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.
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Notes
1. The use of trade names is for product identifcation purposes only and does not imply endorsement.
References
Cummings JL. Alzheimer’s disease. N Engl J Med 2004; 351: 56–67
Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003; 348: 1333–41
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: 317–24
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: 16742–7
Iqbal K, Alonso Adel C, El-Akkad E, et al. Alzheimer neurofibrillary degeneration: therapeutic targets and high-throughput assays. J Mol Neurosci 2003; 20: 425–9
Samuel W, Terry RD, DeTeresa R, et al. Clinical correlates of cortical and nucleus basalis pathology in Alzheimer dementia. Arch Neurol 1994; 51: 772–8
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: 1571–7
Nash JM. Alzheimer’s disease: new insights into its cause lead to new drug strategies. Time 2001; 157: 80–81, 85
Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001; 81: 741–66
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002; 297: 353–6
Lippa CF, Saunders AM, Smith TW, et al. Familial and sporadic Alzheimer’s disease: neuropathology cannot exclude a final common pathway. Neurology 1996; 46: 406–12
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: 864–70
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: 527–31
Davies P. A very incomplete comprehensive theory of Alzheimer’s disease. Ann N Y Acad Sci 2000; 924: 8–16
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: 321–32
Lopez-Toledano MA, Shelanski ML. Neurogenic effect of beta-amyloid peptide in the development of neural stem cells. J Neurosci 2004; 24: 5439–44
Takasugi N, Tomita T, Hayashi I, et al. The role of presenilin cofactors in the gamma-secretase complex. Nature 2003; 422: 438–41
Citron M. Strategies for disease modification in Alzheimer’s disease. Nat Rev Neurosci 2004; 5: 677–85
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: 518–22
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: 341–58
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: 43419–26
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: 12444–9
Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001; 414: 212–6
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): 635–43
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: 126–32
Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 1999; 402: 533–7
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: 735–41
Sinha S, Anderson JP, Barbour R, et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999; 402: 537–40
Hussain I, Powell D, Howlett DR, et al. Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 1999; 14: 419–27
Hong L, Koelsch G, Lin X, et al. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 2000; 290: 150–3
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: 1317–24
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: 231–2
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: 1409–16
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: 6447–50
Blumberg PM. Protein kinase C as the receptor for the phorbol ester tumor promoters. Cancer Res 1988; 48: 1–8
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: 11141–6
Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400: 173–7
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: 2023–8
Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003; 61: 46–54
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: 448–52
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: 1553–62
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: 7873–8
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: 2264–7
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: 10–8
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: 29–33
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: 320–5
Walsh DM, Klyubin I, Fadeeva JV, et al. Amyloid-beta oligomers: their production, toxicity and therapeutic inhibition. Biochem Soc Trans 2002; 30: 552–7
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: 535–9
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: 4050–8
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: 20
Bush AI. The metallobiology of Alzheimer’s disease. Trends Neurosci 2003; 26: 207–14
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: 16157–62
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: 665–76
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: 1685–91
Tateishi J. Subacute myelo-optico-neuropathy: clioquinol intoxication in humans and animals. Neuropathology 2000; 20 Suppl.: S20–4
Gervais F, Chalifour R, Garceau D, et al. Glycosaminoglycan mimetics: a therapeutic approach to cerebral amyloid angiopathy. Amyloid 2001; 8Suppl. 1: 28–35
Gervais F. GAG mimetics: potential to modify underlying disease process in AD. Neurobiol Aging 2004; 25: S11–2
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: 460–73
Findeis MA. Peptide inhibitors of beta amyloid aggregation. Curr Top Med Chem 2002; 2: 417–23
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: 1807–14
Findeis MA. Approaches to discovery and characterization of inhibitors of amyloid beta-peptide polymerization. Biochim Biophys Acta 2000; 1502: 76–84
Sparks DL, Sabbagh MN, Connor DJ, et al. Benefits of atorvastatin in subjects with ALzheimer’s disease. Circulation 2004; 11017: III–813
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: 227–38
Acknowledgements
Dr Aisen is a consultant to Neurochem, and is the US principal investigator for the phase III trial of Alzhemed™ sponsored by Neurochem. No sources of funding were used to assist in the preparation of this review.
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Aisen, P.S. The Development of Anti-Amyloid Therapy for Alzheimer’s Disease. CNS Drugs 19, 989–996 (2005). https://doi.org/10.2165/00023210-200519120-00002
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DOI: https://doi.org/10.2165/00023210-200519120-00002