Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy

Abstract

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.

Suppression of Autophagy in Osteocytes Mimics Skeletal Aging

“…It will now be important to identify the molecular mechanisms that account for the low and unbalanced bone remodeling caused by suppression of autophagy in osteocytes. In addition, recent studies in other organs, such as the brain and liver, have demonstrated that stimulation of autophagy can prevent or reverse age-associated damage (52,53). Thus, it will also be important to complement our loss-of-function studies with gain-of-function studies to determine whether maintenance or stimulation of autophagy in osteocytes is sufficient to prevent any aspects of skeletal aging.…”

FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice

“…13,14 Of note, the chemical-induced enhancement of autophagy has been reported to decrease aggregates in the CNS and retard the progression of neurological symptoms in several animal and cell culture models of neurodegenerative diseases, including TSE. [14][15][16][17][18][19] The autophagy-lysosomal system is regulated by several mechanisms, one example of which is mechanistic target of rapamycin (MTOR) signaling. 20 FK506, also named tacrolimus, is well known as an immunosuppressive drug that is mainly used post-transplantation to decrease the activity of the recipient's immunity.…”

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

“…Trehalose is considered to enhance autophagic activity (21). It has been shown to promote the cellular clearance of pathogenic proteins like mutant huntingtin, ␣-synuclein (21,22), and phosphorylated tau (22)(23)(24) that are associated with Huntington, Parkinson, and Alzheimer diseases, respectively. However, the role of trehalose in the cellular metabolism of the Alzheimer disease-associated APP remains to be investigated.…”