Towards disease-modifying treatment of Alzheimer's disease: Drugs targeting β-amyloid

V. Frisardi, V. Solfrizzi, B. P. Imbimbo, C. Capurso, A. D'Introno, A. M. Colacicco, G. Vendemiale, D. Seripa, A. Pilotto, A. Capurso, F. Panza

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of β-amyloid (Aβ) peptides may cause Alzheimer's disease (AD). Drugs currently used for the treatment of AD produce limited clinical benefits and do not treat the underlying causes of the disease. In the last 10 years, new therapeutic approaches targeting Aβ have been discovered and developed with the hope of modifying the natural history of the disease. Several active and passive immunotherapy approaches are under investigation in clinical trials with the aim of accelerating Aβ clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Aβ monoclonal antibodies, that is being tested in two large late-stage trials. Compounds that interfere with proteases regulating Aβ formation from amyloid precursor protein (APP) are also actively pursued. Unfortunately, the most biologically attractive of these proteases, β-secretase, that regulates the first step of the amyloidogenic APP metabolism, was found to be particularly problematic to block and only one compound (CTS21166) has reached clinical testing so far. Conversely, several inhibitors of γ-secretase, the protease that regulates the last metabolic step generating Aβ, have been identified, the most advanced being LY-450139 (semagacestat), presently in Phase III clinical development. Compounds that stimulate α-secretase, the enzyme responsible for the nonamyloidogenic metabolism of APP, are also being developed one of them, EHT-0202, has recently started a Phase II study. Furthermore, brain penetrant inhibitors of Aβ aggregation have been identified and one of such compounds, PBT-2, has produced encouraging neuropsychological results in a recently completed Phase II study. With all these anti-Aβ approaches in clinical testing, we will know in few years if the Aβ hypothesis of AD is correct.

Original languageEnglish
Pages (from-to)40-55
Number of pages16
JournalCurrent Alzheimer Research
Volume7
Issue number1
DOIs
Publication statusPublished - Jan 2010

Fingerprint

Drug Delivery Systems
Amyloid
N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide
Amyloid Precursor Protein Secretases
Alzheimer Disease
Amyloid beta-Protein Precursor
Peptide Hydrolases
Amyloidogenic Proteins
Serum Amyloid A Protein
Active Immunotherapy
Passive Immunization
Brain
Brain Diseases
Therapeutics
Protease Inhibitors
Molecular Biology
Monoclonal Antibodies
Clinical Trials
Pharmacology
Peptides

Keywords

  • α-secretase activators
  • β-amyloid
  • β-secretase inhibitors
  • γ-secretase inhibitors
  • γ-secretase modulators
  • Active immunotherapy
  • Alzheimer's disease
  • Passive immunotherapy

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Frisardi, V., Solfrizzi, V., Imbimbo, B. P., Capurso, C., D'Introno, A., Colacicco, A. M., ... Panza, F. (2010). Towards disease-modifying treatment of Alzheimer's disease: Drugs targeting β-amyloid. Current Alzheimer Research, 7(1), 40-55. https://doi.org/10.2174/156720510790274400

Towards disease-modifying treatment of Alzheimer's disease : Drugs targeting β-amyloid. / Frisardi, V.; Solfrizzi, V.; Imbimbo, B. P.; Capurso, C.; D'Introno, A.; Colacicco, A. M.; Vendemiale, G.; Seripa, D.; Pilotto, A.; Capurso, A.; Panza, F.

In: Current Alzheimer Research, Vol. 7, No. 1, 01.2010, p. 40-55.

Research output: Contribution to journalArticle

Frisardi, V, Solfrizzi, V, Imbimbo, BP, Capurso, C, D'Introno, A, Colacicco, AM, Vendemiale, G, Seripa, D, Pilotto, A, Capurso, A & Panza, F 2010, 'Towards disease-modifying treatment of Alzheimer's disease: Drugs targeting β-amyloid', Current Alzheimer Research, vol. 7, no. 1, pp. 40-55. https://doi.org/10.2174/156720510790274400
Frisardi V, Solfrizzi V, Imbimbo BP, Capurso C, D'Introno A, Colacicco AM et al. Towards disease-modifying treatment of Alzheimer's disease: Drugs targeting β-amyloid. Current Alzheimer Research. 2010 Jan;7(1):40-55. https://doi.org/10.2174/156720510790274400
Frisardi, V. ; Solfrizzi, V. ; Imbimbo, B. P. ; Capurso, C. ; D'Introno, A. ; Colacicco, A. M. ; Vendemiale, G. ; Seripa, D. ; Pilotto, A. ; Capurso, A. ; Panza, F. / Towards disease-modifying treatment of Alzheimer's disease : Drugs targeting β-amyloid. In: Current Alzheimer Research. 2010 ; Vol. 7, No. 1. pp. 40-55.
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