The mammalian target of rapamycin at the crossroad between cognitive aging and Alzheimer’s disease

npj Aging and Mechanisms of Disease

Volumn 1, Issue 1, 2015, Pages

  Talboom, Joshua S ^a   Velazquez, Ramon ^a   Oddo, Salvatore ^a,b  

^a SUN HEALTH RESEARCH INSTITUTE   (United States)

^b UNIVERSITY OF ARIZONA COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 85043635651     PISSN: None     EISSN: 20563973     Source Type: Journal    
DOI: 10.1038/npjamd.2015.8     Document Type: Review

References (95)

1. Vincent GK, Velkoff VA, U.S. Census Bureau. The Next Four Decades: the Older Population in the United States: 2010 to 2050. U.S. Department of Commerce, Economics and Statistics Administration: U.S. Census Bureau, Washington, DC, USA, 2010.
2. Harper S. Economic and social implications of aging societies. Science 2014; 346: 587–591.
3. Lamming DW, Ye L, Sabatini DM, Baur JA. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest 2013; 123: 980–989.
4. Blagosklonny MV. Calorie restriction: decelerating mTOR-driven aging from cells to organisms (including humans). Cell Cycle 2010; 9: 683–688.
5. Holloszy JO, Fontana L. Caloric restriction in humans. Exp Gerontol 2007; 42: 709–712.
6. Lee JH, Tecedor L, Chen YH, Monteys AM, Sowada MJ, Thompson LM et al. Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes. Neuron 2015; 85: 303–315.
7. Bove J, Martinez-Vicente M, Vila M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci 2011; 12: 437–452.
8. Iyer AM, van Scheppingen J, Milenkovic I, Anink JJ, Adle-Biassette H, Kovacs GG et al. mTOR Hyperactivation in down syndrome hippocampus appears early during development. J Neuropathol Exp Neurol 2014; 73: 671–683.
9. Cai Z, Zhao B, Li K, Zhang L, Li C, Quazi SH et al. Mammalian target of rapamycin: a valid therapeutic target through the autophagy pathway for Alzheimer's disease? J Neurosci Res 2012; 90: 1105–1118.
10. Oddo S. The role of mTOR signaling in Alzheimer disease. Front Biosci 2012; 4: 941–952.
11. Wang C, Yu JT, Miao D, Wu ZC, Tan MS, Tan L. Targeting the mTOR signaling network for Alzheimer's disease therapy. Mol Neurobiol 2014; 49: 120–135.
12. Lafay-Chebassier C, Paccalin M, Page G, Barc-Pain S, Perault-Pochat MC, Gil R et al. mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease. J Neurochem 2005; 94: 215–225.
13. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124: 471–484.
14. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature 2013; 493: 338–345.
15. Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev 1999; 13: 1422–1437.
16. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18: 1926–1945.
17. Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 2015; 125: 25–32.
18. Perluigi M, Di Domenico F, Butterfield DA. mTOR signaling in aging and neurodegeneration: At the crossroad between metabolism dysfunction and impairment of autophagy. Neurobiol Dis 2015. e-pub ahead of print19 March 2015.doi: 10.1016/j.nbd.2015.03.014.
19. Wang X, Proud CG. The mTOR pathway in the control of protein synthesis. Physiology (Bethesda) 2006; 21: 362–369.
20. Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 2006; 16: 1865–1870.
21. Graber TE, McCamphill PK, Sossin WS. A recollection of mTOR signaling in learning and memory. Learn Mem 2013; 20: 518–530.
22. Hands SL, Proud CG, Wyttenbach A. mTOR's role in ageing: protein synthesis or autophagy? Aging (Albany NY) 2009; 1: 586–597.
23. Ruvinsky I, Meyuhas O. Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem Sci 2006; 31: 342–348.
24. Klionsky DJ. The autophagy connection. Dev Cell 2010; 19: 11–12.
25. Nixon RA, Yang DS. Autophagy failure in Alzheimer's disease--locating the primary defect. Neurobiol Dis 2011; 43: 38–45.
26. Martinez-Lopez N, Athonvarangkul D, Singh R. Autophagy and aging. Adv Exp Med Biol 2015; 847: 73–87.
27. Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 2010; 90: 1383–1435.
28. Zhang C, Cuervo AM. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 2008; 14: 959–965.
29. Mizushima N, Tsukamoto S, Kuma A. [Autophagy in embryogenesis and cell differentiation]. Tanpakushitsu Kakusan Koso 2008; 53: 2170–2174.
30. Nah J, Yuan J, Jung YK. Autophagy in neurodegenerative diseases: from mechanism to therapeutic approach. Mol Cells 2015; 38: 381–389.
31. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43: 67–93.
32. Jung CH, Ro SH, Cao J, Otto NM, Kim DH. mTOR regulation of autophagy. FEBS Lett 2010; 584: 1287–1295.
33. Noda NN, Inagaki F. Mechanisms of Autophagy. Annu Rev Biophys 2015; 44: 101–122.
34. Rubinsztein DC, Marino G, Kroemer G. Autophagy and aging. Cell 2011; 146: 682–695.
35. Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD. Regulation of longevity and stress resistance by Sch9 in yeast. Science 2001; 292: 288–290.
36. Jia K, Chen D, Riddle DL. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 2004; 131: 3897–3906.
37. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 2003; 426: 620.
38. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 2004; 14: 885–890.
39. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009; 460: 392–395.
40. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 2009; 326: 140–144.
41. Wu JJ, Liu J, Chen EB, Wang JJ, Cao L, Narayan N et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep 2013; 4: 913–920.
42. Montagne J, Stewart MJ, Stocker H, Hafen E, Kozma SC, Thomas G. Drosophila S6 kinase: a regulator of cell size. Science 1999; 285: 2126–2129.
43. Oldham S, Montagne J, Radimerski T, Thomas G, Hafen E. Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. Genes Dev 2000; 14: 2689–2694.
44. Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 2004; 24: 6710–6718.
45. Richardson A, Galvan V, Lin AL, Oddo S. How longevity research can lead to therapies for Alzheimer's disease: The rapamycin story. Exp Gerontol 2014; 68: 51–58.
46. Li CY, Li X, Liu SF, Qu WS, Wang W, Tian DS. Inhibition of mTOR pathway restrains astrocyte proliferation, migration and production of inflammatory mediators after oxygen-glucose deprivation and reoxygenation. Neurochem Int 2015; 83-84: 9–18.
47. Meijer AJ, Lorin S, Blommaart EF, Codogno P. Regulation of autophagy by amino acids and MTOR-dependent signal transduction. Amino Acids 2014; 47: 2037–2063.
48. Tang SJ, Reis G, Kang H, Gingras AC, Sonenberg N, Schuman EM. A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc Natl Acad Sci USA 2002; 99: 467–472.
49. Cammalleri M, Lutjens R, Berton F, King AR, Simpson C, Francesconi W et al. Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1. Proc Natl Acad Sci USA 2003; 100: 14368–14373.
50. Huang W, Zhu PJ, Zhang S, Zhou H, Stoica L, Galiano M et al. mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat Neurosci 2013; 16: 441–448.
51. Ehninger D, de Vries PJ, Silva AJ. From mTOR to cognition: molecular and cellular mechanisms of cognitive impairments in tuberous sclerosis. J Intellect Disabil Res 2009; 53: 838–851.
52. Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ et al. Reversal of learning deficits in a Tsc2+/ − mouse model of tuberous sclerosis. Nat Med 2008; 14: 843–848.
53. Costa-Mattioli M, Monteggia LM. mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat Neurosci 2013; 16: 1537–1543.
54. Ricciardi S, Boggio EM, Grosso S, Lonetti G, Forlani G, Stefanelli G et al. Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum Mol Genet 2011; 20: 1182–1196.
55. Troca-Marin JA, Alves-Sampaio A, Montesinos ML. Deregulated mTOR-mediated translation in intellectual disability. Prog Neurobiol 2012; 96: 268–282.
56. Majumder S, Caccamo A, Medina DX, Benavides AD, Javors MA, Kraig E et al. Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1beta and enhancing NMDA signaling. Aging Cell 2012; 11: 326–335.
57. Halloran J, Hussong SA, Burbank R, Podlutskaya N, Fischer KE, Sloane LB et al. Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience 2012; 223: 102–113.
58. Kolosova NG, Vitovtov AO, Muraleva NA, Akulov AE, Stefanova NA, Blagosklonny MV. Rapamycin suppresses brain aging in senescence-accelerated OXYS rats. Aging (Albany NY) 2013; 5: 474–484.
59. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med 2010; 362: 329–344.
60. Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat Rev Neurosci 2007; 8: 663–672.
61. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986; 83: 4913–4917.
62. Ihara Y, Nukina N, Miura R, Ogawara M. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J Biochem 1986; 99: 1807–1810.
63. Kosik KS, Joachim CL, Selkoe DJ. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci USA 1986; 83: 4044–4048.
64. Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci USA 1988; 85: 4051–4055.
65. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998; 393: 702–705.
66. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 1998; 95: 7737–7741.
67. Godoy JA, Rios JA, Zolezzi JM, Braidy N, Inestrosa NC. Signaling pathway cross talk in Alzheimer's disease. Cell Commun Signal 2014; 12: 23.
68. Zhou XW, Tanila H, Pei JJ. Parallel increase in p70 kinase activation and tau phosphorylation (S262) with Abeta overproduction. FEBS Lett 2008; 582: 159–164.
69. Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem 2010; 285: 13107–13120.
70. Koo EH, Squazzo SL. Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J Biol Chem 1994; 269: 17386–17389.
71. Caccamo A, Maldonado MA, Majumder S, Medina DX, Holbein W, Magri A et al. Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism. J Biol Chem 2011; 286: 8924–8932.
72. Ma T, Hoeffer CA, Capetillo-Zarate E, Yu F, Wong H, Lin MT et al. Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease. PLoS ONE 2010; 5.
73. An WL, Cowburn RF, Li L, Braak H, Alafuzoff I, Iqbal K et al. Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease. Am J Pathol 2003; 163: 591–607.
74. Chang RC, Wong AK, Ng HK, Hugon J. Phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) is associated with neuronal degeneration in Alzheimer's disease. Neuroreport 2002; 13: 2429–2432.
75. Griffin RJ, Moloney A, Kelliher M, Johnston JA, Ravid R, Dockery P et al. Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology. J Neurochem 2005; 93: 105–117.
76. Onuki R, Bando Y, Suyama E, Katayama T, Kawasaki H, Baba T et al. An RNA-dependent protein kinase is involved in tunicamycin-induced apoptosis and Alzheimer's disease. EMBO J 2004; 23: 959–968.
77. Pei JJ, Bjorkdahl C, Zhang H, Zhou X, Winblad B. p70 S6 kinase and tau in Alzheimer's disease. J Alzheimers Dis 2008; 14: 385–392.
78. Tramutola A, Triplett JC, Di Domenico F, Niedowicz DM, Murphy MP, Coccia R et al. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD. J Neurochem 2015; 133: 739–749.
79. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS ONE 2010; 5: e9979.
80. Jiang T, Yu JT, Zhu XC, Tan MS, Wang HF, Cao L et al. Temsirolimus promotes autophagic clearance of amyloid-beta and provides protective effects in cellular and animal models of Alzheimer's disease. Pharmacol Res 2014; 81: 54–63.
81. Majumder S, Richardson A, Strong R, Oddo S. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS ONE 2011; 6: e25416.
82. Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH et al. Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol 2005; 171: 87–98.
83. Boland B, Kumar A, Lee S, Platt FM, Wegiel J, Yu WH et al. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J Neurosci 2008; 28: 6926–6937.
84. Caccamo A, De Pinto V, Messina A, Branca C, Oddo S. Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer's disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature. J Neurosci 2014; 34: 7988–7998.
85. Khurana V, Lu Y, Steinhilb ML, Oldham S, Shulman JM, Feany MB. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr Biol 2006; 16: 230–241.
86. Steinhilb ML, Dias-Santagata D, Fulga TA, Felch DL, Feany MB. Tau phosphorylation sites work in concert to promote neurotoxicity in vivo. Mol Biol Cell 2007; 18: 5060–5068.
87. Caccamo A, Magri A, Medina DX, Wisely EV, Lopez-Aranda MF, Silva AJ et al. mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies. Aging Cell 2013; 12: 370–380.
88. Frederick C, Ando K, Leroy K, Heraud C, Suain V, Buee L et al. Rapamycin Ester Analog CCI-779/Temsirolimus Alleviates Tau Pathology and Improves Motor Deficit in Mutant Tau Transgenic Mice. J Alzheimers Dis 2014; 44: 1145–1156.
89. Lee MJ, Lee JH, Rubinsztein DC. Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. Prog Neurobiol 2013; 105: 49–59.
90. Wang Y, Mandelkow E. Degradation of tau protein by autophagy and proteaso-mal pathways. Biochem Soc Trans 2012; 40: 644–652.
91. Morita T, Sobue K. Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway. J Biol Chem 2009; 284: 27734–27745.
92. Pei JJ, An WL, Zhou XW, Nishimura T, Norberg J, Benedikz E et al. P70 S6 kinase mediates tau phosphorylation and synthesis. FEBS Lett 2006; 580: 107–114.
93. Tang Z, Bereczki E, Zhang H, Wang S, Li C, Ji X et al. Mammalian target of rapamycin (mTor) mediates tau protein dyshomeostasis: implication for Alzheimer disease. J Biol Chem 2013; 288: 15556–15570.
94. Tang Z, Ioja E, Bereczki E, Hultenby K, Li C, Guan Z et al. mTor mediates tau localization and secretion: Implication for Alzheimer's disease. Biochim Biophys Acta 2015; 1853: 1646–1657.
95. Liu C, Gotz J. How it all started: tau and protein phosphatase 2A. J Alzheimers Dis 2013; 37: 483–494.