underwent more than one CSF sampling in which half of the MC developed MCI during follow-up. The longitudinal data showed an increase in YKL-40 levels in the MC as the expected symptom onset approached. Neurogranin remained stable over time in both the MC and the NC. CONCLUSION These findings support a positive correlation between progression from presymptomatic to symptomatic AD and levels of CSF YKL-40, but not Neurogranin.
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cerebrospinal fluid levels of Neurogranin in parkinsonian disorders
Movement Disorders, 2020Co-Authors: Sara Hall, Kaj Blennow, Henrik Zetterberg, Shorena Janelidze, Britta Brix, Niklas Mattsson, Yulia Surova, Oskar HanssonAbstract:Background: CSF concentration of Neurogranin has been suggested as a biomarker for synapse dysfunction. Objectives: To investigate CSF Neurogranin in parkinsonian disorders compared to controls and Alzheimer's disease and the possible correlations between Neurogranin and cognitive and motor impairment. Methods: We included 157 patients with PD, 29 with PD with dementia, 11 with dementia with Lewy bodies, 26 with MSA, 21 with PSP, 6 with corticobasal syndrome, 47 controls, and 124 with Alzheimer's disease. CSF Neurogranin was measured using two enzyme-linked immunosorbent assays; from EUROIMMUN and the University of Gothenburg. Results: We found a strong correlation between CSF Neurogranin-EI and CSF Neurogranin–University of Gothenburg (Rs = 0.890; P < 0.001). Neurogranin was decreased in PD, PD with dementia, MSA, and PSP compared to controls and Alzheimer's disease. Neurogranin did not correlate with motor or cognitive impairment, longitudinal decline, or progression to dementia in PD. Conclusions: CSF Neurogranin is decreased in parkinsonian disorders compared to controls, emphasizing the importance of synaptic dysfunction in these disorders. (Less)
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csf Neurogranin as a neuronal damage marker in cjd a comparative study with ad
Journal of Neurology Neurosurgery and Psychiatry, 2019Co-Authors: Kaj Blennow, Henrik Zetterberg, Daniela Diazlucena, Anna Villarpique, Andre Karch, Enric Vidal, Peter Hermann, Matthias Schmitz, Isidro Ferrer Abizanda, Inga ZerrAbstract:Objective To investigate whether cerebrospinal fluid (CSF) Neurogranin concentrations are altered in sporadic Creutzfeldt-Jakob disease (CJD), comparatively with Alzheimer’s disease (AD), and associated with neuronal degeneration in brain tissue. Methods CSF Neurogranin, total tau, neurofilament light (NFL) and 14-3-3 protein were measured in neurological controls (NCs, n=64), AD (n=46) and CJD (n=81). The accuracy of Neurogranin discriminating the three diagnostic groups was evaluated. Correlations between Neurogranin and neurodegeneration biomarkers, demographic, genetic and clinical data were assessed. Additionally, Neurogranin expression in postmortem brain tissue was studied. Results Compared with NC, CSF Neurogranin concentrations were increased in CJD (4.75 times of NC; p Conclusions Neurogranin is a new biomarker of prion pathogenesis with diagnostic and prognostic abilities, which reflects the degree of neuronal damage in brain tissue in a CJD subtype manner.
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cerebrospinal fluid concentrations of the synaptic marker Neurogranin in neuro hiv and other neurological disorders
Current Hiv\ aids Reports, 2019Co-Authors: Aylin Yilmaz, Kaj Blennow, Henrik Zetterberg, Dietmar Fuchs, Richard W. Price, Serena Spudich, Magnus GisslénAbstract:Author(s): Yilmaz, Aylin; Fuchs, Dietmar; Price, Richard W; Spudich, Serena; Blennow, Kaj; Zetterberg, Henrik; Gisslen, Magnus | Abstract: PURPOSE OF REVIEW:The aim of this study was to examine the synaptic biomarker Neurogranin in cerebrospinal fluid (CSF) in different stages of HIV infection and in relation to what is known about CSF Neurogranin in other neurodegenerative diseases. RECENT FINDINGS:CSF concentrations of Neurogranin are increased in Alzheimer's disease, but not in other neurodegenerative disorder such as Parkinson's disease, frontotemporal dementia, and Lewy body dementia. Adults with HIV-associated dementia have been found to have decreased levels of Neurogranin in the frontal cortex, which at least to some extent, may be mediated by the proinflammatory cytokines IL-1β and IL-8. CSF Neurogranin concentrations were in the same range for all groups of HIV-infected individuals and uninfected controls. This either indicates that synaptic injury is not an important part of HIV neuropathogenesis or that CSF Neurogranin is not sensitive to the type of synaptic impairment present in HIV-associated neurocognitive disorders.
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Cerebrospinal Fluid Concentrations of the Synaptic Marker Neurogranin in Neuro-HIV and Other Neurological Disorders.
Current Hiv\ aids Reports, 2019Co-Authors: Aylin Yilmaz, Kaj Blennow, Henrik Zetterberg, Dietmar Fuchs, Richard W. Price, Serena Spudich, Magnus GisslénAbstract:PURPOSE OF REVIEW: The aim of this study was to examine the synaptic biomarker Neurogranin in cerebrospinal fluid (CSF) in different stages of HIV infection and in relation to what is known about CSF Neurogranin in other neurodegenerative diseases. RECENT FINDINGS: CSF concentrations of Neurogranin are increased in Alzheimer's disease, but not in other neurodegenerative disorder such as Parkinson's disease, frontotemporal dementia, and Lewy body dementia. Adults with HIV-associated dementia have been found to have decreased levels of Neurogranin in the frontal cortex, which at least to some extent, may be mediated by the proinflammatory cytokines IL-1β and IL-8. CSF Neurogranin concentrations were in the same range for all groups of HIV-infected individuals and uninfected controls. This either indicates that synaptic injury is not an important part of HIV neuropathogenesis or that CSF Neurogranin is not sensitive to the type of synaptic impairment present in HIV-associated neurocognitive disorders.
Henrik Zetterberg - One of the best experts on this subject based on the ideXlab platform.
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cerebrospinal fluid ykl 40 and Neurogranin in familial alzheimer s disease a pilot study
Journal of Alzheimer's Disease, 2020Co-Authors: Kaj Blennow, Henrik Zetterberg, Steinunn Thordardottir, Ove Almkvist, Charlotte Johansson, Caroline GraffAbstract:BACKGROUND YKL-40 and Neurogranin are promising additional cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) which reflect different underlying disease mechanisms. OBJECTIVE To compare the levels of CSF YKL-40 and Neurogranin between asymptomatic carriers of familial AD (FAD) mutations (MC) and non-carriers (NC) from the same families. Another objective was to assess changes in YKL-40 and Neurogranin, from the presymptomatic to clinical phase of FAD. METHODS YKL-40 and Neurogranin, as well as Aβ42, total tau-protein, and phospho-tau, were measured in the CSF of 14 individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G), and PSEN1 (p.H163Y), as well as in 17 NC from the same families. Five of the MC developed mild cognitive impairment (MCI) during follow-up. RESULTS In this pilot study, there was no difference in either CSF YKL-40 or Neurogranin when comparing the presymptomatic MC to the NC. YKL-40 correlated positively with expected years to symptom onset and to age in both the MC and the NC, while Neurogranin had no correlation to either variable in either of the groups. A subgroup of the participants underwent more than one CSF sampling in which half of the MC developed MCI during follow-up. The longitudinal data showed an increase in YKL-40 levels in the MC as the expected symptom onset approached. Neurogranin remained stable over time in both the MC and the NC. CONCLUSION These findings support a positive correlation between progression from presymptomatic to symptomatic AD and levels of CSF YKL-40, but not Neurogranin.
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cerebrospinal fluid levels of Neurogranin in parkinsonian disorders
Movement Disorders, 2020Co-Authors: Sara Hall, Kaj Blennow, Henrik Zetterberg, Shorena Janelidze, Britta Brix, Niklas Mattsson, Yulia Surova, Oskar HanssonAbstract:Background: CSF concentration of Neurogranin has been suggested as a biomarker for synapse dysfunction. Objectives: To investigate CSF Neurogranin in parkinsonian disorders compared to controls and Alzheimer's disease and the possible correlations between Neurogranin and cognitive and motor impairment. Methods: We included 157 patients with PD, 29 with PD with dementia, 11 with dementia with Lewy bodies, 26 with MSA, 21 with PSP, 6 with corticobasal syndrome, 47 controls, and 124 with Alzheimer's disease. CSF Neurogranin was measured using two enzyme-linked immunosorbent assays; from EUROIMMUN and the University of Gothenburg. Results: We found a strong correlation between CSF Neurogranin-EI and CSF Neurogranin–University of Gothenburg (Rs = 0.890; P < 0.001). Neurogranin was decreased in PD, PD with dementia, MSA, and PSP compared to controls and Alzheimer's disease. Neurogranin did not correlate with motor or cognitive impairment, longitudinal decline, or progression to dementia in PD. Conclusions: CSF Neurogranin is decreased in parkinsonian disorders compared to controls, emphasizing the importance of synaptic dysfunction in these disorders. (Less)
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csf Neurogranin as a neuronal damage marker in cjd a comparative study with ad
Journal of Neurology Neurosurgery and Psychiatry, 2019Co-Authors: Kaj Blennow, Henrik Zetterberg, Daniela Diazlucena, Anna Villarpique, Andre Karch, Enric Vidal, Peter Hermann, Matthias Schmitz, Isidro Ferrer Abizanda, Inga ZerrAbstract:Objective To investigate whether cerebrospinal fluid (CSF) Neurogranin concentrations are altered in sporadic Creutzfeldt-Jakob disease (CJD), comparatively with Alzheimer’s disease (AD), and associated with neuronal degeneration in brain tissue. Methods CSF Neurogranin, total tau, neurofilament light (NFL) and 14-3-3 protein were measured in neurological controls (NCs, n=64), AD (n=46) and CJD (n=81). The accuracy of Neurogranin discriminating the three diagnostic groups was evaluated. Correlations between Neurogranin and neurodegeneration biomarkers, demographic, genetic and clinical data were assessed. Additionally, Neurogranin expression in postmortem brain tissue was studied. Results Compared with NC, CSF Neurogranin concentrations were increased in CJD (4.75 times of NC; p Conclusions Neurogranin is a new biomarker of prion pathogenesis with diagnostic and prognostic abilities, which reflects the degree of neuronal damage in brain tissue in a CJD subtype manner.
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cerebrospinal fluid concentrations of the synaptic marker Neurogranin in neuro hiv and other neurological disorders
Current Hiv\ aids Reports, 2019Co-Authors: Aylin Yilmaz, Kaj Blennow, Henrik Zetterberg, Dietmar Fuchs, Richard W. Price, Serena Spudich, Magnus GisslénAbstract:Author(s): Yilmaz, Aylin; Fuchs, Dietmar; Price, Richard W; Spudich, Serena; Blennow, Kaj; Zetterberg, Henrik; Gisslen, Magnus | Abstract: PURPOSE OF REVIEW:The aim of this study was to examine the synaptic biomarker Neurogranin in cerebrospinal fluid (CSF) in different stages of HIV infection and in relation to what is known about CSF Neurogranin in other neurodegenerative diseases. RECENT FINDINGS:CSF concentrations of Neurogranin are increased in Alzheimer's disease, but not in other neurodegenerative disorder such as Parkinson's disease, frontotemporal dementia, and Lewy body dementia. Adults with HIV-associated dementia have been found to have decreased levels of Neurogranin in the frontal cortex, which at least to some extent, may be mediated by the proinflammatory cytokines IL-1β and IL-8. CSF Neurogranin concentrations were in the same range for all groups of HIV-infected individuals and uninfected controls. This either indicates that synaptic injury is not an important part of HIV neuropathogenesis or that CSF Neurogranin is not sensitive to the type of synaptic impairment present in HIV-associated neurocognitive disorders.
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Cerebrospinal Fluid Concentrations of the Synaptic Marker Neurogranin in Neuro-HIV and Other Neurological Disorders.
Current Hiv\ aids Reports, 2019Co-Authors: Aylin Yilmaz, Kaj Blennow, Henrik Zetterberg, Dietmar Fuchs, Richard W. Price, Serena Spudich, Magnus GisslénAbstract:PURPOSE OF REVIEW: The aim of this study was to examine the synaptic biomarker Neurogranin in cerebrospinal fluid (CSF) in different stages of HIV infection and in relation to what is known about CSF Neurogranin in other neurodegenerative diseases. RECENT FINDINGS: CSF concentrations of Neurogranin are increased in Alzheimer's disease, but not in other neurodegenerative disorder such as Parkinson's disease, frontotemporal dementia, and Lewy body dementia. Adults with HIV-associated dementia have been found to have decreased levels of Neurogranin in the frontal cortex, which at least to some extent, may be mediated by the proinflammatory cytokines IL-1β and IL-8. CSF Neurogranin concentrations were in the same range for all groups of HIV-infected individuals and uninfected controls. This either indicates that synaptic injury is not an important part of HIV neuropathogenesis or that CSF Neurogranin is not sensitive to the type of synaptic impairment present in HIV-associated neurocognitive disorders.
Oskar Hansson - One of the best experts on this subject based on the ideXlab platform.
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cerebrospinal fluid levels of Neurogranin in parkinsonian disorders
Movement Disorders, 2020Co-Authors: Sara Hall, Kaj Blennow, Henrik Zetterberg, Shorena Janelidze, Britta Brix, Niklas Mattsson, Yulia Surova, Oskar HanssonAbstract:Background: CSF concentration of Neurogranin has been suggested as a biomarker for synapse dysfunction. Objectives: To investigate CSF Neurogranin in parkinsonian disorders compared to controls and Alzheimer's disease and the possible correlations between Neurogranin and cognitive and motor impairment. Methods: We included 157 patients with PD, 29 with PD with dementia, 11 with dementia with Lewy bodies, 26 with MSA, 21 with PSP, 6 with corticobasal syndrome, 47 controls, and 124 with Alzheimer's disease. CSF Neurogranin was measured using two enzyme-linked immunosorbent assays; from EUROIMMUN and the University of Gothenburg. Results: We found a strong correlation between CSF Neurogranin-EI and CSF Neurogranin–University of Gothenburg (Rs = 0.890; P < 0.001). Neurogranin was decreased in PD, PD with dementia, MSA, and PSP compared to controls and Alzheimer's disease. Neurogranin did not correlate with motor or cognitive impairment, longitudinal decline, or progression to dementia in PD. Conclusions: CSF Neurogranin is decreased in parkinsonian disorders compared to controls, emphasizing the importance of synaptic dysfunction in these disorders. (Less)
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recommendations for cerebrospinal fluid collection for the analysis by elisa of Neurogranin trunc p75 α synuclein and total tau in combination with aβ 1 42 aβ 1 40
Alzheimer's Research & Therapy, 2017Co-Authors: Hugo Vanderstichele, Shorena Janelidze, Leentje Demeyer, Els Coart, Erik Stoops, Kimberley Mauroo, Victor Herbst, Cindy Francois, Oskar HanssonAbstract:The pathophysiology of neurodegeneration is complex. Its diagnosis requires an early identification of sequential changes in several hallmarks in the brains of affected subjects. The presence of brain pathology can be visualized in the cerebrospinal fluid (CSF) by protein profiling. It is clear that the field of Alzheimer’s disease (AD) will benefit from an integration of algorithms including CSF concentrations of individual proteins, especially as an aid in clinical decision-making or to improve patient enrolment in clinical trials. The protein profiling approach requires standard operating procedures for collection and storage of CSF which must be easy to integrate into a routine clinical lab environment. Our study provides recommendations for analysis of Neurogranin trunc P75, α-synuclein, and tau, in combination with the ratio of β-amyloid Aβ(1–42)/Aβ(1–40). Protocols for CSF collection were compared with CSF derived from subjects with normal pressure hydrocephalus (n = 19). Variables included recipient type (collection, storage), tube volume, and addition of detergents at the time of collection. CSF biomarker analysis was performed with enzyme-linked immunosorbent assays (ELISAs). Data were analyzed with linear repeated measures and mixed effects models. Adsorption to recipients is lower for Neurogranin trunc P75, α-synuclein, and tau (<10%), as compared to Aβ(1–42). For Neurogranin trunc P75 and total tau, there is still an effect on analyte concentrations as a function of the tube volume. Protocol-related differences for Aβ(1–42) can be normalized at the (pre-)analytical level using the ratio Aβ(1–42)/Aβ(1–40), but not by using the ratio Aβ(1–42)/tau. The addition of detergent at the time of collection eliminates differences due to adsorption. Our study recommends the use of low protein binding tubes for quantification in CSF (without additives) of all relevant CSF biomarkers. Pre-analytical factors have less effect on α-synuclein, Neurogranin trunc P75, and total tau, as compared to Aβ(1–42). The ratio of Aβ(1–42)/Aβ(1–40), but not Aβ(1–42)/tau, can be used to adjust for pre-analytical differences in analyte concentrations. Our study does not recommend the inclusion of detergents at the time of collection of CSF. The present results provide an experimental basis for new recommendations for parallel analysis of several proteins using one protocol for collection and storage of CSF.
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Cerebrospinal fluid tau, Neurogranin, and neurofilament light in Alzheimer's disease.
Embo Molecular Medicine, 2016Co-Authors: Niklas Mattsson, Kaj Blennow, Henrik Zetterberg, Erik Portelius, Michael W Weiner, Philip S. Insel, Sebastian Palmqvist, Oskar HanssonAbstract:Cerebrospinal fluid (CSF) tau (total tau, T-tau), neurofilament light (NFL), and Neurogranin (Ng) are potential biomarkers for neurodegeneration in Alzheimer's disease (AD). It is unknown whether these biomarkers provide similar or complementary information in AD. We examined 93 patients with AD, 187 patients with mild cognitive impairment, and 109 controls. T-tau, Ng, and NFL were all predictors of AD diagnosis. Combinations improved the diagnostic accuracy (AUC 85.5% for T-tau, Ng, and NFL) compared to individual biomarkers (T-tau 80.8%; Ng 71.4%; NFL 77.7%). T-tau and Ng were highly correlated (ρ = 0.79, P
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cerebrospinal fluid Neurogranin and ykl 40 as biomarkers of alzheimer s disease
Annals of clinical and translational neurology, 2016Co-Authors: Shorena Janelidze, Kaj Blennow, Henrik Zetterberg, Joakim Hertze, Maria Landqvist Waldo, Alexander Frizell Santillo, Oskar HanssonAbstract:Widespread implementation of cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) in clinical settings requires improved accuracy for diagnosis of prodromal disease and for distinguishing AD from non-AD dementias. Novel and promising CSF biomarkers include Neurogranin, a marker of synaptic degeneration, and YKL-40, a marker of neuroinflammation.
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Cerebrospinal fluid Neurogranin and YKL‐40 as biomarkers of Alzheimer's disease
Annals of clinical and translational neurology, 2015Co-Authors: Shorena Janelidze, Kaj Blennow, Henrik Zetterberg, Joakim Hertze, Maria Landqvist Waldo, Alexander Frizell Santillo, Oskar HanssonAbstract:Widespread implementation of cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) in clinical settings requires improved accuracy for diagnosis of prodromal disease and for distinguishing AD from non-AD dementias. Novel and promising CSF biomarkers include Neurogranin, a marker of synaptic degeneration, and YKL-40, a marker of neuroinflammation.
Stuart J Edelstein - One of the best experts on this subject based on the ideXlab platform.
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Neurogranin stimulates ca2 calmodulin dependent kinase ii by suppressing calcineurin activity at specific calcium spike frequencies
PLOS Computational Biology, 2020Co-Authors: Lu Li, Stephen Cole, Nicolas Le Novere, Stuart J EdelsteinAbstract:Calmodulin sits at the center of molecular mechanisms underlying learning and memory. Its complex and sometimes opposite influences, mediated via the binding to various proteins, are yet to be fully understood. Calcium/calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) both bind open calmodulin, favoring Long-Term Potentiation (LTP) or Depression (LTD) respectively. Neurogranin binds to the closed conformation of calmodulin and its impact on synaptic plasticity is less clear. We set up a mechanistic computational model based on allosteric principles to simulate calmodulin state transitions and its interactions with calcium ions and the three binding partners mentioned above. We simulated calcium spikes at various frequencies and show that Neurogranin regulates synaptic plasticity along three modalities. At low spike frequencies, Neurogranin inhibits the onset of LTD by limiting CaN activation. At intermediate frequencies, Neurogranin facilitates LTD, but limits LTP by precluding binding of CaMKII with calmodulin. Finally, at high spike frequencies, Neurogranin promotes LTP by enhancing CaMKII autophosphorylation. While Neurogranin might act as a calmodulin buffer, it does not significantly preclude the calmodulin opening by calcium. On the contrary, Neurogranin synchronizes the opening of calmodulin’s two lobes and promotes their activation at specific frequencies. Neurogranin suppresses basal CaN activity, thus increasing the chance of CaMKII trans-autophosphorylation at high-frequency calcium spikes. Taken together, our study reveals dynamic regulatory roles played by Neurogranin on synaptic plasticity, which provide mechanistic explanations for opposing experimental findings.
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Neurogranin stimulates Ca2+/calmodulin-dependent kinase II by suppressing calcineurin activity at specific calcium spike frequencies.
PLOS Computational Biology, 2020Co-Authors: Lu Li, Stephen Cole, Nicolas Le Novere, Stuart J EdelsteinAbstract:Calmodulin sits at the center of molecular mechanisms underlying learning and memory. Its complex and sometimes opposite influences, mediated via the binding to various proteins, are yet to be fully understood. Calcium/calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) both bind open calmodulin, favoring Long-Term Potentiation (LTP) or Depression (LTD) respectively. Neurogranin binds to the closed conformation of calmodulin and its impact on synaptic plasticity is less clear. We set up a mechanistic computational model based on allosteric principles to simulate calmodulin state transitions and its interactions with calcium ions and the three binding partners mentioned above. We simulated calcium spikes at various frequencies and show that Neurogranin regulates synaptic plasticity along three modalities. At low spike frequencies, Neurogranin inhibits the onset of LTD by limiting CaN activation. At intermediate frequencies, Neurogranin facilitates LTD, but limits LTP by precluding binding of CaMKII with calmodulin. Finally, at high spike frequencies, Neurogranin promotes LTP by enhancing CaMKII autophosphorylation. While Neurogranin might act as a calmodulin buffer, it does not significantly preclude the calmodulin opening by calcium. On the contrary, Neurogranin synchronizes the opening of calmodulin’s two lobes and promotes their activation at specific frequencies. Neurogranin suppresses basal CaN activity, thus increasing the chance of CaMKII trans-autophosphorylation at high-frequency calcium spikes. Taken together, our study reveals dynamic regulatory roles played by Neurogranin on synaptic plasticity, which provide mechanistic explanations for opposing experimental findings.
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Neurogranin stimulates ca2 calmodulin dependent kinase ii by inhibiting calcineurin at specific calcium spike frequencies
bioRxiv, 2019Co-Authors: Lu Li, Stewart T Cole, Le N Novere, Stuart J EdelsteinAbstract:Abstract Calmodulin sits at the centre of molecular mechanisms underlying learning and memory. Its complex, and sometimes opposite influences, via the binding to various proteins, are yet to be fully understood. Calcium/calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) both bind open calmodulin, favouring Long-term potentiation (LTP) or depression (LTD) respectively. Neurogranin binds to the closed conformation of calmodulin and its impact on synaptic plasticity is less clear. We set up a mechanistic computational model based on allosteric principles to simulate calmodulin state transitions and its interaction with calcium ions and the three binding partners mentioned above. We simulated calcium spikes at various frequencies and show that Neurogranin regulates synaptic plasticity along three modalities. At low spike frequencies, Neurogranin inhibits the onset of LTD by limiting CaN activation. At intermediate frequencies, Neurogranin limits LTP by precluding binding of CaMKII with calmodulin. Finally, at high spike frequencies, Neurogranin promotes LTP by enhancing CaMKII autophosphorylation. While Neurogranin might act as a calmodulin buffer, it does not significantly preclude the calmodulin opening by calcium. On the contrary, Neurogranin synchronizes the opening of calmodulin’s two lobes and promotes their activation at specific frequencies, increasing the chance of CaMKII trans-autophosphorylation. Taken together, our study reveals dynamic regulatory roles played by Neurogranin on synaptic plasticity, which provide mechanistic explanations to opposing experimental findings. Author Summary How our brains learn and remember things lies in the subtle changes of the strength with which brain cells connect to each other, the so-called synaptic plasticity. At the level of the recipient neuron, some of the information is encoded into patterns of intracellular calcium spikes. Calmodulin, a small bilobed protein which conformation is regulated by the binding of calcium ions, decodes these signals, and modulates the activity of specific binding partners. Two key regulators, calcineurin and calcium/calmodulin-dependent protein kinase II, which respectively weaken or strengthen synaptic connections, bind both lobes of calmodulin in its open form, favoured by calcium. On the contrary, Neurogranin binds preferentially to one lobe of calmodulin, in the closed form, unfavoured by calcium. It was thus initially suggested that it would inhibit calmodulin activation and decrease synaptic plasticity. However, past research showed that Neurogranin sometimes actually enhances synaptic plasticity, though the mechanism was unclear. Our computational models showed that Neurogranin synchronizes the activation of the two lobes of calmodulin, favouring opening at high frequency calcium spikes. By doing so, Neurogranin increases the impact of calmodulin on calcium/calmodulin-dependent protein kinase II and reduces its effect on calcineurin, resulting in a strengthening of synaptic connections.
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Neurogranin Stimulates Ca2+/calmodulin-dependent Kinase II by Inhibiting Calcineurin at Specific Calcium Spike Frequencies
bioRxiv, 2019Co-Authors: Lu Li, Nicolas Le Novere, Stewart T Cole, Stuart J EdelsteinAbstract:Abstract Calmodulin sits at the centre of molecular mechanisms underlying learning and memory. Its complex, and sometimes opposite influences, via the binding to various proteins, are yet to be fully understood. Calcium/calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) both bind open calmodulin, favouring Long-term potentiation (LTP) or depression (LTD) respectively. Neurogranin binds to the closed conformation of calmodulin and its impact on synaptic plasticity is less clear. We set up a mechanistic computational model based on allosteric principles to simulate calmodulin state transitions and its interaction with calcium ions and the three binding partners mentioned above. We simulated calcium spikes at various frequencies and show that Neurogranin regulates synaptic plasticity along three modalities. At low spike frequencies, Neurogranin inhibits the onset of LTD by limiting CaN activation. At intermediate frequencies, Neurogranin limits LTP by precluding binding of CaMKII with calmodulin. Finally, at high spike frequencies, Neurogranin promotes LTP by enhancing CaMKII autophosphorylation. While Neurogranin might act as a calmodulin buffer, it does not significantly preclude the calmodulin opening by calcium. On the contrary, Neurogranin synchronizes the opening of calmodulin’s two lobes and promotes their activation at specific frequencies, increasing the chance of CaMKII trans-autophosphorylation. Taken together, our study reveals dynamic regulatory roles played by Neurogranin on synaptic plasticity, which provide mechanistic explanations to opposing experimental findings. Author Summary How our brains learn and remember things lies in the subtle changes of the strength with which brain cells connect to each other, the so-called synaptic plasticity. At the level of the recipient neuron, some of the information is encoded into patterns of intracellular calcium spikes. Calmodulin, a small bilobed protein which conformation is regulated by the binding of calcium ions, decodes these signals, and modulates the activity of specific binding partners. Two key regulators, calcineurin and calcium/calmodulin-dependent protein kinase II, which respectively weaken or strengthen synaptic connections, bind both lobes of calmodulin in its open form, favoured by calcium. On the contrary, Neurogranin binds preferentially to one lobe of calmodulin, in the closed form, unfavoured by calcium. It was thus initially suggested that it would inhibit calmodulin activation and decrease synaptic plasticity. However, past research showed that Neurogranin sometimes actually enhances synaptic plasticity, though the mechanism was unclear. Our computational models showed that Neurogranin synchronizes the activation of the two lobes of calmodulin, favouring opening at high frequency calcium spikes. By doing so, Neurogranin increases the impact of calmodulin on calcium/calmodulin-dependent protein kinase II and reduces its effect on calcineurin, resulting in a strengthening of synaptic connections.
Nashaat Z Gerges - One of the best experts on this subject based on the ideXlab platform.
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Neurogranin and synaptic plasticity balance
Communicative & Integrative Biology, 2020Co-Authors: Ling Zhong, Nashaat Z GergesAbstract:Learning-related modifications of synaptic transmission at CA1 hippocampal excitatory synapses are activity- and NMDA receptor (NMDAR)-dependent. While a postsynaptic increase in Ca2+ is absolutely required for synaptic plasticity induction, the molecular mechanisms underlying the transduction of synaptic signals to postsynaptic changes are not clearly understood. In our recent study, we found that the postsynaptic calmodulin (CaM)-binding protein Neurogranin (Ng) enhances synaptic strength in an activity- and NMDAR-dependent manner. Furthermore we have shown that Ng is not only required for the induction of long-term potentiation (LTP), but its mediated synaptic potentiation also mimics and occludes LTP. Our results demonstrate that Ng plays an important role in the regulation of hippocampal synaptic plasticity and synaptic function. Here, we summarize our findings and further discuss their possible implications in aging-related synaptic plasticity deficits.
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Neurogranin Regulates Metaplasticity.
Frontiers in Molecular Neuroscience, 2020Co-Authors: Ling Zhong, Nashaat Z GergesAbstract:Long-term potentiation (LTP) and long-term depression (LTD) are two major forms of synaptic plasticity that are widely accepted as cellular mechanisms involved in learning and memory. Metaplasticity is a process whereby modifications in synaptic processes shift the threshold for subsequent plasticity. While metaplasticity has been functionally observed, its molecular basis is not well understood. Here, we report that Neurogranin (Ng) regulates metaplasticity by shifting the threshold toward potentiation, i.e. increasing Ng in hippocampal neurons lowers the threshold for LTP and augments the threshold for LTD. We also show that Ng does not change the ultrastructural localization of CaMKII or calcineurin, critical enzymes for the induction of LTP and LTD, respectively. Interestingly, while CaMKII concentrates close to the plasma membrane, calcineurin concentrates away from the plasma membrane. These data, along with the previous observation showing Ng targets calmodulin (CaM) closer to the plasma membrane, suggest that shifting the localization of CaM within the dendritic spines and closer to the plasma membrane, where there is more CaMKII, may be favoring the activation of CaMKII versus that of calcineurin. Thus, the regulation of CaM localization/targeting within dendritic spines by Ng may provide a mechanistic basis for the regulation of metaplasticity.
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Neurogranin regulates cam dynamics at dendritic spines
Scientific Reports, 2015Co-Authors: Amber Petersen, Nashaat Z GergesAbstract:Calmodulin (CaM) plays a key role in synaptic function and plasticity due to its ability to mediate Ca2+ signaling. Therefore, it is essential to understand the dynamics of CaM at dendritic spines. In this study we have explored CaM dynamics using live-cell confocal microscopy and fluorescence recovery after photobleaching (FRAP) to study CaM diffusion. We find that only a small fraction of CaM in dendritic spines is immobile. Furthermore, the diffusion rate of CaM was regulated by Neurogranin (Ng), a CaM-binding protein enriched at dendritic spines. Interestingly, Ng did not influence the immobile fraction of CaM at recovery plateau. We have previously shown that Ng enhances synaptic strength in a CaM-dependent manner. Taken together, these data indicate that Ng-mediated enhancement of synaptic strength is due to its ability to target, rather than sequester, CaM within dendritic spines.
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Neurogranin targets calmodulin and lowers the threshold for the induction of long term potentiation
PLOS ONE, 2012Co-Authors: Ling Zhong, Nashaat Z GergesAbstract:Calcium entry and the subsequent activation of CaMKII trigger synaptic plasticity in many brain regions. The induction of long-term potentiation (LTP) in the CA1 region of the hippocampus requires a relatively high amount of calcium-calmodulin. This requirement is usually explained, based on in vitro and theoretical studies, by the low affinity of CaMKII for calmodulin. An untested hypothesis, however, is that calmodulin is not randomly distributed within the spine and its targeting within the spine regulates LTP. We have previously shown that overexpression of Neurogranin enhances synaptic strength in a calmodulin-dependent manner. Here, using post-embedding immunogold labeling, we show that calmodulin is not randomly distributed, but spatially organized in the spine. Moreover, Neurogranin regulates calmodulin distribution such that its overexpression concentrates calmodulin closer to the plasma membrane, where a high level of CaMKII immunogold labeling is also found. Interestingly, the targeting of calmodulin by Neurogranin results in lowering the threshold for LTP induction. These findings highlight the significance of calmodulin targeting within the spine in synaptic plasticity.
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Neurogranin phosphorylation fine tunes long term potentiation
European Journal of Neuroscience, 2011Co-Authors: Ling Zhong, Kanwardeep Kaleka, Nashaat Z GergesAbstract:Learning-related potentiation of synaptic strength at CA1 hippocampal excitatory synapses is dependent on neuronal activity and the activation of glutamate receptors. However, molecular mechanisms that regulate and fine-tune the expression of long-term potentiation (LTP) are not well understood. Recently it has been indicated that Neurogranin, a neuron-specific, postsynaptic protein that is phosphorylated by protein kinase C (PKC), potentiates synaptic transmission in an LTP-like manner. Here, we report that a Neurogranin mutant that is unable to be phosphorylated cannot potentiate synaptic transmission in rat CA1 hippocampal neurons and results in a sub-maximal expression of LTP. Our results provide the first evidence that the phosphorylation of Neurogranin can regulate LTP expression.