Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments.

By A. Caccamo, Smita Majumder, Arlan Richardson, R. Strong, S. Oddo. Journal of Biological Chemistry, 2010

771 citations recorded by the source corpus.

Accumulation of amyloid-beta (Abeta) and Tau is an invariant feature of Alzheimer disease (AD). The upstream role of Abeta accumulation in the disease pathogenesis is widely accepted, and there is strong evidence showing that Abeta accumulation causes cognitive impairments. However, the molecular mechanisms linking Abeta to cognitive decline remain to be elucidated. Here we show that the buildup of Abeta increases the mammalian target of rapamycin (mTOR) signaling, whereas decreasing mTOR signaling reduces Abeta levels, thereby highlighting an interrelation between mTOR signaling and Abeta. 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 Abeta and Tau pathology by increasing autophagy. Indeed, we further show that autophagy induction is necessary for the rapamycin-mediated reduction in Abeta levels. The results presented here provide a molecular basis for the Abeta-induced cognitive deficits and, moreover, show that rapamycin, an FDA approved drug, improves learning and memory and reduces Abeta and Tau pathology.

Subfields: Cellular and Molecular Neuroscience, Pharmacology, Physiology

View Paper: https://www.semanticscholar.org/paper/cd2c8120e3bb9fac6e9b5b946e16332acb918db3

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Citations in the corpus

• Mechanisms of Vascular Aging (2018, background): “Consistent with the concept that mTOR regulates fundamental molecular processes of aging, there is growing evidence that attenuating mTOR activity inhibits or delays the pathogenesis of age-associated diseases, including Alzheimer disease.(155,156) There is growing evidence that mTOR inhibition also”
• Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future (2023, background): “Treatment with rapamycin significantly stimulated autophagy associated with markedly reduced both intracellular Aβ and extracellular amyloid deposition in brains as well as improved cognitive deficits in AD mice.(503,504) Mechanism-based therapies to target these pathological processes will have opt”
• The lysosome: from waste bag to potential therapeutic target. (2013, background): “Indeed, the restoration of lysosomal proteolysis and autophagy efficiency in mouse models of Alzheimer’s disease has yielded promising therapeutic effects on neuronal function and cognitive performance (Pickford et al., 2008; Caccamo et al., 2010; Yang et al., 2011; Steele et al., 2012).”