Hanyang Med Rev.  2017 May;37(1):18-24. 10.7599/hmr.2017.37.1.18.

The role of PI3K/AKT pathway and its therapeutic possibility in Alzheimer's disease

• Yu HJ
• Koh SH

• KMID: 2384003
• DOI: http://doi.org/10.7599/hmr.2017.37.1.18

Abstract

Alzheimer's disease (AD) is the most common form of dementia. Although uncountable clinical trials have been done to develop the treatment of AD, there are a couple of drugs that can be used only for symptomatic treatment. Therefore, many studies based on the amyloid cascade hypothesis and the tauopathy hypothesis are still ongoing. After the failure of numerous huge Phase III clinical trials, arguments on those hypotheses have arisen and efforts to establish other possible therapeutic strategies based on diverse plausible mechanisms associated with AD have been done as well. One of the new therapeutic targets for AD is the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. In this review, questions on the two hypotheses, the definition of the PI3K/AKT pathway, the relationship between the pathway and AD, and the possibility of the modulation of the pathway as a new therapeutic strategy for AD will be discussed briefly.

Keyword

Alzheimer's disease; Phosphatidylinositol 3-kinase; AKT; Amyloid beta; Tau

MeSH Terms

Alzheimer Disease*
Amyloid
Dementia
Phosphatidylinositol 3-Kinase
Tauopathies
Amyloid
Phosphatidylinositol 3-Kinase

Reference

1. Hampel H, Prvulovic D, Teipel S, Jessen F, Luckhaus C, Frolich L, et al. The future of Alzheimer's disease: the next 10 years. Prog Neurobiol. 2011; 95:718–728.

2. Wimo A, Jonsson L, Bond J, Prince M, Winblad B. Alzheimer Disease International. The worldwide economic impact of dementia 2010. Alzheimers Dement. 2013; 9:1–11.e3.

3. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet. 2011; 377:1019–1031.

4. Reitz C, Mayeux R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol. 2014; 88:640–651.

5. Wong CW, Quaranta V, Glenner GG. Neuritic plaques and cerebrovascular amyloid in Alzheimer disease are antigenically related. Proc Natl Acad Sci U S A. 1985; 82:8729–8732.

6. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987; 325:733–736.

7. Roberts GW. Immunocytochemistry of neurofibrillary tangles in dementia pugilistica and Alzheimer's disease: evidence for common genesis. Lancet. 1988; 2:1456–1458.

8. Vanhanen M, Koivisto K, Moilanen L, Helkala EL, Hanninen T, Soininen H, et al. Association of metabolic syndrome with Alzheimer disease: a population-based study. Neurology. 2006; 67:843–847.

9. Razay G, Vreugdenhil A, Wilcock G. The metabolic syndrome and Alzheimer disease. Arch Neurol. 2007; 64:93–96.

10. Kim YS, Yoo A, Son JW, Kim HY, Lee YJ, Hwang S, et al. Early Activation of Phosphatidylinositol 3-Kinase after Ischemic Stroke Reduces Infarct Volume and Improves Long-Term Behavior. Mol Neurobiol. 2016.

11. Koh SH, Lo EH. The Role of the PI3K Pathway in the Regeneration of the Damaged Brain by Neural Stem Cells after Cerebral Infarction. J Clin Neurol. 2015; 11:297–304.

12. Noh MY, Kim YS, Lee KY, Lee YJ, Kim SH, Yu HJ, et al. The early activation of PI3K strongly enhances the resistance of cortical neurons to hypoxic injury via the activation of downstream targets of the PI3K pathway and the normalization of the levels of PARP activity, ATP, and NAD(+). Mol Neurobiol. 2013; 47:757–769.

13. Lee SH, Choi NY, Yu HJ, Park J, Choi H, Lee KY, et al. Atorvastatin Protects NSC-34 Motor Neurons Against Oxidative Stress by Activating PI3K, ERK and Free Radical Scavenging. Mol Neurobiol. 2016; 53:695–705.

14. Choi H, Park HH, Lee KY, Choi NY, Yu HJ, Lee YJ, et al. Coenzyme Q10 restores amyloid beta-inhibited proliferation of neural stem cells by activating the PI3K pathway. Stem Cells Dev. 2013; 22:2112–2120.

15. Choi H, Park HH, Koh SH, Choi NY, Yu HJ, Park J, et al. Coenzyme Q10 protects against amyloid beta-induced neuronal cell death by inhibiting oxidative stress and activating the P13K pathway. Neurotoxicology. 2012; 33:85–90.

16. Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci. 1991; 12:383–388.

17. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996; 274:99–102.

18. Tanzi RE, Bertram L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell. 2005; 120:545–555.

19. Caricasole A, Copani A, Caruso A, Caraci F, Iacovelli L, Sortino MA, et al. The Wnt pathway, cell-cycle activation and beta-amyloid: novel therapeutic strategies in Alzheimer's disease? Trends Pharmacol Sci. 2003; 24:233–238.

20. Xie L, Helmerhorst E, Taddei K, Plewright B, Van Bronswijk W, Martins R. Alzheimer's beta-amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci. 2002; 22:RC221.

21. Kim JW, Lee JE, Kim MJ, Cho EG, Cho SG, Choi EJ. Glycogen synthase kinase 3 beta is a natural activator of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1). J Biol Chem. 2003; 278:13995–14001.

22. Bamberger ME, Landreth GE. Microglial interaction with beta-amyloid: implications for the pathogenesis of Alzheimer's disease. Microsc Res Tech. 2001; 54:59–70.

23. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008; 14:837–842.

24. Bloom GS, Ren K, Glabe CG. Cultured cell and transgenic mouse models for tau pathology linked to beta-amyloid. Biochim Biophys Acta. 2005; 1739:116–124.

25. McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, et al. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol. 1999; 46:860–866.

26. Sakono M, Zako T. Amyloid oligomers: formation and toxicity of Abeta oligomers. FEBS J. 2010; 277:1348–1358.

27. Koh SH, Noh MY, Kim SH. Amyloid-beta-induced neurotoxicity is reduced by inhibition of glycogen synthase kinase-3. Brain Res. 2008; 1188:254–262.

28. Siemers ER, Sundell KL, Carlson C, Case M, Sethuraman G, Liu-Seifert H, et al. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients. Alzheimers Dement. 2016; 12:110–120.

29. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014; 370:311–321.

30. Leyhe T, Andreasen N, Simeoni M, Reich A, von Arnim CA, Tong X, et al. Modulation of beta-amyloid by a single dose of GSK933776 in patients with mild Alzheimer's disease: a phase I study. Alzheimers Res Ther. 2014; 6:19.

31. Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR, Jenkins L, et al. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology. 2005; 64:94–101.

32. Vandenberghe R, Rinne JO, Boada M, Katayama S, Scheltens P, Vellas B, et al. Bapineuzumab for mild to moderate Alzheimer's disease in two global, randomized, phase 3 trials. Alzheimers Res Ther. 2016; 8:18.

33. Aisen PS, Gauthier S, Ferris SH, Saumier D, Haine D, Garceau D, et al. Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci. 2011; 7:102–111.

34. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009; 302:2557–2564.

35. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med. 2013; 369:341–350.

36. Coric V, Salloway S, van Dyck CH, Dubois B, Andreasen N, Brody M, et al. Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial. JAMA Neurol. 2015; 72:1324–1333.

37. Dodel R, Rominger A, Bartenstein P, Barkhof F, Blennow K, Forster S, et al. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol. 2013; 12:233–243.

38. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. 1992; 42:631–639.

39. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A. 1975; 72:1858–1862.

40. Cleveland DW, Hwo SY, Kirschner MW. Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol. 1977; 116:207–225.

41. Iqbal K, Liu F, Gong CX, Grundke-Iqbal I. Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res. 2010; 7:656–664.

42. Alonso AC, Li B, Grundke-Iqbal I, Iqbal K. Mechanism of tau-induced neurodegeneration in Alzheimer disease and related tauopathies. Curr Alzheimer Res. 2008; 5:375–384.

43. Wischik CM, Staff RT, Wischik DJ, Bentham P, Murray AD, Storey JM, et al. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease. J Alzheimers Dis. 2015; 44:705–720.

44. Lovestone S, Boada M, Dubois B, Hull M, Rinne JO, Huppertz HJ, et al. A phase II trial of tideglusib in Alzheimer's disease. J Alzheimers Dis. 2015; 45:75–88.

45. Feldman HH, Doody RS, Kivipelto M, Sparks DL, Waters DD, Jones RW, et al. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2010; 74:956–964.

46. Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, et al. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011; 77:556–563.

47. Group AR, Meinert CL, McCaffrey LD, Breitner JC. Alzheimer's Disease Anti-inflammatory Prevention Trial: design, methods, and baseline results. Alzheimers Dement. 2009; 5:93–104.

48. Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, Irizarry M, et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord. 2010; 30:131–146.

49. Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis. 2004; 9:667–676.

50. Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 2005; 9:59–71.

51. Plyte SE, Hughes K, Nikolakaki E, Pulverer BJ, Woodgett JR. Glycogen synthase kinase-3: functions in oncogenesis and development. Biochim Biophys Acta. 1992; 1114:147–162.

52. Lipton JO, Sahin M. The neurology of mTOR. Neuron. 2014; 84:275–291.

53. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011; 12:21–35.

54. Park HH, Lee KY, Kim S, Lee JW, Choi NY, Lee EH, et al. Novel vaccine peptide GV1001 effectively blocks beta-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase. Neurobiol Aging. 2014; 35:1255–1274.

55. Kitagishi Y, Nakanishi A, Ogura Y, Matsuda S. Dietary regulation of PI3K/AKT/GSK-3beta pathway in Alzheimer's disease. Alzheimers Res Ther. 2014; 6:35.

56. Lee HK, Kumar P, Fu Q, Rosen KM, Querfurth HW. The insulin/Akt signaling pathway is targeted by intracellular beta-amyloid. Mol Biol Cell. 2009; 20:1533–1544.

57. Mercado-Gomez O, Hernandez-Fonseca K, Villavicencio-Queijeiro A, Massieu L, Chimal-Monroy J, Arias C. Inhibition of Wnt and PI3K signaling modulates GSK-3beta activity and induces morphological changes in cortical neurons: role of tau phosphorylation. Neurochem Res. 2008; 33:1599–1609.

58. Embi N, Rylatt DB, Cohen P. Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem. 1980; 107:519–527.

59. Hanger DP, Noble W. Functional implications of glycogen synthase kinase-3-mediated tau phosphorylation. Int J Alzheimers Dis. 2011; 2011:352805.

60. Selkoe DJ. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res. 2008; 192:106–113.

61. 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.

62. Zhang F, Beharry ZM, Harris TE, Lilly MB, Smith CD, Mahajan S, et al. PIM1 protein kinase regulates PRAS40 phosphorylation and mTOR activity in FDCP1 cells. Cancer Biol Ther. 2009; 8:846–853.

63. 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.

64. 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.

65. Pei JJ, Hugon J. mTOR-dependent signalling in Alzheimer's disease. J Cell Mol Med. 2008; 12:2525–2532.

66. 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.

67. Noh MY, Koh SH, Kim SM, Maurice T, Ku SK, Kim SH. Neuroprotective effects of donepezil against Abeta42-induced neuronal toxicity are mediated through not only enhancing PP2A activity but also regulating GSK-3beta and nAChRs activity. J Neurochem. 2013; 127:562–574.