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Fred Van Leuven - One of the best experts on this subject based on the ideXlab platform.
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Age-Related Impairment of Ultrasonic Vocalization in Tau.P301L Mice: Possible Implication for Progressive Language Disorders
2016Co-Authors: Yves Cazals, Peter Borghgraef, Christian Gestreau, Lies Gielis, Fred Van LeuvenAbstract:Background: Tauopathies, including Alzheimer’s Disease, are the most frequent neurodegenerative diseases in elderly people and cause various cognitive, behavioural and motor defects, but also progressive language disorders. For communication and social interactions, mice produce ultrasonic vocalization (USV) via expiratory airflow through the larynx. We examined USV of Tau.P301L mice, a mouse model for Tauopathy expressing human mutant tau protein and developing cognitive, motor and upper airway defects. Methodology/Principal Findings: At age 4–5 months, Tau.P301L mice had normal USV, normal expiratory airflow and no brainstem Tauopathy. At age 8–10 months, Tau.P301L mice presented impaired USV, reduced expiratory airflow and severe Tauopathy in the periaqueductal gray, Kolliker-Fuse and retroambiguus nuclei. Tauopathy in these nuclei that control upper airway function and vocalization correlates well with the USV impairment of old Tau.P301L mice. Conclusions: In a mouse model for Tauopathy, we report for the first time an age-related impairment of USV that correlates with Tauopathy in midbrain and brainstem areas controlling vocalization. The vocalization disorder of old Tau.P301L mic
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Tauopathy differentially affects cell adhesion molecules in mouse brain early down regulation of nectin 3 in stratum lacunosum moleculare
PLOS ONE, 2013Co-Authors: Hervé Maurin, Benoit Lechat, Tomasz Jaworski, Peter Borghgraef, Herman Devijver, Claire M Seymour, Mathias V Schmidt, Sebastian Kuegler, Fred Van LeuvenAbstract:Cell adhesion molecules are important structural substrates, required for synaptic plasticity and synaptogenesis. CAMs differ widely in their expression throughout different brain regions and their specific structural and functional roles in the brain remain to be elucidated. Here, we investigated selected cell adhesion molecules for alterations in expression levels and neuronal localization in validated mouse models for Alzheimer's disease that mimic the age-related progression of amyloid accumulation and Tauopathy. Among the cell adhesion molecules analyzed, Nectin-3 expression was affected most and specifically in all mouse models with Tauopathy. In particular was Nectin-3 depleted from the specific region of the hippocampus, known as the stratum lacunosum and moleculare, in mice that express wild-type or mutant human protein Tau, either chronically or sub-acutely. Tauopathy progresses from the entorhinal cortex to the hippocampus by unknown mechanisms that could involve transport by the myelinated axons of the temporoammonic and perforant pathways. The decreased expression of Nectin-3 in the stratum lacunosum moleculare is an early marker of impaired transport, and eventual synaptic problems, caused by beginning Tauopathy.
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Raphé Tauopathy alters serotonin metabolism and breathing activity in terminal Tau.P301L mice: possible implications for tauopathies and Alzheimer's disease.
Respiratory Physiology and Neurobiology, 2011Co-Authors: Clément Menuet, Peter Borghgraef, Fred Van Leuven, Christian Gestreau, Lies Gielis, Valéry Matarazzo, Anne-marie Lajard, Nicolas Voituron, Mathias Dutschmann, Gérard HilaireAbstract:Tauopathies, including Alzheimer's disease are the most frequent neurodegenerative disorders in elderly people. Patients develop cognitive and behaviour defects induced by the Tauopathy in the forebrain, but most also display early brainstem Tauopathy, with oro-pharyngeal and serotoninergic (5-HT) defects. We studied these aspects in Tau.P301L mice, that express human mutant tau protein and develop Tauopathy first in hindbrain, with cognitive, motor and upper airway defects from 7 to 8 months onwards, until premature death before age 12 months. Using plethysmography, immunohistochemistry and biochemistry, we examined the respiratory and 5-HT systems of aging Tau.P301L and control mice. At 8 months, Tau.P301L mice developed upper airway dysfunction but retained normal respiratory rhythm and normal respiratory regulations. In the following weeks, Tau.P301L mice entered terminal stages with reduced body weight, progressive limb clasping and lethargy. Compared to age 8 months, terminal Tau.P301L mice showed aggravated upper airway dysfunction, abnormal respiratory rhythm and abnormal respiratory regulations. In addition, they showed severe Tauopathy in Kolliker-Fuse, raphé obscurus and raphé magnus nuclei but not in medullary respiratory-related areas. Although the raphé Tauopathy concerned mainly non-5-HT neurons, the 5-HT metabolism of terminal Tau.P301L mice was altered. We propose that the progressive raphé Tauopathy affects the 5-HT metabolism, which affects the 5-HT modulation of the respiratory network and therefore the breathing pattern. Then, 5-HT deficits contribute to the moribund phenotype of Tau.P301L mice, and possibly in patients suffering from tauopathies, including Alzheimer's disease.
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Upper airway dysfunction of Tau-P301L mice correlates with Tauopathy in midbrain and ponto-medullary brainstem nuclei.
Journal of Neuroscience, 2010Co-Authors: Mathias Dutschmann, Peter Borghgraef, Herman Devijver, Christian Gestreau, Lies Gielis, Clément Menuet, Gérard Hilaire, Georg M Stettner, Fred Van LeuvenAbstract:Tauopathy comprises hyperphosphorylation of the microtubule-associated protein tau, causing intracellular aggregation and accumulation as neurofibrillary tangles and neuropil treads. Some primary tauopathies are linked to mutations in the MAPT gene coding for protein tau, but most are sporadic with unknown causes. Also, in Alzheimer's disease, the most frequent secondary Tauopathy, neither the cause nor the pathological mechanisms and repercussions are understood. Transgenic mice expressing mutant Tau-P301L suffer cognitive and motor defects and die prematurely from unknown causes. Here, in situ electrophysiology in symptomatic Tau-P301L mice (7-8 months of age) revealed reduced postinspiratory discharges of laryngeal motor outputs that control laryngeal constrictor muscles. Under high chemical drive (hypercapnia), postinspiratory discharge was nearly abolished, whereas laryngeal inspiratory discharge was increased disproportionally. The latter may suggest a shift of postinspiratory laryngeal constrictor activity into inspiration. In vivo double-chamber plethysmography of Tau-P301L mice showed significantly reduced respiratory airflow but significantly increased chest movements during baseline breathing, but particularly in hypercapnia, confirming a significant increase in inspiratory resistive load. Histological analysis demonstrated hyperphosphorylated tau in brainstem nuclei, directly or indirectly involved in upper airway motor control (i.e., the Kölliker-Fuse, periaqueductal gray, and intermediate reticular nuclei). In contrast, young Tau-P301L mice did not show breathing disorders or brainstem Tauopathy. Consequently, in aging Tau-P301L mice, progressive upper airway dysfunction is linked to progressive Tauopathy in identified neural circuits. Because patients with Tauopathy suffer from upper airway dysfunction, the Tau-P301L mice can serve as an experimental model to study disease-specific synaptic dysfunction in well defined functional neural circuits.
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Amyloid Activates GSK-3β to Aggravate Neuronal Tauopathy in Bigenic Mice
The American journal of pathology, 2008Co-Authors: Dick Terwel, Peter Borghgraef, Herman Devijver, David Muyllaert, Ilse Dewachter, S. Croes, Fred Van LeuvenAbstract:The hypothesis that amyloid pathology precedes and induces the tau pathology of Alzheimer's disease is experimentally supported here through the identification of GSK-3 isozymes as a major link in the signaling pathway from amyloid to tau pathology. This study compares two novel bigenic mouse models: APP-V717I x Tau-P301L mice with combined amyloid and tau pathology and GSK-3beta x Tau-P301L mice with Tauopathy only. Extensive and remarkable parallels were observed between these strains including 1) aggravation of Tauopathy with highly fibrillar tangles in the hippocampus and cortex; 2) prolonged survival correlated to alleviated brainstem Tauopathy; 3) development of severe cognitive and behavioral defects in young adults before the onset of amyloid deposition or Tauopathy; and 4) presence of pathological phospho-epitopes of tau, including the characteristic GSK-3beta motif at S396/S404. Both GSK-3 isozymes were activated in the brain of parental APP-V717I amyloid mice, even at a young age when cognitive and behavioral defects are evident but before amyloid deposition. The data indicate that amyloid induces Tauopathy through activation of GSK-3 and suggest a role for the kinase in maintaining the functional integrity of adult neurons.
Peter Borghgraef - One of the best experts on this subject based on the ideXlab platform.
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Age-Related Impairment of Ultrasonic Vocalization in Tau.P301L Mice: Possible Implication for Progressive Language Disorders
2016Co-Authors: Yves Cazals, Peter Borghgraef, Christian Gestreau, Lies Gielis, Fred Van LeuvenAbstract:Background: Tauopathies, including Alzheimer’s Disease, are the most frequent neurodegenerative diseases in elderly people and cause various cognitive, behavioural and motor defects, but also progressive language disorders. For communication and social interactions, mice produce ultrasonic vocalization (USV) via expiratory airflow through the larynx. We examined USV of Tau.P301L mice, a mouse model for Tauopathy expressing human mutant tau protein and developing cognitive, motor and upper airway defects. Methodology/Principal Findings: At age 4–5 months, Tau.P301L mice had normal USV, normal expiratory airflow and no brainstem Tauopathy. At age 8–10 months, Tau.P301L mice presented impaired USV, reduced expiratory airflow and severe Tauopathy in the periaqueductal gray, Kolliker-Fuse and retroambiguus nuclei. Tauopathy in these nuclei that control upper airway function and vocalization correlates well with the USV impairment of old Tau.P301L mice. Conclusions: In a mouse model for Tauopathy, we report for the first time an age-related impairment of USV that correlates with Tauopathy in midbrain and brainstem areas controlling vocalization. The vocalization disorder of old Tau.P301L mic
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Tauopathy differentially affects cell adhesion molecules in mouse brain early down regulation of nectin 3 in stratum lacunosum moleculare
PLOS ONE, 2013Co-Authors: Hervé Maurin, Benoit Lechat, Tomasz Jaworski, Peter Borghgraef, Herman Devijver, Claire M Seymour, Mathias V Schmidt, Sebastian Kuegler, Fred Van LeuvenAbstract:Cell adhesion molecules are important structural substrates, required for synaptic plasticity and synaptogenesis. CAMs differ widely in their expression throughout different brain regions and their specific structural and functional roles in the brain remain to be elucidated. Here, we investigated selected cell adhesion molecules for alterations in expression levels and neuronal localization in validated mouse models for Alzheimer's disease that mimic the age-related progression of amyloid accumulation and Tauopathy. Among the cell adhesion molecules analyzed, Nectin-3 expression was affected most and specifically in all mouse models with Tauopathy. In particular was Nectin-3 depleted from the specific region of the hippocampus, known as the stratum lacunosum and moleculare, in mice that express wild-type or mutant human protein Tau, either chronically or sub-acutely. Tauopathy progresses from the entorhinal cortex to the hippocampus by unknown mechanisms that could involve transport by the myelinated axons of the temporoammonic and perforant pathways. The decreased expression of Nectin-3 in the stratum lacunosum moleculare is an early marker of impaired transport, and eventual synaptic problems, caused by beginning Tauopathy.
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Raphé Tauopathy alters serotonin metabolism and breathing activity in terminal Tau.P301L mice: possible implications for tauopathies and Alzheimer's disease.
Respiratory Physiology and Neurobiology, 2011Co-Authors: Clément Menuet, Peter Borghgraef, Fred Van Leuven, Christian Gestreau, Lies Gielis, Valéry Matarazzo, Anne-marie Lajard, Nicolas Voituron, Mathias Dutschmann, Gérard HilaireAbstract:Tauopathies, including Alzheimer's disease are the most frequent neurodegenerative disorders in elderly people. Patients develop cognitive and behaviour defects induced by the Tauopathy in the forebrain, but most also display early brainstem Tauopathy, with oro-pharyngeal and serotoninergic (5-HT) defects. We studied these aspects in Tau.P301L mice, that express human mutant tau protein and develop Tauopathy first in hindbrain, with cognitive, motor and upper airway defects from 7 to 8 months onwards, until premature death before age 12 months. Using plethysmography, immunohistochemistry and biochemistry, we examined the respiratory and 5-HT systems of aging Tau.P301L and control mice. At 8 months, Tau.P301L mice developed upper airway dysfunction but retained normal respiratory rhythm and normal respiratory regulations. In the following weeks, Tau.P301L mice entered terminal stages with reduced body weight, progressive limb clasping and lethargy. Compared to age 8 months, terminal Tau.P301L mice showed aggravated upper airway dysfunction, abnormal respiratory rhythm and abnormal respiratory regulations. In addition, they showed severe Tauopathy in Kolliker-Fuse, raphé obscurus and raphé magnus nuclei but not in medullary respiratory-related areas. Although the raphé Tauopathy concerned mainly non-5-HT neurons, the 5-HT metabolism of terminal Tau.P301L mice was altered. We propose that the progressive raphé Tauopathy affects the 5-HT metabolism, which affects the 5-HT modulation of the respiratory network and therefore the breathing pattern. Then, 5-HT deficits contribute to the moribund phenotype of Tau.P301L mice, and possibly in patients suffering from tauopathies, including Alzheimer's disease.
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raphe Tauopathy alters serotonin metabolism and breathing activity in terminal tau p301l mice possible implications for tauopathies and alzheimer s disease
Respiratory Physiology & Neurobiology, 2011Co-Authors: Clément Menuet, Peter Borghgraef, Christian Gestreau, Lies Gielis, Valéry Matarazzo, Anne-marie Lajard, Nicolas Voituron, Mathias Dutschmann, Freddy Van Leuven, Gérard HilaireAbstract:Abstract Tauopathies, including Alzheimer's disease are the most frequent neurodegenerative disorders in elderly people. Patients develop cognitive and behaviour defects induced by the Tauopathy in the forebrain, but most also display early brainstem Tauopathy, with oro-pharyngeal and serotoninergic (5-HT) defects. We studied these aspects in Tau.P301L mice, that express human mutant tau protein and develop Tauopathy first in hindbrain, with cognitive, motor and upper airway defects from 7 to 8 months onwards, until premature death before age 12 months. Using plethysmography, immunohistochemistry and biochemistry, we examined the respiratory and 5-HT systems of aging Tau.P301L and control mice. At 8 months, Tau.P301L mice developed upper airway dysfunction but retained normal respiratory rhythm and normal respiratory regulations. In the following weeks, Tau.P301L mice entered terminal stages with reduced body weight, progressive limb clasping and lethargy. Compared to age 8 months, terminal Tau.P301L mice showed aggravated upper airway dysfunction, abnormal respiratory rhythm and abnormal respiratory regulations. In addition, they showed severe Tauopathy in Kolliker-Fuse, raphe obscurus and raphe magnus nuclei but not in medullary respiratory-related areas. Although the raphe Tauopathy concerned mainly non-5-HT neurons, the 5-HT metabolism of terminal Tau.P301L mice was altered. We propose that the progressive raphe Tauopathy affects the 5-HT metabolism, which affects the 5-HT modulation of the respiratory network and therefore the breathing pattern. Then, 5-HT deficits contribute to the moribund phenotype of Tau.P301L mice, and possibly in patients suffering from tauopathies, including Alzheimer's disease.
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Upper airway dysfunction of Tau-P301L mice correlates with Tauopathy in midbrain and ponto-medullary brainstem nuclei.
Journal of Neuroscience, 2010Co-Authors: Mathias Dutschmann, Peter Borghgraef, Herman Devijver, Christian Gestreau, Lies Gielis, Clément Menuet, Gérard Hilaire, Georg M Stettner, Fred Van LeuvenAbstract:Tauopathy comprises hyperphosphorylation of the microtubule-associated protein tau, causing intracellular aggregation and accumulation as neurofibrillary tangles and neuropil treads. Some primary tauopathies are linked to mutations in the MAPT gene coding for protein tau, but most are sporadic with unknown causes. Also, in Alzheimer's disease, the most frequent secondary Tauopathy, neither the cause nor the pathological mechanisms and repercussions are understood. Transgenic mice expressing mutant Tau-P301L suffer cognitive and motor defects and die prematurely from unknown causes. Here, in situ electrophysiology in symptomatic Tau-P301L mice (7-8 months of age) revealed reduced postinspiratory discharges of laryngeal motor outputs that control laryngeal constrictor muscles. Under high chemical drive (hypercapnia), postinspiratory discharge was nearly abolished, whereas laryngeal inspiratory discharge was increased disproportionally. The latter may suggest a shift of postinspiratory laryngeal constrictor activity into inspiration. In vivo double-chamber plethysmography of Tau-P301L mice showed significantly reduced respiratory airflow but significantly increased chest movements during baseline breathing, but particularly in hypercapnia, confirming a significant increase in inspiratory resistive load. Histological analysis demonstrated hyperphosphorylated tau in brainstem nuclei, directly or indirectly involved in upper airway motor control (i.e., the Kölliker-Fuse, periaqueductal gray, and intermediate reticular nuclei). In contrast, young Tau-P301L mice did not show breathing disorders or brainstem Tauopathy. Consequently, in aging Tau-P301L mice, progressive upper airway dysfunction is linked to progressive Tauopathy in identified neural circuits. Because patients with Tauopathy suffer from upper airway dysfunction, the Tau-P301L mice can serve as an experimental model to study disease-specific synaptic dysfunction in well defined functional neural circuits.
Gérard Hilaire - One of the best experts on this subject based on the ideXlab platform.
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Raphé Tauopathy alters serotonin metabolism and breathing activity in terminal Tau.P301L mice: possible implications for tauopathies and Alzheimer's disease.
Respiratory Physiology and Neurobiology, 2011Co-Authors: Clément Menuet, Peter Borghgraef, Fred Van Leuven, Christian Gestreau, Lies Gielis, Valéry Matarazzo, Anne-marie Lajard, Nicolas Voituron, Mathias Dutschmann, Gérard HilaireAbstract:Tauopathies, including Alzheimer's disease are the most frequent neurodegenerative disorders in elderly people. Patients develop cognitive and behaviour defects induced by the Tauopathy in the forebrain, but most also display early brainstem Tauopathy, with oro-pharyngeal and serotoninergic (5-HT) defects. We studied these aspects in Tau.P301L mice, that express human mutant tau protein and develop Tauopathy first in hindbrain, with cognitive, motor and upper airway defects from 7 to 8 months onwards, until premature death before age 12 months. Using plethysmography, immunohistochemistry and biochemistry, we examined the respiratory and 5-HT systems of aging Tau.P301L and control mice. At 8 months, Tau.P301L mice developed upper airway dysfunction but retained normal respiratory rhythm and normal respiratory regulations. In the following weeks, Tau.P301L mice entered terminal stages with reduced body weight, progressive limb clasping and lethargy. Compared to age 8 months, terminal Tau.P301L mice showed aggravated upper airway dysfunction, abnormal respiratory rhythm and abnormal respiratory regulations. In addition, they showed severe Tauopathy in Kolliker-Fuse, raphé obscurus and raphé magnus nuclei but not in medullary respiratory-related areas. Although the raphé Tauopathy concerned mainly non-5-HT neurons, the 5-HT metabolism of terminal Tau.P301L mice was altered. We propose that the progressive raphé Tauopathy affects the 5-HT metabolism, which affects the 5-HT modulation of the respiratory network and therefore the breathing pattern. Then, 5-HT deficits contribute to the moribund phenotype of Tau.P301L mice, and possibly in patients suffering from tauopathies, including Alzheimer's disease.
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raphe Tauopathy alters serotonin metabolism and breathing activity in terminal tau p301l mice possible implications for tauopathies and alzheimer s disease
Respiratory Physiology & Neurobiology, 2011Co-Authors: Clément Menuet, Peter Borghgraef, Christian Gestreau, Lies Gielis, Valéry Matarazzo, Anne-marie Lajard, Nicolas Voituron, Mathias Dutschmann, Freddy Van Leuven, Gérard HilaireAbstract:Abstract Tauopathies, including Alzheimer's disease are the most frequent neurodegenerative disorders in elderly people. Patients develop cognitive and behaviour defects induced by the Tauopathy in the forebrain, but most also display early brainstem Tauopathy, with oro-pharyngeal and serotoninergic (5-HT) defects. We studied these aspects in Tau.P301L mice, that express human mutant tau protein and develop Tauopathy first in hindbrain, with cognitive, motor and upper airway defects from 7 to 8 months onwards, until premature death before age 12 months. Using plethysmography, immunohistochemistry and biochemistry, we examined the respiratory and 5-HT systems of aging Tau.P301L and control mice. At 8 months, Tau.P301L mice developed upper airway dysfunction but retained normal respiratory rhythm and normal respiratory regulations. In the following weeks, Tau.P301L mice entered terminal stages with reduced body weight, progressive limb clasping and lethargy. Compared to age 8 months, terminal Tau.P301L mice showed aggravated upper airway dysfunction, abnormal respiratory rhythm and abnormal respiratory regulations. In addition, they showed severe Tauopathy in Kolliker-Fuse, raphe obscurus and raphe magnus nuclei but not in medullary respiratory-related areas. Although the raphe Tauopathy concerned mainly non-5-HT neurons, the 5-HT metabolism of terminal Tau.P301L mice was altered. We propose that the progressive raphe Tauopathy affects the 5-HT metabolism, which affects the 5-HT modulation of the respiratory network and therefore the breathing pattern. Then, 5-HT deficits contribute to the moribund phenotype of Tau.P301L mice, and possibly in patients suffering from tauopathies, including Alzheimer's disease.
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Upper airway dysfunction of Tau-P301L mice correlates with Tauopathy in midbrain and ponto-medullary brainstem nuclei.
Journal of Neuroscience, 2010Co-Authors: Mathias Dutschmann, Peter Borghgraef, Herman Devijver, Christian Gestreau, Lies Gielis, Clément Menuet, Gérard Hilaire, Georg M Stettner, Fred Van LeuvenAbstract:Tauopathy comprises hyperphosphorylation of the microtubule-associated protein tau, causing intracellular aggregation and accumulation as neurofibrillary tangles and neuropil treads. Some primary tauopathies are linked to mutations in the MAPT gene coding for protein tau, but most are sporadic with unknown causes. Also, in Alzheimer's disease, the most frequent secondary Tauopathy, neither the cause nor the pathological mechanisms and repercussions are understood. Transgenic mice expressing mutant Tau-P301L suffer cognitive and motor defects and die prematurely from unknown causes. Here, in situ electrophysiology in symptomatic Tau-P301L mice (7-8 months of age) revealed reduced postinspiratory discharges of laryngeal motor outputs that control laryngeal constrictor muscles. Under high chemical drive (hypercapnia), postinspiratory discharge was nearly abolished, whereas laryngeal inspiratory discharge was increased disproportionally. The latter may suggest a shift of postinspiratory laryngeal constrictor activity into inspiration. In vivo double-chamber plethysmography of Tau-P301L mice showed significantly reduced respiratory airflow but significantly increased chest movements during baseline breathing, but particularly in hypercapnia, confirming a significant increase in inspiratory resistive load. Histological analysis demonstrated hyperphosphorylated tau in brainstem nuclei, directly or indirectly involved in upper airway motor control (i.e., the Kölliker-Fuse, periaqueductal gray, and intermediate reticular nuclei). In contrast, young Tau-P301L mice did not show breathing disorders or brainstem Tauopathy. Consequently, in aging Tau-P301L mice, progressive upper airway dysfunction is linked to progressive Tauopathy in identified neural circuits. Because patients with Tauopathy suffer from upper airway dysfunction, the Tau-P301L mice can serve as an experimental model to study disease-specific synaptic dysfunction in well defined functional neural circuits.
Clément Menuet - One of the best experts on this subject based on the ideXlab platform.
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Raphé Tauopathy alters serotonin metabolism and breathing activity in terminal Tau.P301L mice: possible implications for tauopathies and Alzheimer's disease.
Respiratory Physiology and Neurobiology, 2011Co-Authors: Clément Menuet, Peter Borghgraef, Fred Van Leuven, Christian Gestreau, Lies Gielis, Valéry Matarazzo, Anne-marie Lajard, Nicolas Voituron, Mathias Dutschmann, Gérard HilaireAbstract:Tauopathies, including Alzheimer's disease are the most frequent neurodegenerative disorders in elderly people. Patients develop cognitive and behaviour defects induced by the Tauopathy in the forebrain, but most also display early brainstem Tauopathy, with oro-pharyngeal and serotoninergic (5-HT) defects. We studied these aspects in Tau.P301L mice, that express human mutant tau protein and develop Tauopathy first in hindbrain, with cognitive, motor and upper airway defects from 7 to 8 months onwards, until premature death before age 12 months. Using plethysmography, immunohistochemistry and biochemistry, we examined the respiratory and 5-HT systems of aging Tau.P301L and control mice. At 8 months, Tau.P301L mice developed upper airway dysfunction but retained normal respiratory rhythm and normal respiratory regulations. In the following weeks, Tau.P301L mice entered terminal stages with reduced body weight, progressive limb clasping and lethargy. Compared to age 8 months, terminal Tau.P301L mice showed aggravated upper airway dysfunction, abnormal respiratory rhythm and abnormal respiratory regulations. In addition, they showed severe Tauopathy in Kolliker-Fuse, raphé obscurus and raphé magnus nuclei but not in medullary respiratory-related areas. Although the raphé Tauopathy concerned mainly non-5-HT neurons, the 5-HT metabolism of terminal Tau.P301L mice was altered. We propose that the progressive raphé Tauopathy affects the 5-HT metabolism, which affects the 5-HT modulation of the respiratory network and therefore the breathing pattern. Then, 5-HT deficits contribute to the moribund phenotype of Tau.P301L mice, and possibly in patients suffering from tauopathies, including Alzheimer's disease.
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raphe Tauopathy alters serotonin metabolism and breathing activity in terminal tau p301l mice possible implications for tauopathies and alzheimer s disease
Respiratory Physiology & Neurobiology, 2011Co-Authors: Clément Menuet, Peter Borghgraef, Christian Gestreau, Lies Gielis, Valéry Matarazzo, Anne-marie Lajard, Nicolas Voituron, Mathias Dutschmann, Freddy Van Leuven, Gérard HilaireAbstract:Abstract Tauopathies, including Alzheimer's disease are the most frequent neurodegenerative disorders in elderly people. Patients develop cognitive and behaviour defects induced by the Tauopathy in the forebrain, but most also display early brainstem Tauopathy, with oro-pharyngeal and serotoninergic (5-HT) defects. We studied these aspects in Tau.P301L mice, that express human mutant tau protein and develop Tauopathy first in hindbrain, with cognitive, motor and upper airway defects from 7 to 8 months onwards, until premature death before age 12 months. Using plethysmography, immunohistochemistry and biochemistry, we examined the respiratory and 5-HT systems of aging Tau.P301L and control mice. At 8 months, Tau.P301L mice developed upper airway dysfunction but retained normal respiratory rhythm and normal respiratory regulations. In the following weeks, Tau.P301L mice entered terminal stages with reduced body weight, progressive limb clasping and lethargy. Compared to age 8 months, terminal Tau.P301L mice showed aggravated upper airway dysfunction, abnormal respiratory rhythm and abnormal respiratory regulations. In addition, they showed severe Tauopathy in Kolliker-Fuse, raphe obscurus and raphe magnus nuclei but not in medullary respiratory-related areas. Although the raphe Tauopathy concerned mainly non-5-HT neurons, the 5-HT metabolism of terminal Tau.P301L mice was altered. We propose that the progressive raphe Tauopathy affects the 5-HT metabolism, which affects the 5-HT modulation of the respiratory network and therefore the breathing pattern. Then, 5-HT deficits contribute to the moribund phenotype of Tau.P301L mice, and possibly in patients suffering from tauopathies, including Alzheimer's disease.
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Upper airway dysfunction of Tau-P301L mice correlates with Tauopathy in midbrain and ponto-medullary brainstem nuclei.
Journal of Neuroscience, 2010Co-Authors: Mathias Dutschmann, Peter Borghgraef, Herman Devijver, Christian Gestreau, Lies Gielis, Clément Menuet, Gérard Hilaire, Georg M Stettner, Fred Van LeuvenAbstract:Tauopathy comprises hyperphosphorylation of the microtubule-associated protein tau, causing intracellular aggregation and accumulation as neurofibrillary tangles and neuropil treads. Some primary tauopathies are linked to mutations in the MAPT gene coding for protein tau, but most are sporadic with unknown causes. Also, in Alzheimer's disease, the most frequent secondary Tauopathy, neither the cause nor the pathological mechanisms and repercussions are understood. Transgenic mice expressing mutant Tau-P301L suffer cognitive and motor defects and die prematurely from unknown causes. Here, in situ electrophysiology in symptomatic Tau-P301L mice (7-8 months of age) revealed reduced postinspiratory discharges of laryngeal motor outputs that control laryngeal constrictor muscles. Under high chemical drive (hypercapnia), postinspiratory discharge was nearly abolished, whereas laryngeal inspiratory discharge was increased disproportionally. The latter may suggest a shift of postinspiratory laryngeal constrictor activity into inspiration. In vivo double-chamber plethysmography of Tau-P301L mice showed significantly reduced respiratory airflow but significantly increased chest movements during baseline breathing, but particularly in hypercapnia, confirming a significant increase in inspiratory resistive load. Histological analysis demonstrated hyperphosphorylated tau in brainstem nuclei, directly or indirectly involved in upper airway motor control (i.e., the Kölliker-Fuse, periaqueductal gray, and intermediate reticular nuclei). In contrast, young Tau-P301L mice did not show breathing disorders or brainstem Tauopathy. Consequently, in aging Tau-P301L mice, progressive upper airway dysfunction is linked to progressive Tauopathy in identified neural circuits. Because patients with Tauopathy suffer from upper airway dysfunction, the Tau-P301L mice can serve as an experimental model to study disease-specific synaptic dysfunction in well defined functional neural circuits.
Lies Gielis - One of the best experts on this subject based on the ideXlab platform.
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Age-Related Impairment of Ultrasonic Vocalization in Tau.P301L Mice: Possible Implication for Progressive Language Disorders
2016Co-Authors: Yves Cazals, Peter Borghgraef, Christian Gestreau, Lies Gielis, Fred Van LeuvenAbstract:Background: Tauopathies, including Alzheimer’s Disease, are the most frequent neurodegenerative diseases in elderly people and cause various cognitive, behavioural and motor defects, but also progressive language disorders. For communication and social interactions, mice produce ultrasonic vocalization (USV) via expiratory airflow through the larynx. We examined USV of Tau.P301L mice, a mouse model for Tauopathy expressing human mutant tau protein and developing cognitive, motor and upper airway defects. Methodology/Principal Findings: At age 4–5 months, Tau.P301L mice had normal USV, normal expiratory airflow and no brainstem Tauopathy. At age 8–10 months, Tau.P301L mice presented impaired USV, reduced expiratory airflow and severe Tauopathy in the periaqueductal gray, Kolliker-Fuse and retroambiguus nuclei. Tauopathy in these nuclei that control upper airway function and vocalization correlates well with the USV impairment of old Tau.P301L mice. Conclusions: In a mouse model for Tauopathy, we report for the first time an age-related impairment of USV that correlates with Tauopathy in midbrain and brainstem areas controlling vocalization. The vocalization disorder of old Tau.P301L mic
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Raphé Tauopathy alters serotonin metabolism and breathing activity in terminal Tau.P301L mice: possible implications for tauopathies and Alzheimer's disease.
Respiratory Physiology and Neurobiology, 2011Co-Authors: Clément Menuet, Peter Borghgraef, Fred Van Leuven, Christian Gestreau, Lies Gielis, Valéry Matarazzo, Anne-marie Lajard, Nicolas Voituron, Mathias Dutschmann, Gérard HilaireAbstract:Tauopathies, including Alzheimer's disease are the most frequent neurodegenerative disorders in elderly people. Patients develop cognitive and behaviour defects induced by the Tauopathy in the forebrain, but most also display early brainstem Tauopathy, with oro-pharyngeal and serotoninergic (5-HT) defects. We studied these aspects in Tau.P301L mice, that express human mutant tau protein and develop Tauopathy first in hindbrain, with cognitive, motor and upper airway defects from 7 to 8 months onwards, until premature death before age 12 months. Using plethysmography, immunohistochemistry and biochemistry, we examined the respiratory and 5-HT systems of aging Tau.P301L and control mice. At 8 months, Tau.P301L mice developed upper airway dysfunction but retained normal respiratory rhythm and normal respiratory regulations. In the following weeks, Tau.P301L mice entered terminal stages with reduced body weight, progressive limb clasping and lethargy. Compared to age 8 months, terminal Tau.P301L mice showed aggravated upper airway dysfunction, abnormal respiratory rhythm and abnormal respiratory regulations. In addition, they showed severe Tauopathy in Kolliker-Fuse, raphé obscurus and raphé magnus nuclei but not in medullary respiratory-related areas. Although the raphé Tauopathy concerned mainly non-5-HT neurons, the 5-HT metabolism of terminal Tau.P301L mice was altered. We propose that the progressive raphé Tauopathy affects the 5-HT metabolism, which affects the 5-HT modulation of the respiratory network and therefore the breathing pattern. Then, 5-HT deficits contribute to the moribund phenotype of Tau.P301L mice, and possibly in patients suffering from tauopathies, including Alzheimer's disease.
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raphe Tauopathy alters serotonin metabolism and breathing activity in terminal tau p301l mice possible implications for tauopathies and alzheimer s disease
Respiratory Physiology & Neurobiology, 2011Co-Authors: Clément Menuet, Peter Borghgraef, Christian Gestreau, Lies Gielis, Valéry Matarazzo, Anne-marie Lajard, Nicolas Voituron, Mathias Dutschmann, Freddy Van Leuven, Gérard HilaireAbstract:Abstract Tauopathies, including Alzheimer's disease are the most frequent neurodegenerative disorders in elderly people. Patients develop cognitive and behaviour defects induced by the Tauopathy in the forebrain, but most also display early brainstem Tauopathy, with oro-pharyngeal and serotoninergic (5-HT) defects. We studied these aspects in Tau.P301L mice, that express human mutant tau protein and develop Tauopathy first in hindbrain, with cognitive, motor and upper airway defects from 7 to 8 months onwards, until premature death before age 12 months. Using plethysmography, immunohistochemistry and biochemistry, we examined the respiratory and 5-HT systems of aging Tau.P301L and control mice. At 8 months, Tau.P301L mice developed upper airway dysfunction but retained normal respiratory rhythm and normal respiratory regulations. In the following weeks, Tau.P301L mice entered terminal stages with reduced body weight, progressive limb clasping and lethargy. Compared to age 8 months, terminal Tau.P301L mice showed aggravated upper airway dysfunction, abnormal respiratory rhythm and abnormal respiratory regulations. In addition, they showed severe Tauopathy in Kolliker-Fuse, raphe obscurus and raphe magnus nuclei but not in medullary respiratory-related areas. Although the raphe Tauopathy concerned mainly non-5-HT neurons, the 5-HT metabolism of terminal Tau.P301L mice was altered. We propose that the progressive raphe Tauopathy affects the 5-HT metabolism, which affects the 5-HT modulation of the respiratory network and therefore the breathing pattern. Then, 5-HT deficits contribute to the moribund phenotype of Tau.P301L mice, and possibly in patients suffering from tauopathies, including Alzheimer's disease.
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Upper airway dysfunction of Tau-P301L mice correlates with Tauopathy in midbrain and ponto-medullary brainstem nuclei.
Journal of Neuroscience, 2010Co-Authors: Mathias Dutschmann, Peter Borghgraef, Herman Devijver, Christian Gestreau, Lies Gielis, Clément Menuet, Gérard Hilaire, Georg M Stettner, Fred Van LeuvenAbstract:Tauopathy comprises hyperphosphorylation of the microtubule-associated protein tau, causing intracellular aggregation and accumulation as neurofibrillary tangles and neuropil treads. Some primary tauopathies are linked to mutations in the MAPT gene coding for protein tau, but most are sporadic with unknown causes. Also, in Alzheimer's disease, the most frequent secondary Tauopathy, neither the cause nor the pathological mechanisms and repercussions are understood. Transgenic mice expressing mutant Tau-P301L suffer cognitive and motor defects and die prematurely from unknown causes. Here, in situ electrophysiology in symptomatic Tau-P301L mice (7-8 months of age) revealed reduced postinspiratory discharges of laryngeal motor outputs that control laryngeal constrictor muscles. Under high chemical drive (hypercapnia), postinspiratory discharge was nearly abolished, whereas laryngeal inspiratory discharge was increased disproportionally. The latter may suggest a shift of postinspiratory laryngeal constrictor activity into inspiration. In vivo double-chamber plethysmography of Tau-P301L mice showed significantly reduced respiratory airflow but significantly increased chest movements during baseline breathing, but particularly in hypercapnia, confirming a significant increase in inspiratory resistive load. Histological analysis demonstrated hyperphosphorylated tau in brainstem nuclei, directly or indirectly involved in upper airway motor control (i.e., the Kölliker-Fuse, periaqueductal gray, and intermediate reticular nuclei). In contrast, young Tau-P301L mice did not show breathing disorders or brainstem Tauopathy. Consequently, in aging Tau-P301L mice, progressive upper airway dysfunction is linked to progressive Tauopathy in identified neural circuits. Because patients with Tauopathy suffer from upper airway dysfunction, the Tau-P301L mice can serve as an experimental model to study disease-specific synaptic dysfunction in well defined functional neural circuits.
