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Cecília M. P. Rodrigues - One of the best experts on this subject based on the ideXlab platform.
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Modulation of Cell Fate by Tauroursodeoxycholic Acid: All Paths Lead to Mitochondria
Mitochondrial Biology and Experimental Therapeutics, 2018Co-Authors: Susana Solá, Maria F. Ribeiro, Tânia Genebra, Cecília M. P. RodriguesAbstract:Specific endogenous bile Acids, such as ursodeoxycholic (UDCA) Acid and its taurine conjugated form, Tauroursodeoxycholic Acid (TUDCA), are potent modulators of cell fate by regulating pathways that involve mitochondria. Curiously, emerging evidence suggests that mitochondrial changes induced by TUDCA result from its influence on mitochondrial redox state, mitochondrial membrane permeabilization, mitochondrial apoptosis and mitophagy. In fact, the pleiotropic cellular function of TUDCA ranges from its direct interaction with mitochondrial membranes to modulation of kinase survival pathways or gene expression that ultimately impact on mitochondria. Further, regulation of the functional endoplasmatic reticulum (ER)-mitochondria unit by this bile Acid has also been proven as a key counterpart of mitochondria-targeted TUDCA effect. In this chapter, we summarize mechanisms by which this hydrophilic bile Acid affects mitochondria and subsequently cell survival, cell cycle and differentiation. We also discuss the potential therapeutic application of TUDCA in several pathological conditions associated with mitochondrial dysfunction.
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Novel insights into the antioxidant role of Tauroursodeoxycholic Acid in experimental models of Parkinson's disease
Biochimica et biophysica acta. Molecular basis of disease, 2017Co-Authors: Alexandra Isabel Rosa, Cecília M. P. Rodrigues, Inês T.e. Fonseca, Sara Moreira, Maria João Nunes, Maria João Gama, Elsa Rodrigues, Andreia Neves Carvalho, Margarida Castro-caldasAbstract:Abstract Impaired mitochondrial function and generation of reactive oxygen species are deeply implicated in Parkinson's disease progression. Indeed, mutations in genes that affect mitochondrial function account for most of the familial cases of the disease, and post mortem studies in sporadic PD patients brains revealed increased signs of oxidative stress. Moreover, exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial complex I inhibitor, leads to clinical symptoms similar to sporadic PD. The bile Acid Tauroursodeoxycholic Acid (TUDCA) is an anti-apoptotic molecule shown to protect against MPTP-induced neurodegeneration in mice, but the mechanisms involved are still incompletely identified. Herein we used MPTP-treated mice, as well as primary cultures of mice cortical neurons and SH-SY5Y cells treated with MPP + to investigate the modulation of mitochondrial dysfunction by TUDCA in PD models. We show that TUDCA exerts its neuroprotective role in a parkin-dependent manner. Overall, our results point to the pharmacological up-regulation of mitochondrial turnover by TUDCA as a novel neuroprotective mechanism of this molecule, and contribute to the validation of TUDCA clinical application in PD.
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Nrf2 activation by Tauroursodeoxycholic Acid in experimental models of Parkinson's disease
Experimental neurology, 2017Co-Authors: Sara Moreira, Cecília M. P. Rodrigues, Inês T.e. Fonseca, Maria João Nunes, Elsa Rodrigues, Alexandra Isabel Rosa, Luísa Lemos, Andreia Neves Carvalho, Tiago F. Outeiro, Maria João GamaAbstract:Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Although the cause of PD remains elusive, mitochondrial dysfunction and severe oxidative stress are strongly implicated in the cell death that characterizes the disease. Under oxidative stress, the master regulator of cellular redox status, nuclear factor erythroid 2 related factor 2 (Nrf2), is responsible for activating the transcription of several cytoprotective enzymes, namely glutathione peroxidase (GPx) and heme oxygenase-1 (HO-1). Nrf2 is a promising target to limit reactive oxygen species (ROS)-mediated damage in PD. Here, we show that Tauroursodeoxycholic Acid (TUDCA) prevents both 1-methyl-4-phenylpyridinium (MPP+)- and α-synuclein-induced oxidative stress, through Nrf2 activation, in SH-SY5Y cells. Additionally, we used C57BL/6 male mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to elucidate the effect of TUDCA in this in vivo model of PD. In vivo, TUDCA treatment increases the expression of Nrf2, Nrf2 stabilizer DJ-1, and Nrf2 downstream target antioxidant enzymes HO-1 and GPx. Moreover, we found that TUDCA enhances GPx activity in the brain. Altogether, our results suggest that TUDCA is a promising agent to limit ROS-mediated damage, in different models of PD acting, at least in part, through modulation of the Nrf2 signaling pathway. Therefore, TUDCA should be considered a promising therapeutic agent to be implemented in PD.
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Tauroursodeoxycholic Acid Protects Against Mitochondrial Dysfunction and Cell Death via Mitophagy in Human Neuroblastoma Cells
Molecular neurobiology, 2016Co-Authors: Inês T.e. Fonseca, Cecília M. P. Rodrigues, Gisela Gordino, Sara Moreira, Maria João Nunes, Carla Azevedo, Maria João Gama, Elsa Rodrigues, Margarida Castro-caldasAbstract:Mitochondrial dysfunction has been deeply implicated in the pathogenesis of several neurodegenerative diseases. Thus, to keep a healthy mitochondrial population, a balanced mitochondrial turnover must be achieved. Tauroursodeoxycholic Acid (TUDCA) is neuroprotective in various neurodegenerative disease models; however, the mechanisms involved are still incompletely characterized. In this study, we investigated the neuroprotective role of TUDCA against mitochondrial damage triggered by the mitochondrial uncoupler carbonyl cyanide m-chlorophelyhydrazone (CCCP). Herein, we show that TUDCA significantly prevents CCCP-induced cell death, ROS generation, and mitochondrial damage. Our results indicate that the neuroprotective role of TUDCA in this cell model is mediated by parkin and depends on mitophagy. The demonstration that pharmacological up-regulation of mitophagy by TUDCA prevents neurodegeneration provides new insights for the use of TUDCA as a modulator of mitochondrial activity and turnover, with implications in neurodegenerative diseases.
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Tauroursodeoxycholic Acid increases neural stem cell pool and neuronal conversion by regulating mitochondria cell cycle retrograde signaling
Cell Cycle, 2014Co-Authors: Joana M Xavier, Cecília M. P. Rodrigues, Ana L Morgado, Susana SoláAbstract:The low survival and differentiation rates of stem cells after either transplantation or neural injury have been a major concern of stem cell-based therapy. Thus, further understanding long-term survival and differentiation of stem cells may uncover new targets for discovery and development of novel therapeutic approaches. We have previously described the impact of mitochondrial apoptosis-related events in modulating neural stem cell (NSC) fate. In addition, the endogenous bile Acid, Tauroursodeoxycholic Acid (TUDCA) was shown to be neuroprotective in several animal models of neurodegenerative disorders by acting as an anti-apoptotic and anti-oxidant molecule at the mitochondrial level. Here, we hypothesize that TUDCA might also play a role on NSC fate decision. We found that TUDCA prevents mitochondrial apoptotic events typical of early-stage mouse NSC differentiation, preserves mitochondrial integrity and function, while enhancing self-renewal potential and accelerating cell cycle exit of NSCs. Interest...
Ana Nunes - One of the best experts on this subject based on the ideXlab platform.
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Tauroursodeoxycholic Acid tudca supplementation prevents cognitive impairment and amyloid deposition in app ps1 mice
Neurobiology of Disease, 2013Co-Authors: Zsuzsanna Callaertsvegh, Cecília M. P. Rodrigues, Ana Nunes, Rudi DhoogeAbstract:Alzheimer's disease (AD) is a neurodegenerative disease hallmarked by extracellular Aβ(1-42) containing plaques, and intracellular neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein. Progressively, memory deficits and cognitive disabilities start to occur as these hallmarks affect hippocampus and frontal cortex, regions highly involved in memory. Connective tissue growth factor (CTGF) expression, which is high in the vicinity of Aβ plaques and NFTs, was found to influence γ-secretase activity, the molecular crux in Aβ(1-42) production. Tauroursodeoxycholic Acid (TUDCA) is an endogenous bile Acid that downregulates CTGF expression in hepatocytes and has been shown to possess therapeutic efficacy in neurodegenerative models. To investigate the possible in vivo therapeutic effects of TUDCA, we provided 0.4% TUDCA-supplemented food to APP/PS1 mice, a well-established AD mouse model. Six months of TUDCA supplementation prevented the spatial, recognition and contextual memory defects observed in APP/PS1 mice at 8 months of age. Furthermore, TUDCA-supplemented APP/PS1 mice displayed reduced hippocampal and prefrontal amyloid deposition. These effects of TUDCA supplementation suggest a novel mechanistic route for Alzheimer therapeutics.
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Tauroursodeoxycholic Acid suppresses amyloid β induced synaptic toxicity in vitro and in app ps1 mice
Neurobiology of Aging, 2013Co-Authors: Rita M. Ramalho, Ana Nunes, Rudi Dhooge, Raquel B. Dias, Joana D. Amaral, Ana M. Sebastião, Cecília M. P. RodriguesAbstract:Synapses are considered the earliest site of Alzheimer's disease (AD) pathology, where synapse density is reduced, and synaptic loss is highly correlated with cognitive impairment. Tauroursodeoxycholic Acid (TUDCA) has been shown to be neuroprotective in several models of AD, including neuronal exposure to amyloid β (Aβ) and amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mice. Here, we show that TUDCA modulates synaptic deficits induced by Aβ in vitro. Specifically, TUDCA reduced the downregulation of the postsynaptic marker postsynaptic density-95 (PSD-95) and the decrease in spontaneous miniature excitatory postsynaptic currents (mEPSCs) frequency, while increasing the number of dendritic spines. This contributed to the induction of more robust and synaptically efficient neurons, reflected in inhibition of neuronal death. In vivo, TUDCA treatment of APP/PS1 mice abrogated the decrease in PSD-95 reactivity in the hippocampus. Taken together, these results expand the neuroprotective role of TUDCA to a synaptic level, further supporting the use of this molecule as a potential therapeutic strategy for the prevention and treatment of AD.
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Tauroursodeoxycholic Acid (TUDCA) supplementation prevents cognitive impairment and amyloid deposition in APP/PS1 mice
Neurobiology of disease, 2012Co-Authors: Zsuzsanna Callaerts-vegh, Cecília M. P. Rodrigues, Ana Nunes, Rudi D'hoogeAbstract:Alzheimer's disease (AD) is a neurodegenerative disease hallmarked by extracellular Aβ(1-42) containing plaques, and intracellular neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein. Progressively, memory deficits and cognitive disabilities start to occur as these hallmarks affect hippocampus and frontal cortex, regions highly involved in memory. Connective tissue growth factor (CTGF) expression, which is high in the vicinity of Aβ plaques and NFTs, was found to influence γ-secretase activity, the molecular crux in Aβ(1-42) production. Tauroursodeoxycholic Acid (TUDCA) is an endogenous bile Acid that downregulates CTGF expression in hepatocytes and has been shown to possess therapeutic efficacy in neurodegenerative models. To investigate the possible in vivo therapeutic effects of TUDCA, we provided 0.4% TUDCA-supplemented food to APP/PS1 mice, a well-established AD mouse model. Six months of TUDCA supplementation prevented the spatial, recognition and contextual memory defects observed in APP/PS1 mice at 8 months of age. Furthermore, TUDCA-supplemented APP/PS1 mice displayed reduced hippocampal and prefrontal amyloid deposition. These effects of TUDCA supplementation suggest a novel mechanistic route for Alzheimer therapeutics.
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Tauroursodeoxycholic Acid suppresses amyloid β-induced synaptic toxicity in vitro and in APP/PS1 mice
Neurobiology of aging, 2012Co-Authors: Rita M. Ramalho, Ana Nunes, Rudi D'hooge, Raquel B. Dias, Joana D. Amaral, Ana M. Sebastião, Cecília M. P. RodriguesAbstract:Synapses are considered the earliest site of Alzheimer's disease (AD) pathology, where synapse density is reduced, and synaptic loss is highly correlated with cognitive impairment. Tauroursodeoxycholic Acid (TUDCA) has been shown to be neuroprotective in several models of AD, including neuronal exposure to amyloid β (Aβ) and amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mice. Here, we show that TUDCA modulates synaptic deficits induced by Aβ in vitro. Specifically, TUDCA reduced the downregulation of the postsynaptic marker postsynaptic density-95 (PSD-95) and the decrease in spontaneous miniature excitatory postsynaptic currents (mEPSCs) frequency, while increasing the number of dendritic spines. This contributed to the induction of more robust and synaptically efficient neurons, reflected in inhibition of neuronal death. In vivo, TUDCA treatment of APP/PS1 mice abrogated the decrease in PSD-95 reactivity in the hippocampus. Taken together, these results expand the neuroprotective role of TUDCA to a synaptic level, further supporting the use of this molecule as a potential therapeutic strategy for the prevention and treatment of AD.
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Tauroursodeoxycholic Acid prevents E22Q Alzheimer’s Aβ toxicity in human cerebral endothelial cells
Cellular and molecular life sciences : CMLS, 2009Co-Authors: Ricardo J.s. Viana, Ana Nunes, Rui E. Castro, Rita M. Ramalho, Jordana L. Meyerson, Silvia Fossati, Jorge Ghiso, Agueda Rostagno, C. M. P. RodriguesAbstract:The vasculotropic E22Q mutant of the amyloid-β (Aβ) peptide is associated with hereditary cerebral hemorrhage with amyloidosis Dutch type. The cellular mechanism(s) of toxicity and nature of the AβE22Q toxic assemblies are not completely understood. Comparative assessment of structural parameters and cell death mechanisms elicited in primary human cerebral endothelial cells by AβE22Q and wild-type Aβ revealed that only AβE22Q triggered the Bax mitochondrial pathway of apoptosis. AβE22Q neither matched the fast oligomerization kinetics of Aβ42 nor reached its predominant β-sheet structure, achieving a modest degree of oligomerization with a secondary structure that remained a mixture of β and random conformations. The endogenous molecule Tauroursodeoxycholic Acid (TUDCA) was a strong modulator of AβE22Q-triggered apoptosis but did not significantly change the secondary structures and fibrillogenic propensities of Aβ peptides. These data dissociate the pro-apoptotic properties of Aβ peptides from their distinct mechanisms of aggregation/fibrillization in vitro, providing new perspectives for modulation of amyloid toxicity.
Rita M. Ramalho - One of the best experts on this subject based on the ideXlab platform.
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Tauroursodeoxycholic Acid suppresses amyloid β induced synaptic toxicity in vitro and in app ps1 mice
Neurobiology of Aging, 2013Co-Authors: Rita M. Ramalho, Ana Nunes, Rudi Dhooge, Raquel B. Dias, Joana D. Amaral, Ana M. Sebastião, Cecília M. P. RodriguesAbstract:Synapses are considered the earliest site of Alzheimer's disease (AD) pathology, where synapse density is reduced, and synaptic loss is highly correlated with cognitive impairment. Tauroursodeoxycholic Acid (TUDCA) has been shown to be neuroprotective in several models of AD, including neuronal exposure to amyloid β (Aβ) and amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mice. Here, we show that TUDCA modulates synaptic deficits induced by Aβ in vitro. Specifically, TUDCA reduced the downregulation of the postsynaptic marker postsynaptic density-95 (PSD-95) and the decrease in spontaneous miniature excitatory postsynaptic currents (mEPSCs) frequency, while increasing the number of dendritic spines. This contributed to the induction of more robust and synaptically efficient neurons, reflected in inhibition of neuronal death. In vivo, TUDCA treatment of APP/PS1 mice abrogated the decrease in PSD-95 reactivity in the hippocampus. Taken together, these results expand the neuroprotective role of TUDCA to a synaptic level, further supporting the use of this molecule as a potential therapeutic strategy for the prevention and treatment of AD.
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Tauroursodeoxycholic Acid suppresses amyloid β-induced synaptic toxicity in vitro and in APP/PS1 mice
Neurobiology of aging, 2012Co-Authors: Rita M. Ramalho, Ana Nunes, Rudi D'hooge, Raquel B. Dias, Joana D. Amaral, Ana M. Sebastião, Cecília M. P. RodriguesAbstract:Synapses are considered the earliest site of Alzheimer's disease (AD) pathology, where synapse density is reduced, and synaptic loss is highly correlated with cognitive impairment. Tauroursodeoxycholic Acid (TUDCA) has been shown to be neuroprotective in several models of AD, including neuronal exposure to amyloid β (Aβ) and amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mice. Here, we show that TUDCA modulates synaptic deficits induced by Aβ in vitro. Specifically, TUDCA reduced the downregulation of the postsynaptic marker postsynaptic density-95 (PSD-95) and the decrease in spontaneous miniature excitatory postsynaptic currents (mEPSCs) frequency, while increasing the number of dendritic spines. This contributed to the induction of more robust and synaptically efficient neurons, reflected in inhibition of neuronal death. In vivo, TUDCA treatment of APP/PS1 mice abrogated the decrease in PSD-95 reactivity in the hippocampus. Taken together, these results expand the neuroprotective role of TUDCA to a synaptic level, further supporting the use of this molecule as a potential therapeutic strategy for the prevention and treatment of AD.
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Tauroursodeoxycholic Acid prevents E22Q Alzheimer’s Aβ toxicity in human cerebral endothelial cells
Cellular and molecular life sciences : CMLS, 2009Co-Authors: Ricardo J.s. Viana, Ana Nunes, Rui E. Castro, Rita M. Ramalho, Jordana L. Meyerson, Silvia Fossati, Jorge Ghiso, Agueda Rostagno, C. M. P. RodriguesAbstract:The vasculotropic E22Q mutant of the amyloid-β (Aβ) peptide is associated with hereditary cerebral hemorrhage with amyloidosis Dutch type. The cellular mechanism(s) of toxicity and nature of the AβE22Q toxic assemblies are not completely understood. Comparative assessment of structural parameters and cell death mechanisms elicited in primary human cerebral endothelial cells by AβE22Q and wild-type Aβ revealed that only AβE22Q triggered the Bax mitochondrial pathway of apoptosis. AβE22Q neither matched the fast oligomerization kinetics of Aβ42 nor reached its predominant β-sheet structure, achieving a modest degree of oligomerization with a secondary structure that remained a mixture of β and random conformations. The endogenous molecule Tauroursodeoxycholic Acid (TUDCA) was a strong modulator of AβE22Q-triggered apoptosis but did not significantly change the secondary structures and fibrillogenic propensities of Aβ peptides. These data dissociate the pro-apoptotic properties of Aβ peptides from their distinct mechanisms of aggregation/fibrillization in vitro, providing new perspectives for modulation of amyloid toxicity.
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Tauroursodeoxycholic Acid prevents e22q alzheimer s aβ toxicity in human cerebral endothelial cells
Cellular and Molecular Life Sciences, 2009Co-Authors: Ricardo J.s. Viana, Ana Nunes, Rui E. Castro, Rita M. Ramalho, Jordana L. Meyerson, Silvia Fossati, Jorge Ghiso, Agueda Rostagno, C. M. P. RodriguesAbstract:The vasculotropic E22Q mutant of the amyloid-β (Aβ) peptide is associated with hereditary cerebral hemorrhage with amyloidosis Dutch type. The cellular mechanism(s) of toxicity and nature of the AβE22Q toxic assemblies are not completely understood. Comparative assessment of structural parameters and cell death mechanisms elicited in primary human cerebral endothelial cells by AβE22Q and wild-type Aβ revealed that only AβE22Q triggered the Bax mitochondrial pathway of apoptosis. AβE22Q neither matched the fast oligomerization kinetics of Aβ42 nor reached its predominant β-sheet structure, achieving a modest degree of oligomerization with a secondary structure that remained a mixture of β and random conformations. The endogenous molecule Tauroursodeoxycholic Acid (TUDCA) was a strong modulator of AβE22Q-triggered apoptosis but did not significantly change the secondary structures and fibrillogenic propensities of Aβ peptides. These data dissociate the pro-apoptotic properties of Aβ peptides from their distinct mechanisms of aggregation/fibrillization in vitro, providing new perspectives for modulation of amyloid toxicity.
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Tauroursodeoxycholic Acid modulates p53 mediated apoptosis in alzheimer s disease mutant neuroblastoma cells
Journal of Neurochemistry, 2006Co-Authors: Rita M. Ramalho, Clifford J. Steer, Susana Solá, Rui E. Castro, Pedro M Borralho, Cecília M. P. RodriguesAbstract:Early onset familial Alzheimer's disease (FAD) is linked to autosomal dominant mutations in the amyloid precursor protein (APP) and presenilin 1 and 2 (PS1 and PS2) genes. These are critical mediators of total amyloid β-peptide (Aβ) production, inducing cell death through uncertain mechanisms. Tauroursodeoxycholic Acid (TUDCA) modulates exogenous Aβ-induced apoptosis by interfering with E2F-1/p53/Bax. Here, we used mouse neuroblastoma cells that express either wild-type APP, APP with the Swedish mutation (APPswe), or double-mutated human APP and PS1 (APPswe/ΔE9), all exhibiting increased Aβ production and aggregation. Cell viability was decreased in APPswe and APPswe/ΔE9 but was partially reversed by z-VAD.fmk. Nuclear fragmentation and caspase 2, 6 and 8 activation were also readily detected. TUDCA reduced nuclear fragmentation as well as caspase 2 and 6, but not caspase 8 activities. p53 activity, and Bcl-2 and Bax changes, were also modulated by TUDCA. Overexpression of p53, but not mutant p53, in wild-type and mutant neuroblastoma cells was sufficient to induce apoptosis, which, in turn, was reduced by TUDCA. In addition, inhibition of the phosphatidylinositide 3′-OH kinase pathway reduced TUDCA protection against p53-induced apoptosis. In conclusion, FAD mutations are associated with the activation of classical apoptotic pathways. TUDCA reduces p53-induced apoptosis and modulates expression of Bcl-2 family.
Qing Yin Zheng - One of the best experts on this subject based on the ideXlab platform.
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Tauroursodeoxycholic Acid prevents hearing loss and hair cell death in cdh23erl erl mice
Neuroscience, 2016Co-Authors: J. Yuan, S. Entenman, Qing Yin ZhengAbstract:Sensorineural hearing loss has long been the subject of experimental and clinical research for many years. The recently identified novel mutation of the Cadherin23 (Cdh23) gene, Cdh23(erl/erl), was proven to be a mouse model of human autosomal recessive nonsyndromic deafness (DFNB12). Tauroursodeoxycholic Acid (TUDCA), a taurine-conjugated bile Acid, has been used in experimental research and clinical applications related to liver disease, diabetes, neurodegenerative diseases, and other diseases associated with apoptosis. Because hair cell apoptosis was implied to be the cellular mechanism leading to hearing loss in Cdh23(erl/erl) mice (erl mice), this study investigated TUDCA's otoprotective effects in erl mice: preventing hearing impairment and protecting against hair cell death. Our results showed that systemic treatment with TUDCA significantly alleviated hearing loss and suppressed hair cell death in erl mice. Additionally, TUDCA inhibited apoptotic genes and caspase-3 activation in erl mouse cochleae. The data suggest that TUDCA could be a potential therapeutic agent for human DFNB12.
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Tauroursodeoxycholic Acid prevents hearing loss and hair cell death in Cdh23erl/erl mice
Neuroscience, 2015Co-Authors: J. Yuan, S. Entenman, Qing Yin ZhengAbstract:Sensorineural hearing loss has long been the subject of experimental and clinical research for many years. The recently identified novel mutation of the Cadherin23 (Cdh23) gene, Cdh23(erl/erl), was proven to be a mouse model of human autosomal recessive nonsyndromic deafness (DFNB12). Tauroursodeoxycholic Acid (TUDCA), a taurine-conjugated bile Acid, has been used in experimental research and clinical applications related to liver disease, diabetes, neurodegenerative diseases, and other diseases associated with apoptosis. Because hair cell apoptosis was implied to be the cellular mechanism leading to hearing loss in Cdh23(erl/erl) mice (erl mice), this study investigated TUDCA's otoprotective effects in erl mice: preventing hearing impairment and protecting against hair cell death. Our results showed that systemic treatment with TUDCA significantly alleviated hearing loss and suppressed hair cell death in erl mice. Additionally, TUDCA inhibited apoptotic genes and caspase-3 activation in erl mouse cochleae. The data suggest that TUDCA could be a potential therapeutic agent for human DFNB12.
Rudi D'hooge - One of the best experts on this subject based on the ideXlab platform.
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Tauroursodeoxycholic Acid (TUDCA) supplementation prevents cognitive impairment and amyloid deposition in APP/PS1 mice
Neurobiology of disease, 2012Co-Authors: Zsuzsanna Callaerts-vegh, Cecília M. P. Rodrigues, Ana Nunes, Rudi D'hoogeAbstract:Alzheimer's disease (AD) is a neurodegenerative disease hallmarked by extracellular Aβ(1-42) containing plaques, and intracellular neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein. Progressively, memory deficits and cognitive disabilities start to occur as these hallmarks affect hippocampus and frontal cortex, regions highly involved in memory. Connective tissue growth factor (CTGF) expression, which is high in the vicinity of Aβ plaques and NFTs, was found to influence γ-secretase activity, the molecular crux in Aβ(1-42) production. Tauroursodeoxycholic Acid (TUDCA) is an endogenous bile Acid that downregulates CTGF expression in hepatocytes and has been shown to possess therapeutic efficacy in neurodegenerative models. To investigate the possible in vivo therapeutic effects of TUDCA, we provided 0.4% TUDCA-supplemented food to APP/PS1 mice, a well-established AD mouse model. Six months of TUDCA supplementation prevented the spatial, recognition and contextual memory defects observed in APP/PS1 mice at 8 months of age. Furthermore, TUDCA-supplemented APP/PS1 mice displayed reduced hippocampal and prefrontal amyloid deposition. These effects of TUDCA supplementation suggest a novel mechanistic route for Alzheimer therapeutics.
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Tauroursodeoxycholic Acid suppresses amyloid β-induced synaptic toxicity in vitro and in APP/PS1 mice
Neurobiology of aging, 2012Co-Authors: Rita M. Ramalho, Ana Nunes, Rudi D'hooge, Raquel B. Dias, Joana D. Amaral, Ana M. Sebastião, Cecília M. P. RodriguesAbstract:Synapses are considered the earliest site of Alzheimer's disease (AD) pathology, where synapse density is reduced, and synaptic loss is highly correlated with cognitive impairment. Tauroursodeoxycholic Acid (TUDCA) has been shown to be neuroprotective in several models of AD, including neuronal exposure to amyloid β (Aβ) and amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mice. Here, we show that TUDCA modulates synaptic deficits induced by Aβ in vitro. Specifically, TUDCA reduced the downregulation of the postsynaptic marker postsynaptic density-95 (PSD-95) and the decrease in spontaneous miniature excitatory postsynaptic currents (mEPSCs) frequency, while increasing the number of dendritic spines. This contributed to the induction of more robust and synaptically efficient neurons, reflected in inhibition of neuronal death. In vivo, TUDCA treatment of APP/PS1 mice abrogated the decrease in PSD-95 reactivity in the hippocampus. Taken together, these results expand the neuroprotective role of TUDCA to a synaptic level, further supporting the use of this molecule as a potential therapeutic strategy for the prevention and treatment of AD.
