QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, May 31, 2006, 26(22):6011-6018; doi:10.1523/JNEUROSCI.1189-06.2006

This Article Full Text Full Text (PDF) Supplemental data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (39) Citing Articles via Google Scholar Google Scholar Articles by Deshpande, A. Articles by Busciglio, J. Search for Related Content PubMed PubMed Citation Articles by Deshpande, A. Articles by Busciglio, J.

 Previous Article  |  Next Article 

Neurobiology of Disease
Different Conformations of Amyloid Induce Neurotoxicity by Distinct Mechanisms in Human Cortical Neurons

Atul Deshpande,¹ Erene Mina,² Charles Glabe,^2,3 and Jorge Busciglio^1,3

Departments of ¹Neurobiology and Behavior and ²Molecular Biology and Biochemistry, and ³Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, California 92697

Correspondence should be addressed to Jorge Busciglio, Department of Neurobiology and Behavior, University of California, Irvine, 2205 McGaugh Hall, Irvine, CA 92697-4550. Email: jbuscigl{at}uci.edu

Characterization of soluble oligomeric amyloid (A) species in the brains of Alzheimer's disease (AD) patients and transgenic models has raised the possibility that different conformations of A may contribute to AD pathology via different mechanisms. To characterize the toxic effect of different A conformations, we tested side by side the effect of well characterized A oligomers (AOs), A-derived diffusible ligands (ADDLs), and fibrillar A (Af) preparations in human cortical neurons (HCNs). Both AOs and ADDLs bind rapidly and with high affinity to synaptic contacts and cellular membranes. AOs (5 µM) induced rapid and massive neuronal death. Calcium influx accelerated, but was not required for, AO toxicity. AOs elicited a stereotyped succession of cellular changes consistent with the activation of a mitochondrial death apoptotic pathway. At low concentrations AOs caused chronic and subtler mitochondrial alterations but minimal cell death. ADDLs induced similar toxic changes as AOs but on a fivefold longer time scale. Higher concentrations of Af and longer incubation times were required to produce widespread neuritic dystrophy but modest HCN cell death. Thus various A species may play relevant roles in AD, causing neurotoxicity by distinct non-overlapping mechanisms affecting neuronal function and viability over multiple time courses.

Key words: amyloid ; oligomers; Alzheimer's disease; apoptosis; mitochondria; synapses

---

Received March 19, 2006; revised April 20, 2006; accepted April 25, 2006.

Correspondence should be addressed to Jorge Busciglio, Department of Neurobiology and Behavior, University of California, Irvine, 2205 McGaugh Hall, Irvine, CA 92697-4550. Email: jbuscigl{at}uci.edu

This article has been cited by other articles:

				A. Deshpande, K. M. Win, and J. Busciglio Tau isoform expression and regulation in human cortical neurons FASEB J, July 1, 2008; 22(7): 2357 - 2367. [Abstract] [Full Text] [PDF]

				D. M. Hartley, C. Zhao, A. C. Speier, G. A. Woodard, S. Li, Z. Li, and T. Walz Transglutaminase Induces Protofibril-like Amyloid {beta}-Protein Assemblies That Are Protease-resistant and Inhibit Long-term Potentiation J. Biol. Chem., June 13, 2008; 283(24): 16790 - 16800. [Abstract] [Full Text] [PDF]

				E. Sturchler, A. Galichet, M. Weibel, E. Leclerc, and C. W. Heizmann Site-Specific Blockade of RAGE-Vd Prevents Amyloid-{beta} Oligomer Neurotoxicity J. Neurosci., May 14, 2008; 28(20): 5149 - 5158. [Abstract] [Full Text] [PDF]

				G. E. Stutzmann The Pathogenesis of Alzheimers Disease Is It a Lifelong "Calciumopathy"? Neuroscientist, October 1, 2007; 13(5): 546 - 559. [Abstract] [PDF]

				G. Mamikonyan, M. Necula, M. Mkrtichyan, A. Ghochikyan, I. Petrushina, N. Movsesyan, E. Mina, A. Kiyatkin, C. G. Glabe, D. H. Cribbs, et al. Anti-Abeta1 11 Antibody Binds to Different beta-Amyloid Species, Inhibits Fibril Formation, and Disaggregates Preformed Fibrils but Not the Most Toxic Oligomers J. Biol. Chem., August 3, 2007; 282(31): 22376 - 22386. [Abstract] [Full Text] [PDF]

				S. T. DeKosky, E. E. Abrahamson, J. R. Ciallella, W. R. Paljug, S. R. Wisniewski, R. S. B. Clark, and M. D. Ikonomovic Association of Increased Cortical Soluble Abeta42 Levels With Diffuse Plaques After Severe Brain Injury in Humans Arch Neurol, April 1, 2007; 64(4): 541 - 544. [Abstract] [Full Text] [PDF]

				D. J. Garzon and M. Fahnestock Oligomeric Amyloid Decreases Basal Levels of Brain-Derived Neurotrophic factor (BDNF) mRNA via Specific Downregulation of BDNF Transcripts IV and V in Differentiated Human Neuroblastoma Cells J. Neurosci., March 7, 2007; 27(10): 2628 - 2635. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help