Pharmacological mTOR-inhibition facilitates clearance of AD-related tau aggregates in the mouse brain
Martina P. Morawe, Fan Liao, Willi Amberg, J. van Bergeijk, Rui B. Chang, Mary Gulino, Caitlin Hamilton, Carolin Hoft, Casey J. Lumpkin, Bryan Mastis, Emily J. McGlame, Judith Nuber, Christian Plaas, Brinda Ravikumar, Kaushambi Roy, Marion Schanzenbächer, Joseph Tierno, Viktor Lakics, Tammy Dellovade, Matthew Townsend
Abstract
In this study we aimed to reduce tau pathology, a hallmark of Alzheimer's Disease (AD), by activating mTOR-dependent autophagy in a transgenic mouse model of tauopathy by long-term dosing of animals with mTOR-inhibitors. Rapamycin treatment reduced the burden of hyperphosphorylated and aggregated pathological tau in the cerebral cortex only when applied to young mice, prior to the emergence of pathology. Conversely, PQR530 which exhibits better brain exposure and superior pharmacokinetic properties, reduced tau pathology even when the treatment started after the onset of pathology. Our results show that dosing animals twice per week with PQR530 resulted in intermittent, rather than sustained target engagement. Nevertheless, this pulse-like mTOR inhibition followed by longer intervals of re-activation was sufficient to reduce tau pathology in the cerebral cortex in P301S tau transgenic mice. This suggests that balanced therapeutic dosing of blood-brain-barrier permeable mTOR-inhibitors can result in a disease-modifying effect in AD and at the same time prevents toxic side effects due to prolonged over activation of autophagy.