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

doi:10.1371/JOURNAL.PONE.0009979

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

Journal Article•DOI•

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

Patricia Spilman¹, Natalia Podlutskaya², Matthew J. Hart², Jayanta Debnath³, Olivia Gorostiza¹, Dale E. Bredesen¹, Arlan Richardson², Randy Strong², Veronica Galvan² - Show less +5 more•Institutions (3)

Buck Institute for Research on Aging¹, University of Texas Health Science Center at San Antonio², University of California, San Francisco³

01 Jan 2011-PLOS ONE (Public Library of Science)-Vol. 5, Iss: 4

TL;DR: It is shown that long-term inhibition of mTOR by rapamycin prevented AD-like cognitive deficits and lowered levels of Aβ42, a major toxic species in AD, in the PDAPP transgenic mouse model.

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Abstract: 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.

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Journal Article•DOI•

mTOR Signaling in Growth, Metabolism, and Disease.

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Robert A. Saxton, David M. Sabatini

09 Mar 2017-Cell

TL;DR: Recent advances in understanding of mTOR function, regulation, and importance in mammalian physiology are reviewed and how the mTOR signaling network contributes to human disease is highlighted.

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4,719 citations

Cites background from "Inhibition of mTOR by Rapamycin Abo..."

...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....
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...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,…...
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mTOR Signaling in Growth, Metabolism, and Disease

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Robert A. Saxton, David M. Sabatini

01 Mar 2017

TL;DR: Recent advances in understanding of mTOR function, regulation, and importance in mammalian physiology are reviewed and how the mTOR-signaling network contributes to human disease is highlighted.

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Abstract: The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

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2,014 citations

Cites background from "Inhibition of mTOR by Rapamycin Abo..."

...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…...
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...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....
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Journal Article•DOI•

The role of autophagy in neurodegenerative disease

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Ralph A. Nixon¹•Institutions (1)

Nathan Kline Institute for Psychiatric Research¹

01 Aug 2013-Nature Medicine

TL;DR: An overview of the role of autophagy in neurodegenerative disease is provided, focusing particularly on less frequently considered lysosomal clearance mechanisms and their considerable impact on disease.

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Abstract: This Review provides an overview of the role of autophagy, a key lysosomal degradative process, in neurodegenerative diseases. The study of various neurodegenerative diseases has shown that defects in autophagy can arise at different points in the pathway, and this has implications for the successful modulation of autophagy for therapeutic purposes. The Review also discusses the latest developments in targeting alterations in autophagy as a therapeutic strategy for neurodegenerative diseases.

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1,643 citations

Journal Article•DOI•

mTOR is a key modulator of ageing and age-related disease

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Simon C. Johnson¹, Peter S. Rabinovitch¹, Matt Kaeberlein¹, Matt Kaeberlein²•Institutions (2)

University of Washington¹, Guangdong Medical College²

17 Jan 2013-Nature

TL;DR: Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies in humans.

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Abstract: Many experts in the biology of ageing believe that pharmacological interventions to slow ageing are a matter of 'when' rather than 'if'. A leading target for such interventions is the nutrient response pathway defined by the mechanistic target of rapamycin (mTOR). Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies in humans.

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1,351 citations

Journal Article•DOI•

Ageing as a Risk Factor for Disease

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Teresa Niccoli¹, Linda Partridge²•Institutions (2)

University College London¹, Max Planck Society²

11 Sep 2012-Current Biology

TL;DR: Lowered activity of the nutrient-sensing insulin/insulin-like growth factor/Target of Rapamycin signalling network can extend healthy lifespan in yeast, multicellular invertebrates, mice and, possibly, humans.

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1,134 citations

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References

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Open Access

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Journal Article•DOI•

Developments of a water-maze procedure for studying spatial learning in the rat

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Richard G. M. Morris¹•Institutions (1)

University of St Andrews¹

01 May 1984-Journal of Neuroscience Methods

TL;DR: Developments of an open-field water-maze procedure in which rats learn to escape from opaque water onto a hidden platform are described, suggesting that they may lend themselves to a variety of behavioural investigations, including pharmacological work and studies of cerebral function.

...read moreread less

6,609 citations

"Inhibition of mTOR by Rapamycin Abo..." refers methods in this paper

...At the end of treatment (7 mo), learning and memory were tested using the Morris water maze [11,31,33,34]....
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...The Morris water maze (MWM)[11,31,33] was used to test spatial memory....
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...Behavioral testing The Morris water maze (MWM)[11,31,33] was used to test spatial memory....
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...The procedure described by Morris et al.[33] was followed as described[11,31]....
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Journal Article•DOI•

LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing

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Yukiko Kabeya¹, Noboru Mizushima², Noboru Mizushima¹, Takashi Ueno³, Akitsugu Yamamoto⁴, Takayoshi Kirisako¹, Takayoshi Kirisako⁵, Takeshi Noda⁵, Takeshi Noda¹, Eiki Kominami³, Yoshinori Ohsumi⁵, Yoshinori Ohsumi¹, Tamotsu Yoshimori¹, Tamotsu Yoshimori⁵ - Show less +10 more•Institutions (5)

National Institute for Basic Biology, Japan¹, National Presto Industries², Juntendo University³, Kansai Medical University⁴, Graduate University for Advanced Studies⁵

01 Nov 2000-The EMBO Journal

TL;DR: It is demonstrated that the rat microtubule‐associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing.

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Abstract: Little is known about the protein constituents of autophagosome membranes in mammalian cells. Here we demonstrate that the rat microtubule-associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing. Two forms of LC3, called LC3-I and -II, were produced post-translationally in various cells. LC3-I is cytosolic, whereas LC3-II is membrane bound. The autophagic vacuole fraction prepared from starved rat liver was enriched with LC3-II. Immunoelectron microscopy on LC3 revealed specific labelling of autophagosome membranes in addition to the cytoplasmic labelling. LC3-II was present both inside and outside of autophagosomes. Mutational analyses suggest that LC3-I is formed by the removal of the C-terminal 22 amino acids from newly synthesized LC3, followed by the conversion of a fraction of LC3-I into LC3-II. The amount of LC3-II is correlated with the extent of autophagosome formation. LC3-II is the first mammalian protein identified that specifically associates with autophagosome membranes.

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6,244 citations

"Inhibition of mTOR by Rapamycin Abo..." refers background in this paper

...To determine whether rapamycin treatment affected autophagy in PDAPP brains, we examined LC3-II and b-actin in hippocampus of control- and rapamycin-treated PDAPP mice....
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...Antibodies Antibodies used were: anti-IDE (Abcam, ab32216); anti-NEP (R&D AF1126); anti-APP (CT15 (REF); anti-phospho-p70 (Cell Signaling, #9206); anti-b-actin (Sigma, A3853); anti-LC3 (Novus Biologicals, NB100-2331); anti-p62 (Progen, GP62-C)....
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...LC3-immunoreactive puncta were increased in the projections of hippocampal neurons of rapamycin-treated PDAPP mice (Fig....
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...LC3-II is created during autophagosome formation and is subsequently degraded as autophagosomes mature into autolysosomes....
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...Thus, decreased LC3-II levels may be observed as a consequence of robust induction of autophagic flux[43,44]....
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Journal Article•DOI•

Alzheimer's Disease Is a Synaptic Failure

[...]

Dennis J. Selkoe¹•Institutions (1)

Brigham and Women's Hospital¹

25 Oct 2002-Science

TL;DR: Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.

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Abstract: In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.

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3,941 citations

"Inhibition of mTOR by Rapamycin Abo..." refers background in this paper

...ative disorder in the elderly[8], is currently without effective...
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Journal Article•DOI•

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

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David E. Harrison, Randy Strong¹, Zelton D Sharp¹, James F. Nelson¹, Clinton M. Astle, Kevin Flurkey, Nancy L. Nadon², J. Erby Wilkinson³, Krystyna Frenkel⁴, Christy S. Carter⁵, Christy S. Carter⁶, Marco Pahor⁵, Marco Pahor⁶, Martin A. Javors¹, Elizabeth Fernandez¹, Richard A. Miller³ - Show less +12 more•Institutions (6)

University of Texas Health Science Center at San Antonio¹, National Institutes of Health², University of Michigan³, New York University⁴, Wake Forest University⁵, University of Florida⁶

16 Jul 2009-Nature

TL;DR: It is reported that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age.

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Abstract: Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.

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3,216 citations

"Inhibition of mTOR by Rapamycin Abo..." refers background or methods in this paper

...we fed a rapamycin-supplemented diet identical to the diet that extended lifespan in mice[5] or control chow to groups of PDAPP...
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...Rapamycin treatment Mice were fed chow containing either microencapsulated rapamycin at 2.24 mg/kg or a control diet as described by Harrison et al.[5]....
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...24 mg rapamycin per kg body weight/day[5]....
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...A recent report showed that long-term treatment with rapamycin, an inhibitor of the mTOR pathway[5], or ablation of the mTOR target S6K1[6] extends lifespan in mice, possibly by...
[...]
...A recent report showed that microencapsulated rapamycin, an inhibitor of the mTOR pathway[5], or genetic ablation of the mTOR target S6K1[6] extends lifespan in mice, possibly by...
[...]

Journal Article•DOI•

p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death

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Geir Bjørkøy¹, Trond Lamark¹, Andreas Brech, Heidi Outzen¹, Maria Perander¹, Aud Øvervatn¹, Harald Stenmark, Terje Johansen¹ - Show less +4 more•Institutions (1)

University of Tromsø¹

21 Nov 2005-Journal of Cell Biology

TL;DR: In this article, the polyubiquitin-binding protein p62/SQSTM1 has been shown to be involved in linking polyUBiquitinated protein aggregates to the autophagy machinery.

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Abstract: Autophagic degradation of ubiquitinated protein aggregates is important for cell survival, but it is not known how the autophagic machinery recognizes such aggregates. In this study, we report that polymerization of the polyubiquitin-binding protein p62/SQSTM1 yields protein bodies that either reside free in the cytosol and nucleus or occur within autophagosomes and lysosomal structures. Inhibition of autophagy led to an increase in the size and number of p62 bodies and p62 protein levels. The autophagic marker light chain 3 (LC3) colocalized with p62 bodies and coimmunoprecipitated with p62, suggesting that these two proteins participate in the same complexes. The depletion of p62 inhibited recruitment of LC3 to autophagosomes under starvation conditions. Strikingly, p62 and LC3 formed a shell surrounding aggregates of mutant huntingtin. Reduction of p62 protein levels or interference with p62 function significantly increased cell death that was induced by the expression of mutant huntingtin. We suggest that p62 may, via LC3, be involved in linking polyubiquitinated protein aggregates to the autophagy machinery.

...read moreread less

2,708 citations

"Inhibition of mTOR by Rapamycin Abo..." refers background in this paper

...To determine whether the decreased LC3-II/bactin ratios in hippocampi of rapamycin-treated PDAPP mice resulted from the induction of autophagic flux, we examined LC3 distribution, as well as levels of p62SQSTM, an ubiquitin-binding scaffold protein that is specifically degraded by autophagy[22,45], in hippocampi of control- and rapamycin-treated PDAPP mice....
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...autophagic activity can lead to cell death, increased autophagy has been shown to facilitate the clearance of aggregation-prone proteins such as Ab[20,21,22], pathological prion protein[23,24], and a-synuclein[25], and to promote neuronal survival in a variety...
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