Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-beta, and Tau EFFECTS ON COGNITIVE IMPAIRMENTS

作者：Caccamo Antonella; Majumder Smita; Richardson Arlan; Strong Randy; Oddo Salvatore^*

来源：Journal of Biological Chemistry, 2010, 285(17): 13107-13120.

DOI：10.1074/jbc.M110.100420

Accumulation of amyloid-beta (A beta) and Tau is an invariant feature of Alzheimer disease (AD). The upstream role of A beta accumulation in the disease pathogenesis is widely accepted, and there is strong evidence showing that A beta accumulation causes cognitive impairments. However, the molecular mechanisms linking A beta to cognitive decline remain to be elucidated. Here we show that the buildup of A beta increases the mammalian target of rapamycin (mTOR) signaling, whereas decreasing mTOR signaling reduces A beta levels, thereby highlighting an interrelation between mTOR signaling and A beta. The mTOR pathway plays a central role in controlling protein homeostasis and hence, neuronal functions; indeed mTOR signaling regulates different forms of learning and memory. Using an animal model of AD, we show that pharmacologically restoring mTOR signaling with rapamycin rescues cognitive deficits and ameliorates A beta and Tau pathology by increasing autophagy. Indeed, we further show that autophagy induction is necessary for the rapamycin mediated reduction in A beta levels. The results presented here provide a molecular basis for the A beta-induced cognitive deficits and, moreover, show that rapamycin, an FDA approved drug, improves learning and memory and reduces A beta and Tau pathology.

• 出版日期2010-4-23