Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy.
The accumulation of insoluble proteins is a pathological hallmark of several neurodegenerative disorders. Tauopathies are caused by the dysfunction and aggregation of tau protein and an impairment of cellular protein degradation pathways may contribute to their pathogenesis. Thus, a deficiency in autophagy can cause neurodegeneration, while activation of autophagy is protective against some proteinopathies. Little is known about the role of autophagy in animal models of human tauopathy. In the present report, we assessed the effects of autophagy stimulation by trehalose in a transgenic mouse model of tauopathy, the human mutant P301S tau mouse, using biochemical and immunohistochemical analyses. Neuronal survival was evaluated by stereology. Autophagy was activated in the brain, where the number of neurons containing tau inclusions was significantly reduced, as was the amount of insoluble tau protein. This reduction in tau aggregates was associated with improved neuronal survival in the cerebral cortex and the brainstem. We also observed a decrease of p62 protein, suggesting that it may contribute to the removal of tau inclusions. Trehalose failed to activate autophagy in the spinal cord, where it had no impact on the level of sarkosyl-insoluble tau. Accordingly, trehalose had no effect on the motor impairment of human mutant P301S tau transgenic mice. Our findings provide direct evidence in favour of the degradation of tau aggregates by autophagy. Activation of autophagy may be worth investigating in the context of therapies for human tauopathies.
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
Véronique
V
Schaeffer
Isabelle
I
Lavenir
Sefika
S
Ozcelik
Markus
M
Tolnay
David T
DT
Winkler
Michel
M
Goedert
D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D024801:Tauopathies / Q000188:drug therapy / Q000503:physiopathology*; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism; D014199:Trehalose / Q000494:pharmacology* / Q000627:therapeutic use; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
C490981:Gtf2h1 protein, mouse; D014157:Transcription Factors; D016875:tau Proteins; D051758:Transcription Factor TFIIH; D014199:Trehalose