title: Stimulation of autophagy is neuroprotective in a mouse model of human tauopathy.
abstract: The most common neurodegenerative diseases are characterized by the accumulation of misfolded proteins. Tauopathies, which include Alzheimer disease, progressive supranuclear palsy, corticobasal degeneration, Pick disease and cases of frontotemporal dementia and parkinsonism linked to chromosome 17, are characterized by the accumulation of hyperphosphorylated and filamentous MAPT/tau protein. The pathological mechanisms involved in MAPT protein accumulation are not well understood, but a possible impairment of protein degradation pathways has been suggested. We investigated the effects of autophagy stimulation on MAPT pathology in a model tauopathy, the human mutant P301S MAPT transgenic mouse line. In the brain of the trehalose-treated mutant mice, autophagy is activated and a reduced number of neurons containing MAPT inclusions, as well as a decreased amount of insoluble MAPT, are observed. The improvement of MAPT pathology is associated with increased nerve cell survival. Moreover, MAPT inclusions colocalize with SQSTM1/p62- and LC3-positive puncta, suggesting the colocalization of MAPT aggregates with autophagic vacuoles. Autophagy is not activated in the spinal cord of the human P301S MAPT transgenic mice and neuronal survival, as well as MAPT pathology, is unaffected. This study supports a role for autophagy stimulation in the degradation of MAPT aggregates and opens new perspectives for the investigation of autophagy as a pathological mechanism involved in neurodegenerative diseases.
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Véronique
authors.initials: V
authors.lastname: Schaeffer
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D024801:Tauopathies / Q000473:pathology*
chemical_list: D018696:Neuroprotective Agents