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

By P. Spilman, N. Podlutskaya, M. Hart, Jayanta Debnath, Olivia F. Gorostiza, D. Bredesen, Arlan Richardson, R. Strong, V. Galvan. PLoS ONE, 2010

996 citations recorded by the source corpus.

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.

Subfields: Aging, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/4518d54abaa95ea4c639be694c4b58c7a291668e

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Citations in the corpus

Mitophagy and Alzheimer’s disease: cellular and molecular mechanisms (2017, background): “These include the bioenergetic challenges of fasting, caloric restriction and exercise [29] and agents that inhibit the mTOR pathway including rapamycin [30] and the mitochondrial uncoupler 2,4-dinitrophenol [31].”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “Inhibiting mTOR signaling has beneficial effects on mouse models of AD (Spilman et al., 2010), and it remains to be seen whether similar results will be seen in humans.”
Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, positive): “…CMA degrades regulator of calcineurin-1 (RCAN1) (Liu et al., 2009) CMA degrades Tau proteins (Wang, 2009) Raprmycin (Mendelsohn and Larrick, 2011; Spilman et al., 2010) Resveratrol (Kim et al., 2007; Vingtdeux et al., 2011) Nicotinamide (Liu et al., 2013a) Latrepirdine (Steele and Gandy, 2013)…”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “Inhibiting mTOR signaling has beneficial effects on mouse models of AD (Spilman et al., 2010), and it remains to be seen whether similar results will be seen in humans. mTOR in Cancer As discussed above, mTORC1 functions as a downstream effector for many frequently mutated oncogenic pathways…”
Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. (2011, background): “Each study found that rapamycin rescued memory deficits and slowed pathological manifestations in these neurodegenerative models (48,49).”
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “193 Rapamycin is used in clinical settings and has shown promising effectiveness against AD and emerged as a potential therapeutics.”