title: Taking aim at Alzheimer's disease through the mammalian target of rapamycin.
abstract: A significant portion of the world's population suffers from sporadic Alzheimer's disease (AD) with available present therapies limited to symptomatic care that does not alter disease progression. Over the next decade, advancing age of the global population will dramatically increase the incidence of AD and severely impact health care resources, necessitating novel, safe, and efficacious strategies for AD. The mammalian target of rapamycin (mTOR) and its protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) offer exciting and unique avenues of intervention for AD through the oversight of programmed cell death pathways of apoptosis, autophagy, and necroptosis. mTOR modulates multi-faceted signal transduction pathways that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), hamartin (tuberous sclerosis 1)/ tuberin (tuberous sclerosis 2) (TSC1/TSC2) complex, proline-rich Akt substrate 40 kDa (PRAS40), and p70 ribosomal S6 kinase (p70S6K) and can interface with the neuroprotective pathways of growth factors, sirtuins, wingless, forkhead transcription factors, and glycogen synthase kinase-3β. With the ability of mTOR to broadly impact cellular function, clinical strategies for AD that implement mTOR must achieve parallel objectives of protecting neuronal, vascular, and immune cell survival in conjunction with preserving networks that determine memory and cognitive function.
authors.affiliation: Cellular and Molecular Signaling , Newark, New Jersey 07101 , USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Maiese
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D017209:Apoptosis; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008568:Memory / Q000502:physiology; D046912:Multiprotein Complexes / Q000378:metabolism; D018384:Oxidative Stress; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: Alzheimer's disease; amyloid; apoptosis; autophagy; mTORC1; mTORC2; mammalian target of rapamycin (mTOR); necroptosis; oxidative stress; rapamycin
references.citation: J Biol Chem. 2014 Feb 28;289(9):5799-808
references.pmid: 24368770
references.citation: Science. 1991 Aug 23;253(5022):905-9
references.pmid: 1715094
references.citation: Brain Res. 2007 Sep 7;1168:97-105
references.pmid: 17706618
references.citation: Int J Mol Sci. 2012 Oct 26;13(11):13830-66
references.pmid: 23203037
references.citation: Curr Neurovasc Res. 2011 Aug 1;8(3):220-35
references.pmid: 21722091
references.citation: Expert Opin Ther Targets. 2012 Dec;16(12):1203-14
references.pmid: 22924465
references.citation: Prog Neurobiol. 2005 Feb;75(3):207-46
references.pmid: 15882775
references.citation: Cancer Res. 2011 May 1;71(9):3246-56
references.pmid: 21430067
references.citation: PLoS One. 2010 Apr 01;5(4):e9979
references.pmid: 20376313
references.citation: J Clin Invest. 2010 Apr;120(4):1310-23
references.pmid: 20200450
references.citation: J Biol Chem. 2005 Nov 18;280(46):38121-4
references.pmid: 16183639
references.citation: Biochem Biophys Res Commun. 2012 Mar 2;419(1):49-53
references.pmid: 22326868
references.citation: Mol Cell Neurosci. 2011 Jun;47(2):145-53
references.pmid: 21463685
references.citation: Int J Mol Med. 2007 Feb;19(2):263-72
references.pmid: 17203200
references.citation: Curr Neurovasc Res. 2006 Feb;3(1):25-39
references.pmid: 16472123
references.citation: Am J Pathol. 2008 Nov;173(5):1488-95
references.pmid: 18818379
references.citation: PLoS One. 2010 Feb 19;5(2):e9313
references.pmid: 20174468
references.citation: Am J Physiol Heart Circ Physiol. 2011 Jun;300(6):H2123-34
references.pmid: 21421816
references.citation: Brain Res. 2013 Aug 14;1526:94-101
references.pmid: 23806777
references.citation: Biochim Biophys Acta. 2010 Jul-Aug;1802(7-8):593-600
references.pmid: 20441792
references.citation: Growth Factors. 2007 Aug;25(4):209-26
references.pmid: 18092230
references.citation: Mol Cell. 2003 Apr;11(4):895-904
references.pmid: 12718876
references.citation: Acta Neuropathol. 2001 Jun;101(6):616-24
references.pmid: 11515791
references.citation: Curr Neurovasc Res. 2011 Nov;8(4):270-85
references.pmid: 22023617
references.citation: Dev Cell. 2006 Dec;11(6):859-71
references.pmid: 17141160
references.citation: J Biol Chem. 2013 May 31;288(22):15556-70
references.pmid: 23585566
references.citation: J Neurosci. 2009 May 27;29(21):6964-72
references.pmid: 19474323
references.citation: Cell. 2014 May 22;157(5):1189-202
references.pmid: 24813850
references.citation: Expert Opin Ther Targets. 2012 Feb;16(2):167-78
references.pmid: 22233091
references.citation: J Neurotrauma. 2012 Mar 20;29(5):946-56
references.pmid: 21806471
references.citation: Gerontology. 2013;59(3):250-60
references.pmid: 23428737
references.citation: Neurobiol Dis. 2014 Jun;66:43-52
references.pmid: 24583056
references.citation: Cell Signal. 2011 Aug;23(8):1311-9
references.pmid: 21426932
references.citation: J Neurochem. 2011 Aug;118(4):460-74
references.pmid: 21623793
references.citation: Curr Neurovasc Res. 2009 Feb;6(1):20-31
references.pmid: 19355923
references.citation: J Proteome Res. 2014 May 2;13(5):2433-44
references.pmid: 24694195
references.citation: Cell Signal. 2012 Jan;24(1):17-24
references.pmid: 21906675
references.citation: Trends Mol Med. 2008 May;14(5):219-27
references.pmid: 18403263
references.citation: Cardiovasc Diabetol. 2012 Oct 15;11:129
references.pmid: 23066908
references.citation: J Alzheimers Dis. 2013;37(3):495-505
references.pmid: 23948902
references.citation: JAMA. 2005 Jan 5;293(1):90-5
references.pmid: 15632341
references.citation: Indian J Med Res. 2013 Feb;137(2):243-6
references.pmid: 23563366
references.citation: Neurotox Res. 2012 Oct;22(3):195-207
references.pmid: 21965004
references.citation: BMC Syst Biol. 2012 May 30;6:52
references.pmid: 22647208
references.citation: Lab Invest. 2010 May;90(5):762-73
references.pmid: 20142804
references.citation: Aging Cell. 2013 Jun;12(3):370-80
references.pmid: 23425014
references.citation: Diabetes. 2012 Feb;61(2):272-80
references.pmid: 22275084
references.citation: Neuropathology. 2014 Feb;34(1):11-8
references.pmid: 23869942
references.citation: PLoS One. 2012;7(5):e35885
references.pmid: 22567115
references.citation: J Neurosci Res. 2011 Nov;89(11):1723-36
references.pmid: 21826702
references.citation: J Neurochem. 2005 Apr;93(1):105-17
references.pmid: 15773910
references.citation: J Neurochem. 2010 Jan;112(2):366-76
references.pmid: 19878437
references.citation: Cell Signal. 2007 Jun;19(6):1150-62
references.pmid: 17289346
references.citation: Neurosci Res. 2012 Jun;73(2):99-105
references.pmid: 22465415
references.citation: Mol Cell Biochem. 2014 Jan;385(1-2):125-32
references.pmid: 24057122
references.citation: J Agric Food Chem. 2012 Feb 1;60(4):1094-101
references.pmid: 22224971
references.citation: Curr Neuropharmacol. 2014 Jan;12(1):2-36
references.pmid: 24533013
references.citation: Paediatr Drugs. 2012 Oct 1;14(5):299-316
references.pmid: 22845486
references.citation: Brain Res. 2014 Jan 13;1542:12-9
references.pmid: 24505621
references.citation: PLoS One. 2012;7(9):e45456
references.pmid: 23029019
references.citation: J Neurochem. 2005 Jul;94(1):215-25
references.pmid: 15953364
references.citation: Curr Neurovasc Res. 2012 Nov;9(4):239-49
references.pmid: 22873724
references.citation: J Biol Chem. 2011 May 27;286(21):18465-73
references.pmid: 21478152
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12469-74
references.pmid: 20616057
references.citation: Mol Cancer Ther. 2014 Mar;13(3):596-605
references.pmid: 24419061
references.citation: J Biol Chem. 2009 May 29;284(22):14693-7
references.pmid: 19346248
references.citation: Expert Rev Neurother. 2013 Jun;13(6):627-38
references.pmid: 23739000
references.citation: Pharmacol Biochem Behav. 2013 May;106:57-67
references.pmid: 23541491
references.citation: Biochim Biophys Acta. 2013 Aug;1833(8):1960-8
references.pmid: 23602701
references.citation: PLoS One. 2013 Oct 04;8(10):e77182
references.pmid: 24124607
references.citation: Cell Signal. 2010 Sep;22(9):1317-29
references.pmid: 20462515
references.citation: Neuropharmacology. 2010 Sep-Oct;59(4-5):323-33
references.pmid: 20167228
references.citation: Neurobiol Learn Mem. 2008 Jul;90(1):28-35
references.pmid: 18316213
references.citation: Mol Cell Biol. 2008 Jun;28(12):4104-15
references.pmid: 18411301
references.citation: Exp Cell Res. 2012 Jan 1;318(1):33-42
references.pmid: 21925170
references.citation: Restor Neurol Neurosci. 2013;31(5):543-55
references.pmid: 23735313
references.citation: Curr Neurovasc Res. 2012 May;9(2):91-101
references.pmid: 22475393
references.citation: Free Radic Res. 2014 Feb;48(2):146-58
references.pmid: 24151909
references.citation: J Neuroinflammation. 2013 Dec 13;10:151
references.pmid: 24330807
references.citation: Circulation. 2002 Dec 3;106(23):2973-9
references.pmid: 12460881
references.citation: Curr Neurovasc Res. 2011 May;8(2):103-20
references.pmid: 21443457
references.citation: Prog Neurobiol. 2012 Nov;99(2):128-48
references.pmid: 22980037
references.citation: J Matern Fetal Neonatal Med. 2012 Apr;25 Suppl 1:30-4
references.pmid: 22385271
references.citation: Br J Pharmacol. 2007 Apr;150(7):839-50
references.pmid: 17339844
references.citation: J Clin Endocrinol Metab. 2009 Oct;94(10):4107-12
references.pmid: 19723757
references.citation: PLoS One. 2012;7(1):e30012
references.pmid: 22253859
references.citation: Pharmacol Res. 2014 Mar;81:54-63
references.pmid: 24602800
references.citation: J Biol Chem. 2006 Jul 7;281(27):18802-15
references.pmid: 16651266
references.citation: Biochem Biophys Res Commun. 2011 Jan 28;404(4):941-5
references.pmid: 21185267
references.citation: Neurosci Lett. 2011 Jan 20;488(2):112-7
references.pmid: 20849920
references.citation: J Cell Physiol. 2014 Aug;229(8):1069-77
references.pmid: 24347388
references.citation: Biochim Biophys Acta. 2002 Jan 30;1542(1-3):41-56
references.pmid: 11853878
references.citation: Science. 2006 May 12;312(5775):927-30
references.pmid: 16690869
references.citation: Cell Cycle. 2012 Nov 1;11(21):3997-4008
references.pmid: 22992618
references.citation: Lancet. 2011 Dec 10;378(9808):2005-2012
references.pmid: 22119496
references.citation: Curr Neurovasc Res. 2013 Feb;10(1):29-38
references.pmid: 23244622
references.citation: J Neurosci. 2007 Jan 24;27(4):893-900
references.pmid: 17251431
references.citation: J Alzheimers Dis. 2012;29(1):89-98
references.pmid: 22214783
references.citation: J Neurosci. 2006 Dec 13;26(50):12977-83
references.pmid: 17167087
references.citation: Mol Cell. 2006 Apr 21;22(2):159-68
references.pmid: 16603397
references.citation: Biochem Pharmacol. 2012 Jan 1;83(1):16-26
references.pmid: 21964343
references.citation: Mol Med Rep. 2013 Oct;8(4):1011-6
references.pmid: 23942837
references.citation: Exp Dermatol. 2013 May;22(5):311-5
references.pmid: 23614736
references.citation: Cogn Behav Neurol. 2007 Sep;20(3):149-56
references.pmid: 17846513
references.citation: Neurosci Lett. 2013 Oct 25;555:7-11
references.pmid: 24036263
references.citation: Neurochem Int. 2013 Mar;62(4):458-67
references.pmid: 23357480
references.citation: Oxid Med Cell Longev. 2009 Nov-Dec;2(5):279-89
references.pmid: 20716915
references.citation: J Neurosci Res. 2009 Aug 1;87(10):2297-307
references.pmid: 19301428
references.citation: J Biol Chem. 2013 Jul 5;288(27):19773-84
references.pmid: 23687303
references.citation: Br J Pharmacol. 2014 Jun;171(11):2739-50
references.pmid: 24547812
references.citation: Trends Mol Med. 2013 Jan;19(1):51-60
references.pmid: 23265840
references.citation: Biochem J. 2011 May 15;436(1):169-79
references.pmid: 21413931
references.citation: Am J Pathol. 2003 Aug;163(2):591-607
references.pmid: 12875979
references.citation: Dement Geriatr Cogn Disord. 2006;22(4):320-6
references.pmid: 16954686
references.citation: J Neurosci. 2013 Aug 7;33(32):13138-49
references.pmid: 23926267
references.citation: N Engl J Med. 2010 Nov 4;363(19):1801-11
references.pmid: 21047224
references.citation: Genes Dev. 2008 Jan 15;22(2):239-51
references.pmid: 18198340
references.citation: Am J Chin Med. 2013;41(6):1329-41
references.pmid: 24228604
references.citation: Mol Cell Biol. 2012 Oct;32(19):4001-11
references.pmid: 22851690
references.citation: PLoS One. 2010 Sep 20;5(9):
references.pmid: 20862226
references.citation: Aging (Albany NY). 2012 Mar;4(3):187-201
references.pmid: 22388478
references.citation: Mol Med Rep. 2013 Nov;8(5):1556-62
references.pmid: 24002737