Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer's Disease

PLoS One

Veronica Galvan¹  Jayanta Debnath²  Olivia Gorostiza³  Natalia Podlutskaya⁴  Matthew J. Hart⁵  Randy Strong⁵  Arlan Richardson⁶  Patricia Spilman⁶  Dale Bredesen⁶ 

[1] Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America;Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America;Department of Pathology, University of California San Francisco, San Francisco, California, United States of America;Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America;The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America;The Buck Institute for Age Research, Novato, California, United States of America

关键词: Mouse models;    Autophagic cell death;    Genetically modified animals;    Alzheimer's disease;    Cognitive impairment;    Mice;    Learning;    Hippocampus;   

DOI  :  10.1371/journal.pone.0009979

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Background Reduced TOR signaling has been shown to significantly increase lifespan in a variety of organisms [1], [2], [3], [4]. It was recently demonstrated that long-term treatment with rapamycin, an inhibitor of the mTOR pathway[5], or ablation of the mTOR target p70S6K[6] extends lifespan in mice, possibly by delaying aging. Whether inhibition of the mTOR pathway would delay or prevent age-associated disease such as AD remained to be determined.Methodology/Principal Findings We used rapamycin administration and behavioral tools in a mouse model of AD as well as standard biochemical and immunohistochemical measures in brain tissue to provide answers for this question. Here we show that long-term inhibition of mTOR by rapamycin prevented AD-like cognitive deficits and lowered levels of Aβ42, a major toxic species in AD[7], in the PDAPP transgenic mouse model. These data indicate that inhibition of the mTOR pathway can reduce Aβ42 levels in vivo and block or delay AD in mice. As expected from the inhibition of mTOR, autophagy was increased in neurons of rapamycin-treated transgenic, but not in non-transgenic, PDAPP mice, suggesting that the reduction in Aβ and the improvement in cognitive function are due in part to increased autophagy, possibly as a response to high levels of Aβ.Conclusions/Significance Our data suggest that inhibition of mTOR by rapamycin, an intervention that extends lifespan in mice, can slow or block AD progression in a transgenic mouse model of the disease. Rapamycin, already used in clinical settings, may be a potentially effective therapeutic agent for the treatment of AD.

【 授权许可】

CC BY