Skip to main content
SpringerLink
Log in

Drug discovery for Alzheimer’s disease

The end of the beginning

  • Introduction
  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  • Aisen P. S., Schafer K. A., Grundman M., Pfeiffer E., Sano M., Davis K. L., et al. (2003) Alzheimer’s Disease Cooperative Study. JAMA 289, 2819–2826.

    Article  PubMed  CAS  Google Scholar 

  • Allain H., Bentue-Ferrer D., Tribut O., Gauthier S., Michel B. F., and Drieu-La Rochelle C. (2003) Alzheimer’s disease: the pharmacological pathway. Fundam. Clin. Pharmacol. 17(4), 419–428.

    Article  PubMed  CAS  Google Scholar 

  • Baum L., Hansen L., Masliah E., and Saitoh T. (1996) Glycogen synthase kinase 3 alteration in Alzheimer disease is related to neurofibrillary tangle formation. Mol. Chem. Neuropathol. 29, 253–261.

    Article  PubMed  CAS  Google Scholar 

  • Butterfield D. A. and Pocernich C. B. (2003) The glutamatergic system and Alzheimer’s disease: therapeutic implications. CNS Drugs 17(9), 641–652.

    Article  PubMed  CAS  Google Scholar 

  • Chang L., Bakhos L., Wang Z., Venton D. L., and Klein W. L. (2003) Femtomole immunodetection of synthetic and endogenous amyloid-beta oligomers and its application to Alzheimer’s disease drug candidate screening. J. Mol. Neurosci. 20, 305–313.

    Article  PubMed  CAS  Google Scholar 

  • Chen H. S., Pellegrini, J. W., Aggarwal S. K., Lei S. Z., Warach S., Jensen F. E., and Lipton S. A. (1992) Open-channel block of NMDA responses by memantine: therapeutic advantage against NMDA receptor-mediated toxicity. J. Neurosci. 12, 4427–4436.

    PubMed  CAS  Google Scholar 

  • Das C., Berezovska O., Diehl T. S., Genet C., Buldyrev I., Tsai J. Y., et al. (2003) Designed helical peptides inhibit an intramembrane protease. J. Am. Chem. Soc. 125, 11794–11795.

    Article  PubMed  CAS  Google Scholar 

  • Farris W., Mansourian S., Chang Y., Lindsley L., Eckman E. A., Frosch M. P., et al. (2003) 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. 100, 4162–4167.

    Article  PubMed  CAS  Google Scholar 

  • Fassbender K., Simons M., Bergmann C., Stroick M., Lutjohann D., Keller P., et al. (2001) Simvastatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc. Natl. Acad. Sci. U. S. A. 98, 5856–5861.

    Article  PubMed  CAS  Google Scholar 

  • Gamblin T. C., Berry R. W., and Binder L. I. (2003) Modeling tau polymerization in vitro: a review and synthesis. Biochemistry 42, 15009–15017.

    Article  PubMed  CAS  Google Scholar 

  • Ghosh A. K., Bilcer G., Harwood C., Kawahama R., Shin D., Hussain K. A., et al. (2001) Structure-based design: potent inhibitors of human brain memapsin 2 (beta-secretase). J. Med. Chem. 44, 2865–2868.

    Article  PubMed  CAS  Google Scholar 

  • Hardy J. A. and Higgins G. A. (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054), 184–185.

    Article  PubMed  CAS  Google Scholar 

  • He X., Zhu G., Koelsch G., Rodgers K. K., Zhang X. C., and Tang J. (2003) Biochemical and structural characterization of the interaction of memapsin 2 (beta-secretase) cytosolic domain with the VHS domain of GGA proteins. Biochemistry 42, 12174–12180.

    Article  PubMed  CAS  Google Scholar 

  • Holtzman D. M., Bales K. R., Paul S. M., and DeMattos R. B. (2002) Abeta immunization and anti-Abeta antibodies: potential therapies for the prevention and treatment of Alzheimer’s disease. Adv. Drug Deliv. Rev. 541, 1603–1613.

    Article  Google Scholar 

  • Hom R. K., Gailunas A. F., Mamo S., Fang L. Y., Tung J. S., Walker D. E., et al. (2004) design and synthesis of hydroxyethylene-based peptidomimetic inhibitors of human beta-secretase. J. Med. Chem. 47, 158–164.

    Article  PubMed  CAS  Google Scholar 

  • Hutton M., Lendon C. L., Rizzu P., Baker M., Froelich S., Houlden H., et al. (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705.

    Article  PubMed  CAS  Google Scholar 

  • Iqbal K., Alonso Adel C., El-Akkad E., Gong C. X., Haque N., Khatoon S., et al. (2003) Alzheimer neurofibrillary degeneration: therapeutic targets and high-throughput assays. J. Mol. Neurosci. 20, 425–429.

    Article  PubMed  CAS  Google Scholar 

  • Iwata N., Tsubuki S., Takaki Y., Watanabe K., Sekiguchi M., Hosoki E., et al. (2000) Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat. Med. 6, 143–150.

    Article  PubMed  CAS  Google Scholar 

  • Jick H., Zornberg G. L., Jick S. S., Seshadri S., and Drachman D. A. (2000) Statins and the risk of dementia. Lancet 356, 1627–1631.

    Article  PubMed  CAS  Google Scholar 

  • Kimberly W. T. and Wolfe M. S. (2003) Identity and function of gamma-secretase. J. Neurosci. Res. 74, 353–360.

    Article  PubMed  CAS  Google Scholar 

  • Klunk W. E., Bacskai B. J., Mathis C. A., Kajdasz S. T., McLellan M. E., Frosch M. P., et al. (2002) Imaging Abeta plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative. J. Neuropathol. Exp. Neurol. 61, 797–805.

    PubMed  CAS  Google Scholar 

  • Kolsch H., Lutjohann D., Ludwig M., Schulte A., Ptok U., Jessen F., et al. (2003) Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer’s disease. Mol. Psychiatry 7, 899–902.

    Article  CAS  Google Scholar 

  • Kosik, K. S., Ahn, J., Stein, R., and Yeh L. A. (2002) Discovery of compounds that will prevent Tau pathology. J. Mol. Neurosci. 19, 261–266.

    Article  PubMed  CAS  Google Scholar 

  • Kung M. P., Hou C., Zhuang Z. P., Skovronsky D. M., Zhang B., Gur T. L., et al. (2002) Radioiodinated styryl-benzene derivatives as potential SPECT imaging agents for amyloid plaque detection in Alzheimer’s disease. J. Mol. Neurosci. 19, 7–10.

    Article  PubMed  CAS  Google Scholar 

  • Kung M. P., Zhuang Z. P., Hou C., Jin L. W., and Kung H. F. (2003) Characterization of radioiodinated ligand binding to amyloid beta plaques. J. Mol. Neurosci. 20, 249–254.

    Article  PubMed  CAS  Google Scholar 

  • Lambert M. P., Barlow A. K., Chromy B. A., Edwards C., Freed R., Liosatos M., et al. (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. U. S. A. 95, 6448–6453.

    Article  PubMed  CAS  Google Scholar 

  • Lau L. F. and Ahlijanian M. K. (2003) Role of cdk5 in the pathogenesis of Alzheimer’s disease. Neurosignals 12, 209–214.

    Article  PubMed  CAS  Google Scholar 

  • Launer L. (2003) Nonsteroidal anti-inflammatory drug use and the risk for Alzheimer’s disease: dissecting the epidemiological evidence. Drugs 63, 731–739.

    Article  PubMed  Google Scholar 

  • Lewis J., McGowan E., Rockwood J., Melrose H., Nacharaju P., Van Slegtenhorst M., et al. (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet. 25, 402–405.

    Article  PubMed  CAS  Google Scholar 

  • Mandelkow E. M., Stamer K., Vogel R., Thies E., and Mandelkow E. (2003) Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses. Neurobiol. Aging 24, 1079–1085.

    Article  PubMed  CAS  Google Scholar 

  • Mathis C. A., Bacskai B J., Kajdasz S. T., McLellan M. E., Frosch M. P., Hyman B. T., et al. (2002) A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg. Med. Chem. Lett. 12, 295–298.

    Article  PubMed  CAS  Google Scholar 

  • McGeer E. G. and McGeer P. L. (2003) Inflammatory processes in Alzheimer’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 741–749.

    Article  PubMed  CAS  Google Scholar 

  • Mirzoeva S., Sawkar A., Zasadzki M., Guo L., Velentza A. V., Dunlap V., et al. (2002) Discovery of a 3-amino-6-phenyl-pyridazine derivative as a new synthetic antineuroinflammatory compound. J. Med. Chem. 45, 563–566.

    Article  PubMed  CAS  Google Scholar 

  • Moore A. H. and O’Banion M. K. (2002) Neuroinflammation and anti-inflammatory therapy for Alzheimer’s disease. Adv. Drug Deliv. Rev. 54, 1627–1656.

    Article  PubMed  CAS  Google Scholar 

  • Owens A. P., Nadin A., Talbot A. C., Clarke E. E., Harrison T., Lewis H. D., et al. (2003) High affinity, bioavailable 3-amino-1,4-benzodiazepine-based gamma-secretase inhibitors. Bioorg. Med. Chem. Lett. 13, 4143–4145.

    Article  PubMed  CAS  Google Scholar 

  • Papassotiropoulos A., Streffer J. R., Tsolaki M., Schmid S., Thal D., Nicosia F., et al. (2003) Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch. Neurol. 60, 29–35.

    Article  PubMed  Google Scholar 

  • Petit A., Pasini A., Alves Da Costa C., Ayral E., Hernandez J. F., Dumanchin-Njock C., et al. (2003) JLK isocoumarin inhibitors: selective gamma-secretase inhibitors that do not interfere with notch pathway in vitro or in vivo. J. Neurosci. Res. 74, 370–377.

    Article  PubMed  CAS  Google Scholar 

  • Petanceska S. S., DeRosa S., Olm V., Diaz N., Sharma A., Thomas-Bryant T., et al. (2002) Statin therapy for Alzheimer’s disease: will it work? J. Mol. Neurosci. 19, 155–161.

    Article  PubMed  CAS  Google Scholar 

  • Planel E., Yasutake K., Fujita S. C., and Ishiguro K. (2001) Inhibition of protein phosphatase 2A overrides tau protein kinase I/glycogen synthase kinase 3 beta and cyclin-dependent kinase 5 inhibition and results in tau hyperphosphorylation in the hippocampus of starved mouse. J. Biol. Chem. 276, 34298–34306.

    Article  PubMed  CAS  Google Scholar 

  • Puglielli L., Tanzi R. E., and Kovacs D. M. (2001) Alzheimer’s disease: the cholesterol connection. Nat. Cell. Biol. 3, 905–912.

    Article  PubMed  CAS  Google Scholar 

  • Reisberg B., Doody R., Stoffler A., Schmitt F., Ferris S., and Mobius H. J. (2003) Memantine in moderate-to-severe Alzheimer’s disease. N. Engl. J. Med. 348, 1333–1341.

    Article  PubMed  CAS  Google Scholar 

  • Refolo L. M., Malester B., LaFrancois J., Bryant-Thomas T., Wang R., Tint G. S., et al. (2000) Hypercholesterolemia accelerates β-amyloid accumulation in a transgenic mouse model of Alzheimer’s disease. Neurobiol. Dis. 7, 321–331.

    Article  PubMed  CAS  Google Scholar 

  • Schenk D. B., Seubert P, Lieberburg I., and Wallace J. (2000) Beta-peptide immunization: a possible new treatment for Alzheimer disease. Arch. Neurol. 57, 934–936.

    Article  PubMed  CAS  Google Scholar 

  • Simons M., Schwarzler F., Lutjohann D., von Bergmann K., Beyreuther K., Dichgans J., et al. (2002) Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann. Neurol. 52, 346–350.

    Article  PubMed  CAS  Google Scholar 

  • Solomon B. (2003) Immunological approach for the treatment of Alzheimer’s disease. J. Mol. Neurosci. 20, 283–286.

    Article  PubMed  CAS  Google Scholar 

  • Sparks D. L., Martin T. A., Gross D. R., and Hunsaker J. C. III (2000) Link between heart disease, cholesterol, and Alzheimer’s disease: a review. Microsc. Res. Tech. 50, 287–290.

    Article  PubMed  CAS  Google Scholar 

  • Tang J., Ghosh A. K., Hong L., Koelsch G., Turner R. T. III, and Chang W. (2003) Study of memapsin 2 (beta-secretase) and strategy of inhibitor design. J. Mol. Neurosci. 20, 299–304.

    Article  PubMed  CAS  Google Scholar 

  • Wang Y., Klunk W. E., Huang G. F., Debnath M. L., Holt D. P., and Mathis C. A. (2002) Synthesis and evaluation of 2-(3′-iodo-4′-aminophenyl)-6-hydroxybenzothiazole for in vivo quantitation of amyloid deposits in Alzheimer’s disease. J. Mol. Neurosci. 19, 11–16.

    Article  PubMed  Google Scholar 

  • Wang Y., Mathis C. A., Huang G. F., Debnath M. L., Holt D. P., Shao L., and Klunk W. E. (2003) Effects of lipophilicity on the affinity and nonspecific binding of iodinated benzothiazole derivatives. J. Mol. Neurosci. 20, 255–260.

    Article  PubMed  Google Scholar 

  • Wolfe M. S., Esler W. P., and Das C. (2002) Continuing strategies for inhibiting Alzheimer’s gamma-secretase. J. Mol. Neurosci. 19, 83–87.

    Article  PubMed  CAS  Google Scholar 

  • Wolozin B. (2004) Cholesterol and the biology of Alzheimer’s disease. Neuron 41, 7–10.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Institute for the Study of Aging, New York, NY

    Lorenzo M. Refolo & Howard M. Fillit

Authors
  1. Lorenzo M. Refolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Howard M. Fillit
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lorenzo M. Refolo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Refolo, L.M., Fillit, H.M. Drug discovery for Alzheimer’s disease. J Mol Neurosci 24, 1–8 (2004). https://doi.org/10.1385/JMN:24:1:001

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/JMN:24:1:001

Search

Navigation