RT Journal Article
T1 mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies.
A1 Caccamo, Antonella
A1 Magrì, Andrea
A1 Medina, David X.
A1 Wisely, Elena V.
A1 López-Aranda, Manuel Francisco
A1 Silva, Alcino J.
A1 Oddo, Salvatore
K1 Alzheimer, Enfermedad de
K1 Regulación celular
K1 Muerte celular
K1 Sistema nervioso - Enfermedades
K1 Sirolimus
AB Accumulation of tau is a critical event in several neurodegenerative disorders, collectively known as tauopathies, which include Alzheimer's disease and frontotemporal dementia. Pathological tau is hyperphosphorylated and aggregates to form neurofibrillary tangles. The molecular mechanisms leading to tau accumulation remain unclear and more needs to be done to elucidate them. Age is a major risk factor for all tauopathies, suggesting that molecular changes contributing to the aging process may facilitate tau accumulation and represent common mechanisms across different tauopathies. Here, we use multiple animal models and complementary genetic and pharmacological approaches to show that the mammalian target of rapamycin (mTOR) regulates tau phosphorylation and degradation. Specifically, we show that genetically increasing mTOR activity elevates endogenous mouse tau levels and phosphorylation. Complementary to it, we further demonstrate that pharmacologically reducing mTOR signaling with rapamycin ameliorates tau pathology and the associated behavioral deficits in a mouse model overexpressing mutant human tau. Mechanistically, we provide compelling evidence that the association between mTOR and tau is linked to GSK3β and autophagy function. In summary, we show that increasing mTOR signaling facilitates tau pathology, while reducing mTOR signaling ameliorates tau pathology. Given the overwhelming evidence that reducing mTOR signaling increases lifespan and healthspan, the data presented here have profound clinical implications for aging and tauopathies and provide the molecular basis for how aging may contribute to tau pathology. Additionally, these results provide preclinical data indicating that reducing mTOR signaling may be a valid therapeutic approach for tauopathies.
PB Wiley-Blackwell
YR 2013
FD 2013-02-20
LK https://hdl.handle.net/10630/38774
UL https://hdl.handle.net/10630/38774
LA eng
NO Caccamo A, Magrì A, Medina DX, et al. mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies. Aging Cell. 2013;12(3):370-380. doi:10.1111/acel.12057
NO https://openpolicyfinder.jisc.ac.uk/id/publication/80
NO This study was supported by grants to S.O. from the National Institute on Aging (R01 AG037637), the Glenn Foundation and the William and Ella Owens Medical Research Foundation; and by a grant to A.J.S. from the National Institute on Mental Health (R01 MH084315).
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 21 ene 2026