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CNS Drugs

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01-12-2005 | Leading Article

The Development of Anti-Amyloid Therapy for Alzheimer’s Disease

From Secretase Modulators to Polymerisation Inhibitors

Author: Dr Paul S. Aisen

Published in: CNS Drugs | Issue 12/2005

Abstract

The leading hypothesis of the pathophysiology of Alzheimer’s disease holds that the pivotal event is cleavage of the amyloid precursor protein to release intact the 42-amino-acid amyloid-β peptide (Aβ); this hypothesis best explains the known genetic causes of Alzheimer’s disease. If this theory is correct, optimal strategies for altering the disease process should be directed toward modifying the generation, clearance and/or toxicity of Aβ. Aβ is highly aggregable, spontaneously assuming a β-sheet conformation and polymerising into oligomers, protofibrils, fibrils and plaques. The relative contribution of the various forms of Aβ to neuronal dysfunction in Alzheimer’s disease remains uncertain; however, recent evidence implicates diffusible oligomeric species.

This article reviews the range of strategies that have been investigated to target Aβ to slow the progression of Alzheimer’s disease, from secretase modulators to anti-polymerisation agents. One amyloid-binding drug, tramiprosate (3-amino-1-propanesulfonic acid; Alzhemed™), which is effective in reducing polymerisation in vitro and plaque deposition in animals, has now reached phase III clinical trials. Thus, it is plausible that an effective anti-amyloid strategy will become available for the treatment of Alzheimer’s disease within the next few years.

1. The use of trade names is for product identifcation purposes only and does not imply endorsement.

Cummings JL. Alzheimer’s disease. N Engl J Med 2004; 351: 56–67PubMedCrossRef

Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003; 348: 1333–41PubMedCrossRef

Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004; 291: 317–24PubMedCrossRef

Selkoe DJ. Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci 2000; 924: 17–25

Petkova AT, Ishii Y, Baibach JJ, et al. A structural model for Alzheimer’s beta -amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci U S A 2002; 99: 16742–7PubMedCrossRef

Iqbal K, Alonso Adel C, El-Akkad E, et al. Alzheimer neurofibrillary degeneration: therapeutic targets and high-throughput assays. J Mol Neurosci 2003; 20: 425–9PubMedCrossRef

Samuel W, Terry RD, DeTeresa R, et al. Clinical correlates of cortical and nucleus basalis pathology in Alzheimer dementia. Arch Neurol 1994; 51: 772–8PubMedCrossRef

Naslund J, Haroutunian V, Mohs R, et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 2000; 283: 1571–7PubMedCrossRef

Nash JM. Alzheimer’s disease: new insights into its cause lead to new drug strategies. Time 2001; 157: 80–81, 85PubMed

10.

Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001; 81: 741–66PubMed

11.

Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002; 297: 353–6PubMedCrossRef

12.

Lippa CF, Saunders AM, Smith TW, et al. Familial and sporadic Alzheimer’s disease: neuropathology cannot exclude a final common pathway. Neurology 1996; 46: 406–12PubMedCrossRef

13.

Scheuner D, Eckman C, Jensen M, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 1996; 2: 864–70PubMedCrossRef

14.

Smith MA, Drew KL, Nunomura A, et al. Amyloid-beta, tau alterations and mitochondrial dysfunction in Alzheimer disease: the chickens or the eggs? Neurochem Int 2002; 40: 527–31PubMedCrossRef

15.

Davies P. A very incomplete comprehensive theory of Alzheimer’s disease. Ann N Y Acad Sci 2000; 924: 8–16PubMedCrossRef

16.

Oddo S, Billings L, Kesslak JP, et al. Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 2004; 43: 321–32PubMedCrossRef

17.

Lopez-Toledano MA, Shelanski ML. Neurogenic effect of beta-amyloid peptide in the development of neural stem cells. J Neurosci 2004; 24: 5439–44PubMedCrossRef

18.

Takasugi N, Tomita T, Hayashi I, et al. The role of presenilin cofactors in the gamma-secretase complex. Nature 2003; 422: 438–41PubMedCrossRef

19.

Citron M. Strategies for disease modification in Alzheimer’s disease. Nat Rev Neurosci 2004; 5: 677–85PubMedCrossRef

20.

De Strooper B, Annaert W, Cupers P, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 1999; 398: 518–22PubMedCrossRef

21.

Milano J, McKay J, Dagenais C, et al. Modulation of Notch Processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 2004; 82: 341–58PubMedCrossRef

22.

Beher D, Clarke EE, Wrigley JD, et al. Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site: evidence for an allosteric mechanism. J Biol Chem 2004; 279: 43419–26PubMedCrossRef

23.

Netzer WJ, Dou F, Cai D, et al. Gleevec inhibits beta-amyloid production but not Notch cleavage. Proc Natl Acad Sci U S A 2003; 100: 12444–9PubMedCrossRef

24.

Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001; 414: 212–6PubMedCrossRef

25.

Barten DM, Guss VL, Corsa JA, et al. Dynamics of ta-amyloid reductions in brain, cerebrospinal fluid and plasma of ta-amyloid precursor protein transgenic mice treated with a gamma-secretase inhibitor. J Pharmacol Exp Ther 2005 Feb; 312(2): 635–43PubMedCrossRef

26.

Siemers E, Skinner M, Dean RA, et al. Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitors in volunteers. Clin Neuropharmacol 2005; 28: 126–32PubMedCrossRef

27.

Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 1999; 402: 533–7PubMedCrossRef

28.

Vassar R, Bennett BD, Babu-Khan S, et al. beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286: 735–41PubMedCrossRef

29.

Sinha S, Anderson JP, Barbour R, et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999; 402: 537–40PubMedCrossRef

30.

Hussain I, Powell D, Howlett DR, et al. Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 1999; 14: 419–27PubMedCrossRef

31.

Hong L, Koelsch G, Lin X, et al. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 2000; 290: 150–3PubMedCrossRef

32.

Roberds SL, Anderson J, Basi G, et al. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet 2001; 10: 1317–24PubMedCrossRef

33.

Luo Y, Bolon B, Kahn S, et al. Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 2001; 4: 231–2PubMedCrossRef

34.

Chang WP, Koelsch G, Wong S, et al. In vivo inhibition of A beta production by memopsin 2 (beta-secretase) inhibitors. J Neurochem 2004; 89: 1409–16PubMedCrossRef

35.

Stachel SJ, Coburn CA, Steele TG, et al. Structure-based design of potent and selective ceel-permeable inhibitors of human beta-secretase (BACE-1). J Med Chem 2004; 47: 6447–50PubMedCrossRef

36.

Blumberg PM. Protein kinase C as the receptor for the phorbol ester tumor promoters. Cancer Res 1988; 48: 1–8PubMed

37.

Etcheberrigaray R, Tan M, Dewachter I, et al. Therapeutic effects of PKC activators in Alzheimer’s disease transgenic mice. Proc Natl Acad Sci U S A 2004; 101: 11141–6PubMedCrossRef

38.

Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400: 173–7PubMedCrossRef

39.

Bard F, Barbour R, Cannon C, et al. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer’s disease-like neuropathology. Proc Natl Acad Sci U S A 2003; 100: 2023–8PubMedCrossRef

40.

Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003; 61: 46–54PubMedCrossRef

41.

Nicoll JA, Wilkinson D, Holmes C, et al. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003; 9: 448–52PubMedCrossRef

42.

Gilman S, Koller M, Black RS, et al. Clinical effects of A beta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005; 10: 1553–62CrossRef

43.

Bacskai BJ, Kajdasz ST, McLellan ME, et al. Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J Neurosci 2002; 22: 7873–8PubMed

44.

DeMattos RB, Bales KR, Cummins DJ, et al. Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 2002; 295: 2264–7PubMedCrossRef

45.

Lemere CA, Spooner ET, LaFrancois J, et al. Evidence for peripheral clearance of cerebral Abeta protein following chronic, active Abeta immunization in PSAPP mice. Neurobiol Dis 2003; 14: 10–8PubMedCrossRef

46.

Matsuoka Y, Saito M, LaFrancois J, et al. Novel therapeutic approach for the treatment of Alzheimer’s disease by peripheral administration of agents with an affinity to beta-amyloid. J Neurosci 2003; 23: 29–33PubMed

47.

Ye C, Walsh DM, Selkoe DJ, et al. Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state: N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activation. Neurosci Lett 2004; 366: 320–5PubMedCrossRef

48.

Walsh DM, Klyubin I, Fadeeva JV, et al. Amyloid-beta oligomers: their production, toxicity and therapeutic inhibition. Biochem Soc Trans 2002; 30: 552–7PubMedCrossRef

49.

Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416: 535–9PubMedCrossRef

50.

Mucke L, Masliah E, Yu GQ, et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000; 20: 4050–8PubMed

51.

Aisen PS, Mehran M, Poole R, et al. Clinical data on Alzhemed after 12 months of treatment in patients with mild to moderate Alzheimer’s disease [abstract]. Neurobiol Aging 2004; 25: 20CrossRef

52.

Bush AI. The metallobiology of Alzheimer’s disease. Trends Neurosci 2003; 26: 207–14PubMedCrossRef

53.

Raman B, Ban T, Yamaguchi K, et al. Metal ion-dependent effects of clioquinol on the fibril growth of an anyloid beta peptide. J Biol Chem 2005; 280: 16157–62PubMedCrossRef

54.

Cherny RA, Atwood CS, Xilinas ME, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 2001; 30: 665–76PubMedCrossRef

55.

Ritchie CW, Bush AI, Mackinnon A, et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 2003; 60: 1685–91PubMedCrossRef

56.

Tateishi J. Subacute myelo-optico-neuropathy: clioquinol intoxication in humans and animals. Neuropathology 2000; 20 Suppl.: S20–4PubMedCrossRef

57.

Gervais F, Chalifour R, Garceau D, et al. Glycosaminoglycan mimetics: a therapeutic approach to cerebral amyloid angiopathy. Amyloid 2001; 8Suppl. 1: 28–35PubMed

58.

Gervais F. GAG mimetics: potential to modify underlying disease process in AD. Neurobiol Aging 2004; 25: S11–2

59.

Hilbich C, Kisters-Woike B, Reed J, et al. Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer’s disease beta A4 peptides. J Mol Biol 1992; 228: 460–73PubMedCrossRef

60.

Findeis MA. Peptide inhibitors of beta amyloid aggregation. Curr Top Med Chem 2002; 2: 417–23PubMedCrossRef

61.

Klunk WE, Debnath ML, Koros AM, et al. Chrysamine-G, a lipophilic analogue of Congo red, inhibits A beta-induced toxicity in PC12 cells. Life Sci 1998; 63: 1807–14PubMedCrossRef

62.

Findeis MA. Approaches to discovery and characterization of inhibitors of amyloid beta-peptide polymerization. Biochim Biophys Acta 2000; 1502: 76–84PubMedCrossRef

63.

Sparks DL, Sabbagh MN, Connor DJ, et al. Benefits of atorvastatin in subjects with ALzheimer’s disease. Circulation 2004; 11017: III–813

64.

Hutter-Paier B, Huttunen HJ, Puglielli L, et al. The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer’s disease. Neuron 2004; 44: 227–38PubMedCrossRef

Title: The Development of Anti-Amyloid Therapy for Alzheimer’s Disease
From Secretase Modulators to Polymerisation Inhibitors
Author: Dr Paul S. Aisen
Publication date: 01-12-2005
Publisher: Springer International Publishing
Published in: CNS Drugs / Issue 12/2005
Print ISSN: 1172-7047
Electronic ISSN: 1179-1934
DOI: https://doi.org/10.2165/00023210-200519120-00002

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The Development of Anti-Amyloid Therapy for Alzheimer’s Disease

From Secretase Modulators to Polymerisation Inhibitors

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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