The Experts below are selected from a list of 92532 Experts worldwide ranked by ideXlab platform
Frank M. Laferla - One of the best experts on this subject based on the ideXlab platform.
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neural stem cells improve cognition via bdnf in a Transgenic Model of alzheimer disease
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Mathew Blurtonjones, Masashi Kitazawa, Tritia R Yamasaki, Kim N Green, Hilda Martinezcoria, Nicholas A Castello, Franzjosef Muller, Jeanne F Loring, Wayne W Poon, Frank M. LaferlaAbstract:Neural stem cell (NSC) transplantation represents an unexplored approach for treating neurodegenerative disorders associated with cognitive decline such as Alzheimer disease (AD). Here, we used aged triple Transgenic mice (3xTg-AD) that express pathogenic forms of amyloid precursor protein, presenilin, and tau to investigate the effect of neural stem cell transplantation on AD-related neuropathology and cognitive dysfunction. Interestingly, despite widespread and established As plaque and neurofibrillary tangle pathology, hippocampal neural stem cell transplantation rescues the spatial learning and memory deficits in aged 3xTg-AD mice. Remarkably, cognitive function is improved without altering As or tau pathology. Instead, the mechanism underlying the improved cognition involves a robust enhancement of hippocampal synaptic density, mediated by brain-derived neurotrophic factor (BDNF). Gain-of-function studies show that recombinant BDNF mimics the beneficial effects of NSC transplantation. Furthermore, loss-of-function studies show that depletion of NSC-derived BDNF fails to improve cognition or restore hippocampal synaptic density. Taken together, our findings demonstrate that neural stem cells can ameliorate complex behavioral deficits associated with widespread Alzheimer disease pathology via BDNF.
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lipopolysaccharide induced inflammation exacerbates tau pathology by a cyclin dependent kinase 5 mediated pathway in a Transgenic Model of alzheimer s disease
The Journal of Neuroscience, 2005Co-Authors: Masashi Kitazawa, Salvatore Oddo, Tritia R Yamasaki, Kim N Green, Frank M. LaferlaAbstract:Inflammation is a critical component of the pathogenesis of Alzheimer's disease (AD). Although not an initiator of this disorder, inflammation nonetheless plays a pivotal role as a driving force that can modulate the neuropathology. Here, we characterized the time course of microglia activation in the brains of a Transgenic Model of AD (3xTg-AD) and discerned its relationship to the plaque and tangle pathology. We find that microglia became activated in a progressive and age-dependent manner, and this activation correlated with the onset of fibrillar amyloidβ-peptide plaque accumulation and tau hyperphosphorylation. To determine whether microglial activation can exacerbate the pathology, we exposed young 3xTg-AD mice to lipopolysaccharide (LPS), a known inducer of CNS inflammation. Although amyloid precursor protein processing appeared unaffected, we find that LPS significantly induced tau hyperphosphorylation at specific sites that were mediated by the activation of cyclin-dependent kinase 5 (cdk5) through increased formation of the p25 fragment. We further show that administration of roscovitine, a selective and potent inhibitor of cdk5, markedly blocked the LPS-induced tau phosphorylation in the hippocampus. Therefore, this study clearly demonstrates that microglial activation exacerbates key neuropathological features such as tangle formation.
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triple Transgenic Model of alzheimer s disease with plaques and tangles intracellular aβ and synaptic dysfunction
Neuron, 2003Co-Authors: Salvatore Oddo, Antonella Caccamo, Jason D Shepherd, Paul M Murphy, Todd E Golde, Rakez Kayed, Raju Metherate, Mark P Mattson, Yama Akbari, Frank M. LaferlaAbstract:The neuropathological correlates of Alzheimer's disease (AD) include amyloid-beta (Abeta) plaques and neurofibrillary tangles. To study the interaction between Abeta and tau and their effect on synaptic function, we derived a triple-Transgenic Model (3xTg-AD) harboring PS1(M146V), APP(Swe), and tau(P301L) transgenes. Rather than crossing independent lines, we microinjected two transgenes into single-cell embryos from homozygous PS1(M146V) knockin mice, generating mice with the same genetic background. 3xTg-AD mice progressively develop plaques and tangles. Synaptic dysfunction, including LTP deficits, manifests in an age-related manner, but before plaque and tangle pathology. Deficits in long-term synaptic plasticity correlate with the accumulation of intraneuronal Abeta. These studies suggest a novel pathogenic role for intraneuronal Abeta with regards to synaptic plasticity. The recapitulation of salient features of AD in these mice clarifies the relationships between Abeta, synaptic dysfunction, and tangles and provides a valuable Model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.
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Amyloid deposition precedes tangle formation in a triple Transgenic Model of Alzheimer's disease.
Neurobiology of aging, 2003Co-Authors: Salvatore Oddo, Antonella Caccamo, Masashi Kitazawa, Bertrand P. Tseng, Frank M. LaferlaAbstract:Amyloid-beta (Abeta) containing plaques and tau-laden neurofibrillary tangles are the defining neuropathological features of Alzheimer's disease (AD). To better mimic this neuropathology, we generated a novel triple Transgenic Model of AD (3xTg-AD) harboring three mutant genes: beta-amyloid precursor protein (betaAPPSwe), presenilin-1 (PS1M146V), and tauP301L. The 3xTg-AD mice progressively develop Abeta and tau pathology, with a temporal- and regional-specific profile that closely mimics their development in the human AD brain. We find that Abeta deposits initiate in the cortex and progress to the hippocampus with aging, whereas tau pathology is first apparent in the hippocampus and then progresses to the cortex. Despite equivalent overexpression of the human betaAPP and human tau transgenes, Abeta deposition develops prior to the tangle pathology, consistent with the amyloid cascade hypothesis. As these 3xTg-AD mice phenocopy critical aspects of AD neuropathology, this Model will be useful in pre-clinical intervention trials, particularly because the efficacy of anti-AD compounds in mitigating the neurodegenerative effects mediated by both signature lesions can be evaluated.
C D Sigmund - One of the best experts on this subject based on the ideXlab platform.
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Genetic manipulation of the renin-angiotensin system: targeted expression of the renin-angiotensin system in the kidney.
American journal of hypertension, 2001Co-Authors: C D SigmundAbstract:The renin-angiotensin system is a classic endocrine system that also exists within individual tissues. All components of the renin-angiotensin system (RAS) are expressed in the kidney suggesting the potential for local production and action of angiotensin II. Although the importance of the kidney in hypertension is unequivocal, our understanding of the functional significance of intrarenal production of angiotensin II remains incomplete. Using genetic manipulation of the mouse genome we generated a novel Transgenic Model expressing human angiotensinogen specifically in the proximal tubule cells of the kidney. Herein I describe the generation and physiologic characterization of this Model, and discuss the implications of our findings in terms of the genetics of human hypertension. The experimental results presented support the hypothesis that a tissue-specific RAS cascade exists in the kidney of this Transgenic Model, and that this system may play an important role in blood pressure (BP) and renal homeostasis in this Model.
Salvatore Oddo - One of the best experts on this subject based on the ideXlab platform.
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lipopolysaccharide induced inflammation exacerbates tau pathology by a cyclin dependent kinase 5 mediated pathway in a Transgenic Model of alzheimer s disease
The Journal of Neuroscience, 2005Co-Authors: Masashi Kitazawa, Salvatore Oddo, Tritia R Yamasaki, Kim N Green, Frank M. LaferlaAbstract:Inflammation is a critical component of the pathogenesis of Alzheimer's disease (AD). Although not an initiator of this disorder, inflammation nonetheless plays a pivotal role as a driving force that can modulate the neuropathology. Here, we characterized the time course of microglia activation in the brains of a Transgenic Model of AD (3xTg-AD) and discerned its relationship to the plaque and tangle pathology. We find that microglia became activated in a progressive and age-dependent manner, and this activation correlated with the onset of fibrillar amyloidβ-peptide plaque accumulation and tau hyperphosphorylation. To determine whether microglial activation can exacerbate the pathology, we exposed young 3xTg-AD mice to lipopolysaccharide (LPS), a known inducer of CNS inflammation. Although amyloid precursor protein processing appeared unaffected, we find that LPS significantly induced tau hyperphosphorylation at specific sites that were mediated by the activation of cyclin-dependent kinase 5 (cdk5) through increased formation of the p25 fragment. We further show that administration of roscovitine, a selective and potent inhibitor of cdk5, markedly blocked the LPS-induced tau phosphorylation in the hippocampus. Therefore, this study clearly demonstrates that microglial activation exacerbates key neuropathological features such as tangle formation.
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triple Transgenic Model of alzheimer s disease with plaques and tangles intracellular aβ and synaptic dysfunction
Neuron, 2003Co-Authors: Salvatore Oddo, Antonella Caccamo, Jason D Shepherd, Paul M Murphy, Todd E Golde, Rakez Kayed, Raju Metherate, Mark P Mattson, Yama Akbari, Frank M. LaferlaAbstract:The neuropathological correlates of Alzheimer's disease (AD) include amyloid-beta (Abeta) plaques and neurofibrillary tangles. To study the interaction between Abeta and tau and their effect on synaptic function, we derived a triple-Transgenic Model (3xTg-AD) harboring PS1(M146V), APP(Swe), and tau(P301L) transgenes. Rather than crossing independent lines, we microinjected two transgenes into single-cell embryos from homozygous PS1(M146V) knockin mice, generating mice with the same genetic background. 3xTg-AD mice progressively develop plaques and tangles. Synaptic dysfunction, including LTP deficits, manifests in an age-related manner, but before plaque and tangle pathology. Deficits in long-term synaptic plasticity correlate with the accumulation of intraneuronal Abeta. These studies suggest a novel pathogenic role for intraneuronal Abeta with regards to synaptic plasticity. The recapitulation of salient features of AD in these mice clarifies the relationships between Abeta, synaptic dysfunction, and tangles and provides a valuable Model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.
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Amyloid deposition precedes tangle formation in a triple Transgenic Model of Alzheimer's disease.
Neurobiology of aging, 2003Co-Authors: Salvatore Oddo, Antonella Caccamo, Masashi Kitazawa, Bertrand P. Tseng, Frank M. LaferlaAbstract:Amyloid-beta (Abeta) containing plaques and tau-laden neurofibrillary tangles are the defining neuropathological features of Alzheimer's disease (AD). To better mimic this neuropathology, we generated a novel triple Transgenic Model of AD (3xTg-AD) harboring three mutant genes: beta-amyloid precursor protein (betaAPPSwe), presenilin-1 (PS1M146V), and tauP301L. The 3xTg-AD mice progressively develop Abeta and tau pathology, with a temporal- and regional-specific profile that closely mimics their development in the human AD brain. We find that Abeta deposits initiate in the cortex and progress to the hippocampus with aging, whereas tau pathology is first apparent in the hippocampus and then progresses to the cortex. Despite equivalent overexpression of the human betaAPP and human tau transgenes, Abeta deposition develops prior to the tangle pathology, consistent with the amyloid cascade hypothesis. As these 3xTg-AD mice phenocopy critical aspects of AD neuropathology, this Model will be useful in pre-clinical intervention trials, particularly because the efficacy of anti-AD compounds in mitigating the neurodegenerative effects mediated by both signature lesions can be evaluated.
Sylvie Burnouf - One of the best experts on this subject based on the ideXlab platform.
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nmda receptor dysfunction contributes to impaired brain derived neurotrophic factor induced facilitation of hippocampal synaptic transmission in a tau Transgenic Model
Aging Cell, 2013Co-Authors: Karim Belarbi, Sylvie Burnouf, Alberto Martire, Maxime Derisbourg, Cyril Laurent, Antoine LeboucherAbstract:Summary While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus-dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor-dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N-methyl-d-Aspartate receptors (NMDAR). Using THY-Tau22 Transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies.
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Early Tau pathology involving the septo-hippocampal pathway in a Tau Transgenic Model: relevance to Alzheimer's disease.
Current Alzheimer Research, 2009Co-Authors: Karim Belarbi, Katharina Schindowski, Sylvie Burnouf, Raphaëlle Caillierez, Marie-eve Grosjean, Dominique Demeyer, Malika Hamdane, Nicolas Sergeant, David Blum, Luc BueeAbstract:Alzheimer's disease is a neurodegenerative disorder characterized by amyloid deposits and neurofibrillary tangles. Cholinergic dysfunction is also a main pathological feature of the disease. Nevertheless, the links between cholinergic dysfunction and neuropathological hallmarks of Alzheimer's are still unknown. In the present study, we aimed to further investigate Tau aggregation in cholinergic systems, in a Tau Transgenic mouse Model. THY-Tau22 mice have recently been described as a novel Model of Alzheimer-like Tau pathology without motor deficits. This strain presents an age-dependent development of Tau pathology leading to synaptic dysfunctions as well as learning and memory impairments. In the present work, we observed that Tau pathology differentially affects cerebral structures. Interestingly, early Tau pathology was observed in both hippocampus and basal forebrain. Moreover, some morphological as well as functional alterations of the septohippocampal pathway suggest a disconnection between these two key brain regions in Alzheimer's disease. Finally, these data suggest that Tau pathology may participate in cholinergic degeneration.
Karim Belarbi - One of the best experts on this subject based on the ideXlab platform.
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nmda receptor dysfunction contributes to impaired brain derived neurotrophic factor induced facilitation of hippocampal synaptic transmission in a tau Transgenic Model
Aging Cell, 2013Co-Authors: Karim Belarbi, Sylvie Burnouf, Alberto Martire, Maxime Derisbourg, Cyril Laurent, Antoine LeboucherAbstract:Summary While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus-dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor-dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N-methyl-d-Aspartate receptors (NMDAR). Using THY-Tau22 Transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies.
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Early Tau pathology involving the septo-hippocampal pathway in a Tau Transgenic Model: relevance to Alzheimer's disease.
Current Alzheimer Research, 2009Co-Authors: Karim Belarbi, Katharina Schindowski, Sylvie Burnouf, Raphaëlle Caillierez, Marie-eve Grosjean, Dominique Demeyer, Malika Hamdane, Nicolas Sergeant, David Blum, Luc BueeAbstract:Alzheimer's disease is a neurodegenerative disorder characterized by amyloid deposits and neurofibrillary tangles. Cholinergic dysfunction is also a main pathological feature of the disease. Nevertheless, the links between cholinergic dysfunction and neuropathological hallmarks of Alzheimer's are still unknown. In the present study, we aimed to further investigate Tau aggregation in cholinergic systems, in a Tau Transgenic mouse Model. THY-Tau22 mice have recently been described as a novel Model of Alzheimer-like Tau pathology without motor deficits. This strain presents an age-dependent development of Tau pathology leading to synaptic dysfunctions as well as learning and memory impairments. In the present work, we observed that Tau pathology differentially affects cerebral structures. Interestingly, early Tau pathology was observed in both hippocampus and basal forebrain. Moreover, some morphological as well as functional alterations of the septohippocampal pathway suggest a disconnection between these two key brain regions in Alzheimer's disease. Finally, these data suggest that Tau pathology may participate in cholinergic degeneration.
