Temsirolimus promotes autophagic clearance of amyloid-β and provides protective effects in cellular and animal models of Alzheimer's disease

Accumulation of amyloid-beta peptides (A beta) within brain is a major pathogenic hallmark of Alzheimer's disease (AD). Emerging evidence suggests that autophagy, an important intracellular catabolic process, is involved in A beta clearance. Here, we investigated whether temsirolimus, a newly developed compound approved by Food and Drug Administration and European Medicines Agency for renal cell carcinoma treatment, would promote autophagic clearance of A beta and thus provide protective effects in cellular and animal models of AD. HEK293 cells expressing the Swedish mutant of APP695 (HEK293-APP695) were treated with vehicle or 100 nM temsirolimus for 24 h in the presence or absence of 3-methyladenine (5mM) or Atg5-siRNA, and intracellular A beta levels as well as autophagy biomarkers were measured. Meanwhile, APP/PS1 mice received intraperitoneal injection of temsirolimus (20 mg/kg) every 2 days for 60 days, and brain A beta burden, autophagy biomarkers, cellular apoptosis in hippocampus, and spatial cognitive functions were assessed. Our results showed that temsirolimus enhanced A beta clearance in HEK293-APP695 cells and in brain of APP/PSI mice in an autophagy-dependent manner. Meanwhile, temsirolimus attenuated cellular apoptosis in hippocampus of APP/PSI mice, which was accompanied by an improvement in spatial learning and memory abilities. In conclusion, our study provides the first evidence that temsirolimus promotes autophagic A beta clearance and exerts protective effects in cellular and animal models of AD, suggesting that temsirolimus administration may represent a new therapeutic strategy for AD treatment. Meanwhile, these findings emphasize the notion that many therapeutic agents possess pleiotropic actions aside from their main applications. (C) 2014 Elsevier Ltd. All rights reserved.