Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau

Abstract

Accumulation of amyloid-␤ (A␤) and Tau is an invariant feature of Alzheimer disease (AD). The upstream role of A␤ accumulation in the disease pathogenesis is widely accepted, and there is strong evidence showing that A␤ accumulation causes cognitive impairments. However, the molecular mechanisms linking A␤ to cognitive decline remain to be elucidated. Here we show that the buildup of A␤ increases the mammalian target of rapamycin (mTOR) signaling, whereas decreasing mTOR signaling reduces A␤ levels, thereby highlighting an interrelation between mTOR signaling and A␤. 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␤ and Tau pathology by increasing autophagy. Indeed, we further show that autophagy induction is necessary for the rapamycinmediated reduction in A␤ levels. The results presented here provide a molecular basis for the A␤-induced cognitive deficits and, moreover, show that rapamycin, an FDA approved drug, improves learning and memory and reduces A␤ and Tau pathology. Neurofibrillary tangles (NFTs)2 and amyloid plaques represent the two major hallmark neuropathological lesions of AD (1). NFTs are intraneuronal inclusions that are mainly formed of the hyperphosphorylated microtubule-binding protein Tau (2-5). In contrast, amyloid plaques accumulate extracellularly and are mainly composed of a peptide called amyloid-␤ (A␤) (6, 7). Although the key role of A␤ accumulation in the pathogenesis of AD is widely accepted, the molecular pathways by which A␤ accumulation leads to cognitive decline and Tau pathology remain to be elucidated.The mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that forms two multiprotein complexes known as mTOR complex (mTORC) 1 and 2 (8). mTORC1 controls cellular homeostasis, and its activity is inhibited by rapamycin; in contrast mTORC2 is insensitive to rapamycin and controls cellular shape by modulating actin function (8, 9). By regulating both protein synthesis and degradation, mTOR plays a key role in controlling protein homeostasis and hence brain function; indeed, mTOR activity has been directly linked to learning and memory (10 -13). Additionally, genetic and pharmacological reduction of mTOR activity has been shown to increase the lifespan in different organisms including yeast, Drosophila, and mice (14 -19).mTOR is an inhibitor of macroautophagy, which is a conserved intracellular system designed for the degradation of long-lived proteins and organelles in lysosomes (20 -22). Cumulative evidence suggests that an age-dependent decrease in the autophagy/lysosome system may account for the accumulation of abnormal proteins during aging (23). Macroautophagy (herein referred to as autophagy) is induced when an isolation membrane is generated surrounding cytosolic components, forming an autopha...

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