| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Departamento de Bioquímica Médica and
Departamento de Anatomia, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;
* Departamento de Química Orgânica, Instituto Militar de Engenharia, Rio de Janeiro, Brazil; and
Department of Neurobiology and Physiology, Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Institute for Neuroscience, Evanston, Illinois, USA
1Correspondence: Departamento de Bioquímica Médica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil. E-mail: felice{at}bioqmed.ufrj.br; ferreira{at}bioqmed.ufrj.br
In the past two decades, a large body of evidence has established a causative role for the ß-amyloid peptide (Aß) in Alzheimer’s disease (AD). However, recent debate has focused on whether amyloid fibrils or soluble oligomers of Aß are the main neurotoxic species that contribute to neurodegeneration and dementia. Considerable early evidence has indicated that amyloid fibrils are toxic, but some recent studies support the notion that Aß oligomers are the primary neurotoxins. While this crucial aspect of AD pathogenesis remains controversial, effective therapeutic strategies should ideally target both oligomeric and fibrillar species of Aß. Here, we describe the anti-amyloidogenic and neuroprotective actions of some di- and tri-substituted aromatic compounds. Inhibition of the formation of soluble Aß oligomers was monitored using a specific antibody-based assay that discriminates between Aß oligomers and monomers. Thioflavin T and electron microscopy were used to screen for inhibitors of fibril formation. Taken together, these results led to the identification of compounds that more effectively block Aß oligomerization than fibrillization. It is significant that such compounds completely blocked the neurotoxicity of Aß to rat hippocampal neurons in culture. These findings provide a basis for the development of novel small molecule Aß inhibitors with potential applications in AD.—De Felice, F. G., Vieira, M. N. N., Saraiva, L. M., Figueroa-Villar, J. D., Garcia-Abreu, J., Liu, R., Chang, L., Klein, W. L., Ferreira, S. T. Targeting the neurotoxic species in Alzheimer’s disease: inhibitors of Aß oligomerization.
Key Words: amyloid • oligomers • neuroprotection • small molecule inhibitors
This article has been cited by other articles:
|
|
 |
|
  S. K. Maji, R. R. Ogorzalek Loo, M. Inayathullah, S. M. Spring, S. S. Vollers, M. M. Condron, G. Bitan, J. A. Loo, and D. B. Teplow Amino Acid Position-specific Contributions to Amyloid {beta}-Protein Oligomerization J. Biol. Chem., August 28, 2009; 284(35): 23580 - 23591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Davis, D. D. Soto-Ortega, J. A. Kotarek, F. J. Gonzalez-Velasquez, K. Sivakumar, L. Wu, Q. Wang, and M. A. Moss Comparative Study of Inhibition at Multiple Stages of Amyloid-{beta} Self-Assembly Provides Mechanistic Insight Mol. Pharmacol., August 1, 2009; 76(2): 405 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ariga, M. P. McDonald, and R. K. Yu Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease--a review J. Lipid Res., June 1, 2008; 49(6): 1157 - 1175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Zhang, Y. Dong, G. Zhang, R. D. Moir, W. Xia, Y. Yue, M. Tian, D. J. Culley, G. Crosby, R. E. Tanzi, et al. The Inhalation Anesthetic Desflurane Induces Caspase Activation and Increases Amyloid {beta}-Protein Levels under Hypoxic Conditions J. Biol. Chem., May 2, 2008; 283(18): 11866 - 11875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Necula, R. Kayed, S. Milton, and C. G. Glabe Small Molecule Inhibitors of Aggregation Indicate That Amyloid beta Oligomerization and Fibrillization Pathways Are Independent and Distinct J. Biol. Chem., April 6, 2007; 282(14): 10311 - 10324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Xie, Y. Dong, U. Maeda, R. D. Moir, W. Xia, D. J. Culley, G. Crosby, and R. E. Tanzi The Inhalation Anesthetic Isoflurane Induces a Vicious Cycle of Apoptosis and Amyloid {beta}-Protein Accumulation J. Neurosci., February 7, 2007; 27(6): 1247 - 1254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Xie, Y. Dong, U. Maeda, R. Moir, S. K. Inouye, D. J. Culley, G. Crosby, and R. E. Tanzi Isoflurane-Induced Apoptosis: A Potential Pathogenic Link Between Delirium and Dementia J Gerontol A Biol Sci Med Sci, December 1, 2006; 61(12): 1300 - 1306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Wasilewska-Sampaio, M. S. Silveira, O. Holub, R. Goecking, F. C. A. Gomes, V. M. Neto, R. Linden, S. T. Ferreira, and F. G. De Felice Neuritogenesis and neuronal differentiation promoted by 2,4-dinitrophenol, a novel anti-amyloidogenic compound FASEB J, October 1, 2005; 19(12): 1627 - 1636. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
