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

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, January 24, 2007, 27(4):796-807; doi:10.1523/JNEUROSCI.3501-06.2007

This Article Full Text Full Text (PDF) 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 (41) Citing Articles via Google Scholar Google Scholar Articles by Lacor, P. N. Articles by Klein, W. L. Search for Related Content PubMed PubMed Citation Articles by Lacor, P. N. Articles by Klein, W. L. Pubmed/NCBI databases Medline Plus Health Information Alzheimer's Disease

 Previous Article  |  Next Article 

Neurobiology of Disease
Aß Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease

Pascale N. Lacor, Maria C. Buniel, Paul W. Furlow, Antonio Sanz Clemente, Pauline T. Velasco, Margaret Wood, Kirsten L. Viola, and William L. Klein

Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208

Correspondence should be addressed to either William L. Klein or Pascale N. Lacor, Department of Neurobiology and Physiology, Northwestern University, O. T. Hogan Biological Sciences, Room 5-110, 2205 Tech Drive, Evanston, IL 60208. Email: wklein{at}northwestern.edu, Email: p-lacor{at}northwestern.edu

The basis for memory loss in early Alzheimer's disease (AD) seems likely to involve synaptic damage caused by soluble Aß-derived oligomers (ADDLs). ADDLs have been shown to build up in the brain and CSF of AD patients and are known to interfere with mechanisms of synaptic plasticity, acting as gain-of-function ligands that attach to synapses. Because of the correlation between AD dementia and synaptic degeneration, we investigated here the ability of ADDLs to affect synapse composition, structure, and abundance. Using highly differentiated cultures of hippocampal neurons, a preferred model for studies of synapse cell biology, we found that ADDLs bound to neurons with specificity, attaching to presumed excitatory pyramidal neurons but not GABAergic neurons. Fractionation of ADDLs bound to forebrain synaptosomes showed association with postsynaptic density complexes containing NMDA receptors, consistent with observed attachment of ADDLs to dendritic spines. During binding to hippocampal neurons, ADDLs promoted a rapid decrease in membrane expression of memory-related receptors (NMDA and EphB2). Continued exposure resulted in abnormal spine morphology, with induction of long thin spines reminiscent of the morphology found in mental retardation, deafferentation, and prionoses. Ultimately, ADDLs caused a significant decrease in spine density. Synaptic deterioration, which was accompanied by decreased levels of the spine cytoskeletal protein drebrin, was blocked by the Alzheimer's therapeutic drug Namenda. The observed disruption of dendritic spines links ADDLs to a major facet of AD pathology, providing strong evidence that ADDLs in AD brain cause neuropil damage believed to underlie dementia.

Key words: ADDLs; dendritic spine; synaptosomes; NMDA-R; EphB2; memantine; drebrin

---

Received Aug. 11, 2006; revised Dec. 13, 2006; accepted Dec. 15, 2006.

Correspondence should be addressed to either William L. Klein or Pascale N. Lacor, Department of Neurobiology and Physiology, Northwestern University, O. T. Hogan Biological Sciences, Room 5-110, 2205 Tech Drive, Evanston, IL 60208. Email: wklein{at}northwestern.edu, Email: p-lacor{at}northwestern.edu

This article has been cited by other articles:

				S. Knafo, L. Alonso-Nanclares, J. Gonzalez-Soriano, P. Merino-Serrais, I. Fernaud-Espinosa, I. Ferrer, and J. DeFelipe Widespread Changes in Dendritic Spines in a Model of Alzheimer's Disease Cereb Cortex, July 28, 2008; (2008) bhn111v2. [Abstract] [Full Text] [PDF]

				K. L. Richard, M. Filali, P. Prefontaine, and S. Rivest Toll-Like Receptor 2 Acts as a Natural Innate Immune Receptor to Clear Amyloid {beta}1-42 and Delay the Cognitive Decline in a Mouse Model of Alzheimer's Disease J. Neurosci., May 28, 2008; 28(22): 5784 - 5793. [Abstract] [Full Text] [PDF]

				Q.-L. Ma, F. Yang, F. Calon, O. J. Ubeda, J. E. Hansen, R. H. Weisbart, W. Beech, S. A. Frautschy, and G. M. Cole p21-activated Kinase-aberrant Activation and Translocation in Alzheimer Disease Pathogenesis J. Biol. Chem., May 16, 2008; 283(20): 14132 - 14143. [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]

				V. Nimmrich, C. Grimm, A. Draguhn, S. Barghorn, A. Lehmann, H. Schoemaker, H. Hillen, G. Gross, U. Ebert, and C. Bruehl Amyloid {beta} Oligomers (A{beta}1-42 Globulomer) Suppress Spontaneous Synaptic Activity by Inhibition of P/Q-Type Calcium Currents J. Neurosci., January 23, 2008; 28(4): 788 - 797. [Abstract] [Full Text] [PDF]

				S. Petratos, Q.-X. Li, A. J. George, X. Hou, M. L. Kerr, S. E. Unabia, I. Hatzinisiriou, D. Maksel, M.-I. Aguilar, and D. H. Small The -amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism Brain, January 1, 2008; 131(1): 90 - 108. [Abstract] [Full Text] [PDF]

				D. V. Venkitaramani, J. Chin, W. J. Netzer, G. K. Gouras, S. Lesne, R. Malinow, and P. J. Lombroso {beta}-Amyloid Modulation of Synaptic Transmission and Plasticity J. Neurosci., October 31, 2007; 27(44): 11832 - 11837. [Full Text] [PDF]

				F. G. De Felice, P. T. Velasco, M. P. Lambert, K. Viola, S. J. Fernandez, S. T. Ferreira, and W. L. Klein Abeta Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine J. Biol. Chem., April 13, 2007; 282(15): 11590 - 11601. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help