TY - JOUR
T1 - Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation
AU - Rodríguez-Navarro, Jose A.
AU - Rodríguez, Laura
AU - Casarejos, María J.
AU - Solano, Rosa M.
AU - Gómez, Ana
AU - Perucho, Juan
AU - Cuervo, Ana María
AU - García de Yébenes, Justo
AU - Mena, María A.
N1 - Funding Information:
This study has been supported in part by grants from the Spanish Ministry of Health , FIS 2007/0037 , CAM 0202/2006 , and CIBER 2006/05/0059 . JP and JAR have a CIBER predoctoral and CAM postdoctoral fellowships, respectively. The authors thank Izaskun Rodal and M. Paz Muñoz for excellent technical assistance, and Mrs. Claire Marsden for editorial help.
PY - 2010/9
Y1 - 2010/9
N2 - Tauopathies are neurodegenerative diseases, sporadic or familial, mainly characterized by dementia and parkinsonism associated to atrophy of the frontotemporal cortex and the basal ganglia, with deposition of abnormal tau in brain. Hereditary tauopathies are related with mutations of the tau gene. Up to the present, these diseases have not been helped by any disease-modifying treatment, and patients die a few years after the onset of symptoms.We have developed and characterized a mouse model of tauopathy with parkinsonism, overexpressing human mutated tau protein with deletion of parkin (PK-/-/TauVLW). At 3months of age, these mice present abnormal dopamine-related behavior, severe dropout of dopamine neurons in the ventral midbrain, reduced dopamine levels in the striatum and abundant phosphorylated tau-positive neuritic plaques, neurofibrillary tangles, astrogliosis, and, at 12months old, plaques of murine β-amyloid in the hippocampus.Trehalose is a natural disaccharide that increases the removal of abnormal proteins through enhancement of autophagy. In this work, we tested if 1% trehalose in the drinking water reverts the PK-/-/TauVLW phenotype. The treatment with trehalose of 3-month-old PK-/-/TauVLW mice for 2.5months reverted the dropout of dopamine neurons, which takes place in the ventral midbrain of vehicle treated PK-/-/TauVLW and the reduced dopamine-related proteins levels in the midbrain and striatum. The number of phosphorylated tau-positive neuritic plaques and the levels of phosphorylated tau decreased, as well as astrogliosis in brain regions. The autophagy markers in the brain, the autophagic vacuoles isolated from the liver, and the electron microscopy data indicate that these effects of trehalose are mediated by autophagy. The treatment with trehalose for 4months of 3-month-old PK-/-/TauVLW mice maintained the amelioration of the tau pathology and astrogliosis but failed to revert DA-related pathology in the striatum. Furthermore, the 3-week treatment with trehalose of 14-month-old PK-/-/TauVLW mice, at the limit of their life expectancy, improved the motor behavior and anxiety of these animals, and reduced their levels of phosphorylated tau and the number of murine β-amyloid plaques.Trehalose is neuroprotective in this model of tauopathy. Since trehalose is free of toxic effects at high concentrations, this study opens the way for clinical studies of the effects of trehalose in human tauopathies.
AB - Tauopathies are neurodegenerative diseases, sporadic or familial, mainly characterized by dementia and parkinsonism associated to atrophy of the frontotemporal cortex and the basal ganglia, with deposition of abnormal tau in brain. Hereditary tauopathies are related with mutations of the tau gene. Up to the present, these diseases have not been helped by any disease-modifying treatment, and patients die a few years after the onset of symptoms.We have developed and characterized a mouse model of tauopathy with parkinsonism, overexpressing human mutated tau protein with deletion of parkin (PK-/-/TauVLW). At 3months of age, these mice present abnormal dopamine-related behavior, severe dropout of dopamine neurons in the ventral midbrain, reduced dopamine levels in the striatum and abundant phosphorylated tau-positive neuritic plaques, neurofibrillary tangles, astrogliosis, and, at 12months old, plaques of murine β-amyloid in the hippocampus.Trehalose is a natural disaccharide that increases the removal of abnormal proteins through enhancement of autophagy. In this work, we tested if 1% trehalose in the drinking water reverts the PK-/-/TauVLW phenotype. The treatment with trehalose of 3-month-old PK-/-/TauVLW mice for 2.5months reverted the dropout of dopamine neurons, which takes place in the ventral midbrain of vehicle treated PK-/-/TauVLW and the reduced dopamine-related proteins levels in the midbrain and striatum. The number of phosphorylated tau-positive neuritic plaques and the levels of phosphorylated tau decreased, as well as astrogliosis in brain regions. The autophagy markers in the brain, the autophagic vacuoles isolated from the liver, and the electron microscopy data indicate that these effects of trehalose are mediated by autophagy. The treatment with trehalose for 4months of 3-month-old PK-/-/TauVLW mice maintained the amelioration of the tau pathology and astrogliosis but failed to revert DA-related pathology in the striatum. Furthermore, the 3-week treatment with trehalose of 14-month-old PK-/-/TauVLW mice, at the limit of their life expectancy, improved the motor behavior and anxiety of these animals, and reduced their levels of phosphorylated tau and the number of murine β-amyloid plaques.Trehalose is neuroprotective in this model of tauopathy. Since trehalose is free of toxic effects at high concentrations, this study opens the way for clinical studies of the effects of trehalose in human tauopathies.
KW - Autophagy
KW - Dopamine
KW - Parkin
KW - Parkinson's disease
KW - Tau
KW - Tauopathies
KW - Trehalose
UR - http://www.scopus.com/inward/record.url?scp=77954955573&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77954955573&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2010.05.014
DO - 10.1016/j.nbd.2010.05.014
M3 - Article
C2 - 20546895
AN - SCOPUS:77954955573
SN - 0969-9961
VL - 39
SP - 423
EP - 438
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 3
ER -