J Korean Med Sci.  2014 Jul;29(7):893-902. 10.3346/jkms.2014.29.7.893.

Diverse Molecular Targets for Therapeutic Strategies in Alzheimer's Disease

• Han SH
• Mook-Jung

• KMID: 1789947
• DOI: http://doi.org/10.3346/jkms.2014.29.7.893

Abstract

Alzheimer's disease (AD) is the most common form of dementia caused by neurodegenerative process and is tightly related to amyloid beta (Abeta) and neurofibrillary tangles. The lack of early diagnostic biomarker and therapeutic remedy hinders the prevention of increasing population of AD patients every year. In spite of accumulated scientific information, numerous clinical trials for candidate drug targets have failed to be preceded into therapeutic development, therefore, AD-related sufferers including patients and caregivers, are desperate to seek the solution. Also, effective AD intervention is desperately needed to reduce AD-related societal threats to public health. In this review, we summarize various drug targets and strategies in recent preclinical studies and clinical trials for AD therapy: Allopathic treatment, immunotherapy, Abeta production/aggregation modulator, tau-targeting therapy and metabolic targeting. Some has already failed in their clinical trials and the others are still in various stages of investigations, both of which give us valuable information for future research in AD therapeutic development.

Keyword

Alzheimer Disease; Amyloid Beta-Peptides; Tau Protein; Immunotherapy; Glucose Metabolism; Aggregation

MeSH Terms

Alzheimer Disease/immunology/pathology/*therapy
Amyloid beta-Peptides/antagonists & inhibitors/immunology/metabolism
Antibodies, Monoclonal/therapeutic use
Brain/metabolism/pathology
Humans
Immunotherapy
N-Methylaspartate/therapeutic use
tau Proteins/antagonists & inhibitors/metabolism
Amyloid beta-Peptides
Antibodies, Monoclonal
N-Methylaspartate
tau Proteins

Figure

• 

  Fig. 1 Diverse AD therapeutic strategies and their example chemicals tested in pre-clinical or clinical studies. APP, Amyloid precursor protein; Aβ, Amyloid β; QC, Glutaminyl cyclase; AchEI, Acetylcholinesterase inhibitors; nAchRc, Nicotinic acetylcholine receptor; 5-HT6 Rc, 5-hydroxytryptamine 6 receptor; NSAIDS, Nonsteroidal anti-inflammatory drugs; O-GlcNAc, O-linked β-N-acetylglucosamine; NButGT, 1, 2-dideoxy-2'-propyl-α-D-glucopyranoso-[2,1-d]-Δ2'-thiazoline; HDAC, Histone deacetylation.

Reference

1. Thies W, Bleiler L. Alzheimer's Association. 2013 Alzheimer's disease facts and figures. Alzheimers Dement. 2013; 9:208–245.

2. Wimo A, Winblad B, Jönsson L. The worldwide societal costs of dementia: estimates for 2009. Alzheimers Dement. 2010; 6:98–103.

3. Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992; 256:184–185.

4. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002; 297:353–356.

5. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011; 10:698–712.

6. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, et al. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999; 286:735–741.

7. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999; 398:513–517.

8. De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998; 391:387–390.

9. Mucke L. Neuroscience: Alzheimer's disease. Nature. 2009; 461:895–897.

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

11. Mandelkow EM, Mandelkow E. Tau in Alzheimer's disease. Trends Cell Biol. 1998; 8:425–427.

12. Geschwind DH. Tau phosphorylation, tangles, and neurodegeneration: the chicken or the egg? Neuron. 2003; 40:457–460.

13. Götz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. 2001; 293:1491–1495.

14. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001; 293:1487–1491.

15. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010; 142:387–397.

16. Buckholtz NS. Perspective: in search of biomarkers. Nature. 2011; 475:S8.

17. Callaway E. Alzheimer's drugs take a new tack. Nature. 2012; 489:13–14.

18. Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension: the Galantamine USA-1 Study Group. Neurology. 2000; 54:2261–2268.

19. Van Dyck CH, Tariot PN, Meyers B, Malca Resnick E. Memantine MEM-MD-01 Study Group. A 24-week randomized, controlled trial of memantine in patients with moderate-to-severe Alzheimer disease. Alzheimer Dis Assoc Disord. 2007; 21:136–143.

20. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004; 291:317–324.

21. Winblad B, Kilander L, Eriksson S, Minthon L, Båtsman S, Wetterholm AL, Jansson-Blixt C, Haglund A. Severe Alzheimer's Disease Study Group. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study. Lancet. 2006; 367:1057–1065.

22. Atri A, Shaughnessy LW, Locascio JJ, Growdon JH. Long-term course and effectiveness of combination therapy in Alzheimer disease. Alzheimer Dis Assoc Disord. 2008; 22:209–221.

23. Lopez OL, Becker JT, Wahed AS, Saxton J, Sweet RA, Wolk DA, Klunk W, Dekosky ST. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009; 80:600–607.

24. Sabbagh MN. Drug development for Alzheimer's disease: where are we now and where are we headed. Am J Geriatr Pharmacother. 2009; 7:167–185.

25. Froestl W, Gallagher M, Jenkins H, Madrid A, Melcher T, Teichman S, Mondadori CG, Pearlman R. SGS742: the first GABA(B) receptor antagonist in clinical trials. Biochem Pharmacol. 2004; 68:1479–1487.

26. Grill JD, Cummings JL. Current therapeutic targets for the treatment of Alzheimer's disease. Expert Rev Neurother. 2010; 10:711–728.

27. Potter A, Corwin J, Lang J, Piasecki M, Lenox R, Newhouse PA. Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer's disease. Psychopharmacology (Berl). 1999; 142:334–342.

28. Arnt J, Bang-Andersen B, Grayson B, Bymaster FP, Cohen MP, DeLapp NW, Giethlen B, Kreilgaard M, McKinzie DL, Neill JC, et al. Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. Int J Neuropsychopharmacol. 2010; 13:1021–1033.

29. DeKosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA, Lopez OL, Burke G, Carlson MC, Fried LP, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA. 2008; 300:2253–2262.

30. Park SJ, Jung HJ, Son MS, Jung JM, Kim DH, Jung IH, Cho YB, Lee EH, Ryu JH. Neuroprotective effects of INM-176 against lipopolysaccharide-induced neuronal injury. Pharmacol Biochem Behav. 2012; 101:427–433.

31. Shi C, Zhao L, Zhu B, Li Q, Yew DT, Yao Z, Xu J. Protective effects of Ginkgo biloba extract (EGb761) and its constituents quercetin and ginkgolide B against beta-amyloid peptide-induced toxicity in SH-SY5Y cells. Chem Biol Interact. 2009; 181:115–123.

32. LaFerla FM, Green KN, Oddo S. Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci. 2007; 8:499–509.

33. Ghosh AK, Gemma S, Tang J. Beta-Secretase as a therapeutic target for Alzheimer's disease. Neurotherapeutics. 2008; 5:399–408.

34. Ghosh AK, Bilcer G, Harwood C, Kawahama R, Shin D, Hussain KA, Hong L, Loy JA, Nguyen C, Koelsch G, et al. Structure-based design: potent inhibitors of human brain memapsin 2 (beta-secretase). J Med Chem. 2001; 44:2865–2868.

35. Ghosh AK, Brindisi M, Tang J. Developing β-secretase inhibitors for treatment of Alzheimer's disease. J Neurochem. 2012; 120:71–83.

36. Sisodia SS, St George-Hyslop PH. Gamma-Secretase, Notch, Abeta and Alzheimer's disease: where do the presenilins fit in? Nat Rev Neurosci. 2002; 3:281–290.

37. Louvi A, Artavanis-Tsakonas S. Notch signalling in vertebrate neural development. Nat Rev Neurosci. 2006; 7:93–102.

38. Henley DB, May PC, Dean RA, Siemers ER. Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer's disease. Expert Opin Pharmacother. 2009; 10:1657–1664.

39. Walsh DM, Selkoe DJ. A beta oligomers - a decade of discovery. J Neurochem. 2007; 101:1172–1184.

40. Glabe CG. Structural classification of toxic amyloid oligomers. J Biol Chem. 2008; 283:29639–29643.

41. Nakagami Y, Nishimura S, Murasugi T, Kaneko I, Meguro M, Marumoto S, Kogen H, Koyama K, Oda T. A novel beta-sheet breaker, RS-0406, reverses amyloid beta-induced cytotoxicity and impairment of long-term potentiation in vitro. Br J Pharmacol. 2002; 137:676–682.

42. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005; 280:5892–5901.

43. McKoy AF, Chen J, Schupbach T, Hecht MH. A novel inhibitor of amyloid β (Aβ) peptide aggregation: from high throughput screening to efficacy in an animal model of Alzheimer disease. J Biol Chem. 2012; 287:38992–39000.

44. Bush AI. Drug development based on the metals hypothesis of Alzheimer's disease. J Alzheimers Dis. 2008; 15:223–240.

45. Faux NG, Ritchie CW, Gunn A, Rembach A, Tsatsanis A, Bedo J, Harrison J, Lannfelt L, Blennow K, Zetterberg H, et al. PBT2 rapidly improves cognition in Alzheimer's disease: additional phase II analyses. J Alzheimers Dis. 2010; 20:509–516.

46. Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E, Cortes M, Volitakis I, Liu X, Smith JP, Perez K, et al. Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron. 2008; 59:43–55.

47. Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ. Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis. 1996; 3:16–32.

48. Saido TC, Yamao-Harigaya W, Iwatsubo T, Kawashima S. Amino- and carboxyl-terminal heterogeneity of beta-amyloid peptides deposited in human brain. Neurosci Lett. 1996; 215:173–176.

49. Kuo YM, Emmerling MR, Woods AS, Cotter RJ, Roher AE. Isolation, chemical characterization, and quantitation of A beta 3-pyroglutamyl peptide from neuritic plaques and vascular amyloid deposits. Biochem Biophys Res Commun. 1997; 237:188–191.

50. Schilling S, Appl T, Hoffmann T, Cynis H, Schulz K, Jagla W, Friedrich D, Wermann M, Buchholz M, Heiser U, et al. Inhibition of glutaminyl cyclase prevents pGlu-Abeta formation after intracortical/hippocampal microinjection in vivo/in situ. J Neurochem. 2008; 106:1225–1236.

51. Schilling S, Hoffmann T, Manhart S, Hoffmann M, Demuth HU. Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions. FEBS Lett. 2004; 563:191–196.

52. Sastre M, Klockgether T, Heneka MT. Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms. Int J Dev Neurosci. 2006; 24:167–176.

53. Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer's disease, role of cytokines. ScientificWorldJournal. 2012; 2012:756357.

54. Weninger SC, Yankner BA. Inflammation and Alzheimer disease: the good, the bad, and the ugly. Nat Med. 2001; 7:527–528.

55. Lambert JC, Grenier-Boley B, Chouraki V, Heath S, Zelenika D, Fievet N, Hannequin D, Pasquier F, Hanon O, Brice A, et al. Implication of the immune system in Alzheimer's disease: evidence from genome-wide pathway analysis. J Alzheimers Dis. 2010; 20:1107–1118.

56. Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology. 2008; 70:1672–1677.

57. Imbimbo BP, Solfrizzi V, Panza F. Are NSAIDs useful to treat Alzheimer's disease or mild cognitive impairment? Front Aging Neurosci. 2010; 2:pii: 19.

58. Szekely CA, Breitner JC, Fitzpatrick AL, Rea TD, Psaty BM, Kuller LH, Zandi PP. NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type. Neurology. 2008; 70:17–24.

59. Szekely CA, Thorne JE, Zandi PP, Ek M, Messias E, Breitner JC, Goodman SN. Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer's disease: a systematic review. Neuroepidemiology. 2004; 23:159–169.

60. Scharf S, Mander A, Ugoni A, Vajda F, Christophidis N. A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's disease. Neurology. 1999; 53:197–201.

61. Reines SA, Block GA, Morris JC, Liu G, Nessly ML, Lines CR, Norman BA, Baranak CC. Rofecoxib Protocol 091 Study Group. Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology. 2004; 62:66–71.

62. Soininen H, West C, Robbins J, Niculescu L. Long-term efficacy and safety of celecoxib in Alzheimer's disease. Dement Geriatr Cogn Disord. 2007; 23:8–21.

63. De Jong D, Jansen R, Hoefnagels W, Jellesma-Eggenkamp M, Verbeek M, Borm G, Kremer B. No effect of one-year treatment with indomethacin on Alzheimer's disease progression: a randomized controlled trial. PLoS One. 2008; 3:e1475.

64. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, Zavitz KH. Tarenflurbil Phase 3 Study Group. 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.

65. Pasqualetti P, Bonomini C, Dal Forno G, Paulon L, Sinforiani E, Marra C, Zanetti O, Rossini PM. A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer's disease. Aging Clin Exp Res. 2009; 21:102–110.

66. Delrieu J, Ousset PJ, Caillaud C, Vellas B. 'Clinical trials in Alzheimer's disease': immunotherapy approaches. J Neurochem. 2012; 120:186–193.

67. Fu HJ, Liu B, Frost JL, Lemere CA. Amyloid-beta immunotherapy for Alzheimer's disease. CNS Neurol Disord Drug Targets. 2010; 9:197–206.

68. Panza F, Frisardi V, Solfrizzi V, Imbimbo BP, Logroscino G, Santamato A, Greco A, Seripa D, Pilotto A. Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based immunization strategies. Immunotherapy. 2012; 4:213–238.

69. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999; 400:173–177.

70. Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE. Amyloid-beta immunization effectively reduces amyloid deposition in FcRgamma-/- knock-out mice. J Neurosci. 2003; 23:8532–8538.

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

72. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001; 98:8850–8855.

73. Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, et al. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci. 2002; 5:452–457.

74. Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003; 61:46–54.

75. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, et al. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008; 372:216–223.

76. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007; 316:750–754.

77. Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005; 309:476–481.

78. Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM. Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron. 2004; 43:321–332.

79. Vogelsberg-Ragaglia V, Schuck T, Trojanowski JQ, Lee VM. PP2A mRNA expression is quantitatively decreased in Alzheimer's disease hippocampus. Exp Neurol. 2001; 168:402–412.

80. Sontag E, Luangpirom A, Hladik C, Mudrak I, Ogris E, Speciale S, White CL 3rd. Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology. J Neuropathol Exp Neurol. 2004; 63:287–301.

81. Schneider A, Mandelkow E. Tau-based treatment strategies in neurodegenerative diseases. Neurotherapeutics. 2008; 5:443–457.

82. Hampel H, Ewers M, Bürger K, Annas P, Mörtberg A, Bogstedt A, Frölich L, Schröder J, Schönknecht P, Riepe MW, et al. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry. 2009; 70:922–931.

83. Tariot PN, Aisen PS. Can lithium or valproate untie tangles in Alzheimer's disease? J Clin Psychiatry. 2009; 70:919–921.

84. Arendash GW, Mori T, Cao C, Mamcarz M, Runfeldt M, Dickson A, Rezai-Zadeh K, Tane J, Citron BA, Lin X, et al. Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice. J Alzheimers Dis. 2009; 17:661–680.

85. Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L, LaFrancois J, Feinstein B, et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A. 2005; 102:6990–6995.

86. Domínguez JM, Fuertes A, Orozco L, del Monte-Millán M, Delgado E, Medina M. Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib. J Biol Chem. 2012; 287:893–904.

87. Eldar-Finkelman H, Martinez A. GSK-3 inhibitors: preclinical and clinical focus on CNS. Front Mol Neurosci. 2011; 4:32.

88. Del Ser T, Steinwachs KC, Gertz HJ, Andrés MV, Gómez-Carrillo B, Medina M, Vericat JA, Redondo P, Fleet D, León T. Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib: a pilot study. J Alzheimers Dis. 2013; 33:205–215.

89. Wischik CM, Harrington CR, Storey JM. Tau-aggregation inhibitor therapy for Alzheimer's disease. Biochem Pharmacol. 2014; 88:529–539.

90. Pickhardt M, Gazova Z, von Bergen M, Khlistunova I, Wang Y, Hascher A, Mandelkow EM, Biernat J, Mandelkow E. Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells. J Biol Chem. 2005; 280:3628–3635.

91. Taniguchi S, Suzuki N, Masuda M, Hisanaga S, Iwatsubo T, Goedert M, Hasegawa M. Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins. J Biol Chem. 2005; 280:7614–7623.

92. Crowe A, Huang W, Ballatore C, Johnson RL, Hogan AM, Huang R, Wichterman J, McCoy J, Huryn D, Auld DS, et al. Identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening. Biochemistry. 2009; 48:7732–7745.

93. Blass JP. Brain metabolism and brain disease: is metabolic deficiency the proximate cause of Alzheimer dementia? J Neurosci Res. 2001; 66:851–856.

94. Blass JP, Gibson GE, Hoyer S. The role of the metabolic lesion in Alzheimer's disease. J Alzheimers Dis. 2002; 4:225–232.

95. Hoyer S. Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease: causes and consequences: an update. Exp Gerontol. 2000; 35:1363–1372.

96. Kurochkin IV, Goto S. Alzheimer's beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett. 1994; 345:33–37.

97. McDermott JR, Gibson AM. Degradation of Alzheimer's beta-amyloid protein by human and rat brain peptidases: involvement of insulin-degrading enzyme. Neurochem Res. 1997; 22:49–56.

98. Sudoh S, Frosch MP, Wolf BA. Differential effects of proteases involved in intracellular degradation of amyloid beta-protein between detergent-soluble and -insoluble pools in CHO-695 cells. Biochemistry. 2002; 41:1091–1099.

99. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003; 100:4162–4167.

100. Vekrellis K, Ye Z, Qiu WQ, Walsh D, Hartley D, Chesneau V, Rosner MR, Selkoe DJ. Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci. 2000; 20:1657–1665.

101. Bosco D, Fava A, Plastino M, Montalcini T, Pujia A. Possible implications of insulin resistance and glucose metabolism in Alzheimer's disease pathogenesis. J Cell Mol Med. 2011; 15:1807–1821.

102. Son SM, Song H, Byun J, Park KS, Jang HC, Park YJ, Mook-Jung I. Accumulation of autophagosomes contributes to enhanced amyloidogenic APP processing under insulin-resistant conditions. Autophagy. 2012; 8:1842–1844.

103. Gupta A, Bisht B, Dey CS. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer's-like changes. Neuropharmacology. 2011; 60:910–920.

104. Colca JR, McDonald WG, Cavey GS, Cole SL, Holewa DD, Brightwell-Conrad AS, Wolfe CL, Wheeler JS, Coulter KR, Kilkuskie PM, et al. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT): relationship to newly identified mitochondrial pyruvate carrier proteins. PLoS One. 2013; 8:e61551.

105. Divakaruni AS, Wiley SE, Rogers GW, Andreyev AY, Petrosyan S, Loviscach M, Wall EA, Yadava N, Heuck AP, Ferrick DA, et al. Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier. Proc Natl Acad Sci U S A. 2013; 110:5422–5427.

106. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, et al. Mitochondrial abnormalities in Alzheimer's disease. J Neurosci. 2001; 21:3017–3023.

107. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH. Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet. 2006; 15:1437–1449.

108. Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, Xu HW, Stern D, McKhann G, Yan SD. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J. 2005; 19:2040–2041.

109. Du H, Guo L, Yan S, Sosunov AA, McKhann GM, Yan SS. Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model. Proc Natl Acad Sci U S A. 2010; 107:18670–18675.

110. Cha MY, Han SH, Son SM, Hong HS, Choi YJ, Byun J, Mook-Jung I. Mitochondria-specific accumulation of amyloid β induces mitochondrial dysfunction leading to apoptotic cell death. PLoS One. 2012; 7:e34929.

111. Correia SC, Santos RX, Carvalho C, Cardoso S, Candeias E, Santos MS, Oliveira CR, Moreira PI. Insulin signaling, glucose metabolism and mitochondria: major players in Alzheimer's disease and diabetes interrelation. Brain Res. 2012; 1441:64–78.

112. Valla J, Schneider L, Niedzielko T, Coon KD, Caselli R, Sabbagh MN, Ahern GL, Baxter L, Alexander G, Walker DG, et al. Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment. Mitochondrion. 2006; 6:323–330.

113. Parihar MS, Brewer GJ. Mitoenergetic failure in Alzheimer disease. Am J Physiol Cell Physiol. 2007; 292:C8–C23.

114. Swerdlow RH. Brain aging, Alzheimer's disease, and mitochondria. Biochim Biophys Acta. 2011; 1812:1630–1639.

115. Bezprozvanny I. The rise and fall of Dimebon. Drug News Perspect. 2010; 23:518–523.

116. Malykh AG, Sadaie MR. Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders. Drugs. 2010; 70:287–312.

117. Leuner K, Kurz C, Guidetti G, Orgogozo JM, Müller WE. Improved mitochondrial function in brain aging and Alzheimer disease - the new mechanism of action of the old metabolic enhancer piracetam. Front Neurosci. 2010; 4:pii: 44.

118. Calkins MJ, Manczak M, Mao P, Shirendeb U, Reddy PH. Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. Hum Mol Genet. 2011; 20:4515–4529.

119. Chen S, Owens GC, Makarenkova H, Edelman DB. HDAC6 regulates mitochondrial transport in hippocampal neurons. PLoS One. 2010; 5:e10848.

120. Kim C, Choi H, Jung ES, Lee W, Oh S, Jeon NL, Mook-Jung I. HDAC6 inhibitor blocks amyloid beta-induced impairment of mitochondrial transport in hippocampal neurons. PLoS One. 2012; 7:e42983.

121. Kim C, Nam DW, Park SY, Song H, Hong HS, Boo JH, Jung ES, Kim Y, Baek JY, Kim KS, et al. O-linked β-N-acetylglucosaminidase inhibitor attenuates β-amyloid plaque and rescues memory impairment. Neurobiol Aging. 2013; 34:275–285.

122. Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer's disease. J Alzheimers Dis. 2006; 9:13–33.

123. Tallent MK, Varghis N, Skorobogatko Y, Hernandez-Cuebas L, Whelan K, Vocadlo DJ, Vosseller K. In vivo modulation of O-GlcNAc levels regulates hippocampal synaptic plasticity through interplay with phosphorylation. J Biol Chem. 2009; 284:174–181.

124. Yuzwa SA, Macauley MS, Heinonen JE, Shan X, Dennis RJ, He Y, Whitworth GE, Stubbs KA, McEachern EJ, Davies GJ. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol. 2008; 4:483–490.

125. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, Szoeke C, Macaulay SL, Martins R, Maruff P, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol. 2013; 12:357–367.