title: Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice.
abstract: Altered autophagy contributes to the pathogenesis of Alzheimer's disease and other tauopathies, for which curative treatment options are still lacking. We have recently shown that trehalose reduces tau pathology in a tauopathy mouse model by stimulation of autophagy. Here, we studied the effect of the autophagy inducing drug rapamycin on the progression of tau pathology in P301S mutant tau transgenic mice. Rapamycin treatment resulted in a significant reduction in cortical tau tangles, less tau hyperphosphorylation, and lowered levels of insoluble tau in the forebrain. The favourable effect of rapamycin on tau pathology was paralleled by a qualitative reduction in astrogliosis. These effects were visible with early preventive or late treatment. We further noted an accumulation of the autophagy associated proteins p62 and LC3 in aged tangle bearing P301S mice that was lowered upon rapamycin treatment. Thus, rapamycin treatment defers the progression of tau pathology in a tauopathy animal model and autophagy stimulation may constitute a therapeutic approach for patients suffering from tauopathies.
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Sefika
authors.initials: S
authors.lastname: Ozcelik
authors.forename: Graham
authors.initials: G
authors.lastname: Fraser
authors.forename: Perrine
authors.initials: P
authors.lastname: Castets
authors.forename: Véronique
authors.initials: V
authors.lastname: Schaeffer
authors.forename: Zhiva
authors.initials: Z
authors.lastname: Skachokova
authors.forename: Karin
authors.initials: K
authors.lastname: Breu
authors.forename: Florence
authors.initials: F
authors.lastname: Clavaguera
authors.forename: Michael
authors.initials: M
authors.lastname: Sinnreich
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
authors.forename: Markus
authors.initials: M
authors.lastname: Tolnay
authors.forename: David Theo
authors.initials: DT
authors.lastname: Winkler
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D012995:Solubility; D024801:Tauopathies / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D016875:tau Proteins; D020123:Sirolimus