Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation

Jose A. Rodríguez-Navarro, Laura Rodríguez, María J. Casarejos, Rosa M. Solano, Ana Gómez, Juan Perucho, Ana Maria Cuervo, Justo García de Yébenes, María A. Mena

Research output: Contribution to journalArticle

172 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)423-438
Number of pages16
JournalNeurobiology of Disease
Volume39
Issue number3
DOIs
StatePublished - Sep 2010

Fingerprint

Trehalose
Autophagy
Tauopathies
Pathology
Amyloid Plaques
Mesencephalon
Dopamine
Dopaminergic Neurons
Parkinsonian Disorders
Brain
Animal Behavior
Neurofibrillary Tangles
Disaccharides
Poisons
Population Growth
Life Expectancy
Vacuoles
Basal Ganglia
Drinking Water
Neurodegenerative Diseases

Keywords

  • Autophagy
  • Dopamine
  • Parkin
  • Parkinson's disease
  • Tau
  • Tauopathies
  • Trehalose

ASJC Scopus subject areas

  • Neurology

Cite this

Rodríguez-Navarro, J. A., Rodríguez, L., Casarejos, M. J., Solano, R. M., Gómez, A., Perucho, J., ... Mena, M. A. (2010). Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiology of Disease, 39(3), 423-438. https://doi.org/10.1016/j.nbd.2010.05.014

Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. / Rodríguez-Navarro, Jose A.; Rodríguez, Laura; Casarejos, María J.; Solano, Rosa M.; Gómez, Ana; Perucho, Juan; Cuervo, Ana Maria; García de Yébenes, Justo; Mena, María A.

In: Neurobiology of Disease, Vol. 39, No. 3, 09.2010, p. 423-438.

Research output: Contribution to journalArticle

Rodríguez-Navarro, JA, Rodríguez, L, Casarejos, MJ, Solano, RM, Gómez, A, Perucho, J, Cuervo, AM, García de Yébenes, J & Mena, MA 2010, 'Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation', Neurobiology of Disease, vol. 39, no. 3, pp. 423-438. https://doi.org/10.1016/j.nbd.2010.05.014
Rodríguez-Navarro, Jose A. ; Rodríguez, Laura ; Casarejos, María J. ; Solano, Rosa M. ; Gómez, Ana ; Perucho, Juan ; Cuervo, Ana Maria ; García de Yébenes, Justo ; Mena, María A. / Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. In: Neurobiology of Disease. 2010 ; Vol. 39, No. 3. pp. 423-438.
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