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

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, April 1, 2009, 29(13):4004-4015; doi:10.1523/JNEUROSCI.5980-08.2009

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 Related articles in J. Neurosci. Similar articles in this journal Similar articles in 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 Web of Science (7) 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
A Role for Synaptic Zinc in Activity-Dependent Aβ Oligomer Formation and Accumulation at Excitatory Synapses

Atul Deshpande,¹ Hideki Kawai,¹ Raju Metherate,¹ Charles G. 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, MH 2205, Irvine, CA 92697-4550. Email: jbuscigl{at}uci.edu

Soluble amyloid β oligomers (AβOs) interfere with synaptic function and bind with high affinity to synapses, but the mechanism underlying AβO synaptic targeting is not known. Here, we show that the accumulation of synthetic or native Alzheimer's disease (AD)-brain oligomers at synapses is regulated by synaptic activity. Electrical or chemical stimulation increased AβO synaptic localization and enhanced oligomer formation at synaptic terminals, whereas inhibition with TTX blocked AβO synaptic localization and reduced AβO synaptic load. The zinc-binding 8-OH-quinoline clioquinol markedly reduced AβO synaptic targeting, which was also reduced in brain sections of animals deficient in the synaptic vesicle zinc transporter ZnT3, indicating that vesicular zinc released during neurotransmission is critical for AβO synaptic targeting. Oligomers were not internalized in recycled vesicles but remained at the cell surface, where they colocalized with NR2B NMDA receptor subunits. Furthermore, NMDA antagonists blocked AβO synaptic targeting, implicating excitatory receptor activity in oligomer formation and accumulation at synapses. In AD brains, oligomers of different size colocalized with synaptic markers in hippocampus and cortex, where oligomer synaptic accumulation correlated with synaptic loss.

---

Received Dec. 16, 2008; revised Feb. 16, 2009; accepted Feb. 20, 2009.

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

Related articles in J. Neurosci.:

This Week in The Journal

J. Neurosci. 2009 29: i. [Full Text]  

This article has been cited by other articles:

				G. McColl, B. R. Roberts, A. P. Gunn, K. A. Perez, D. J. Tew, C. L. Masters, K. J. Barnham, R. A. Cherny, and A. I. Bush The Caenorhabditis elegans A{beta}1-42 Model of Alzheimer Disease Predominantly Expresses A{beta}3-42 J. Biol. Chem., August 21, 2009; 284(34): 22697 - 22702. [Abstract] [Full Text] [PDF]

				D. Tampellini, N. Rahman, E. F. Gallo, Z. Huang, M. Dumont, E. Capetillo-Zarate, T. Ma, R. Zheng, B. Lu, D. M. Nanus, et al. Synaptic Activity Reduces Intraneuronal A{beta}, Promotes APP Transport to Synapses, and Protects against A{beta}-Related Synaptic Alterations J. Neurosci., August 5, 2009; 29(31): 9704 - 9713. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help