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The Journal of Neuroscience, November 10, 2004, 24(45):10191-10200; doi:10.1523/JNEUROSCI.3432-04.2004
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Neurobiology of Disease
Synaptic Targeting by Alzheimer's-Related Amyloid  Oligomers
Pascale N. Lacor,1
Maria C. Buniel,1
Lei Chang,1
Sara J. Fernandez,1
Yuesong Gong,1
Kirsten L. Viola,1
Mary P. Lambert,1
Pauline T. Velasco,1
Eileen H. Bigio,2
Caleb E. Finch,3
Grant A. Krafft,4 and
William L. Klein1
1Neurobiology and Physiology Department, Northwestern University, Evanston, Illinois 60208, 2Neuropathology Core, Northwestern Alzheimer's Disease Center, Northwestern Feinberg School of Medicine, Chicago, Illinois 60611, 3Andrus Gerontology Center, University of Southern California, Los Angeles, California 90089, and 4Acumen Pharmaceuticals, Glenview, Illinois 60025
The cognitive hallmark of early Alzheimer's disease (AD) is an extraordinary inability to form new memories. For many years, this dementia was attributed to nerve-cell death induced by deposits of fibrillar amyloid  (A). A newer hypothesis has emerged, however, in which early memory loss is considered a synapse failure caused by soluble A oligomers. Such oligomers rapidly block long-term potentiation, a classic experimental paradigm for synaptic plasticity, and they are strikingly elevated in AD brain tissue and transgenic-mouse AD models. The current work characterizes the manner in which A oligomers attack neurons. Antibodies raised against synthetic oligomers applied to AD brain sections were found to give diffuse stain around neuronal cell bodies, suggestive of a dendritic pattern, whereas soluble brain extracts showed robust AD-dependent reactivity in dot immunoblots. Antigens in unfractionated AD extracts attached with specificity to cultured rat hippocampal neurons, binding within dendritic arbors at discrete puncta. Crude fractionation showed ligand size to be between 10 and 100 kDa. Synthetic A oligomers of the same size gave identical punctate binding, which was highly selective for particular neurons. Image analysis by confocal double-label immunofluorescence established that >90% of the punctate oligomer binding sites colocalized with the synaptic marker PSD-95 (postsynaptic density protein 95). Synaptic binding was accompanied by ectopic induction of Arc, a synaptic immediate-early gene, the overexpression of which has been linked to dysfunctional learning. Results suggest the hypothesis that targeting and functional disruption of particular synapses by A oligomers may provide a molecular basis for the specific loss of memory function in early AD.
Key words: ADDLs; amyloid; synapse; dendritic spines; immediate-early gene; arc
Received March 12, 2004;
revised September 30, 2004;
accepted September 30, 2004.
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A. Noguchi, S. Matsumura, M. Dezawa, M. Tada, M. Yanazawa, A. Ito, M. Akioka, S. Kikuchi, M. Sato, S. Ideno, et al.
Isolation and Characterization of Patient-derived, Toxic, High Mass Amyloid {beta}-Protein (A{beta}) Assembly from Alzheimer Disease Brains
J. Biol. Chem.,
November 20, 2009;
284(47):
32895 - 32905.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Durakoglugil, Y. Chen, C. L. White, E. T. Kavalali, and J. Herz
Reelin signaling antagonizes {beta}-amyloid at the synapse
PNAS,
September 15, 2009;
106(37):
15938 - 15943.
[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]
|
|
|
|
|
|
|
Q.-L. Ma, F. Yang, E. R. Rosario, O. J. Ubeda, W. Beech, D. J. Gant, P. P. Chen, B. Hudspeth, C. Chen, Y. Zhao, et al.
{beta}-Amyloid Oligomers Induce Phosphorylation of Tau and Inactivation of Insulin Receptor Substrate via c-Jun N-Terminal Kinase Signaling: Suppression by Omega-3 Fatty Acids and Curcumin
J. Neurosci.,
July 15, 2009;
29(28):
9078 - 9089.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Wang, B. Su, H.-g. Lee, X. Li, G. Perry, M. A. Smith, and X. Zhu
Impaired Balance of Mitochondrial Fission and Fusion in Alzheimer's Disease
J. Neurosci.,
July 15, 2009;
29(28):
9090 - 9103.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.-Q. Zhao, P. N. Lacor, H. Chen, M. P. Lambert, M. J. Quon, G. A. Krafft, and W. L. Klein
Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric A{beta}
J. Biol. Chem.,
July 10, 2009;
284(28):
18742 - 18753.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. G. Farias, I. E. Alfaro, W. Cerpa, C. P. Grabowski, J. A. Godoy, C. Bonansco, and N. C. Inestrosa
Wnt-5a/JNK Signaling Promotes the Clustering of PSD-95 in Hippocampal Neurons
J. Biol. Chem.,
June 5, 2009;
284(23):
15857 - 15866.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Gralle, M. G. Botelho, and F. S. Wouters
Neuroprotective Secreted Amyloid Precursor Protein Acts by Disrupting Amyloid Precursor Protein Dimers
J. Biol. Chem.,
May 29, 2009;
284(22):
15016 - 15025.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. E. Hoey, R. J. Williams, and M. S. Perkinton
Synaptic NMDA Receptor Activation Stimulates {alpha}-Secretase Amyloid Precursor Protein Processing and Inhibits Amyloid-{beta} Production
J. Neurosci.,
April 8, 2009;
29(14):
4442 - 4460.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Deshpande, H. Kawai, R. Metherate, C. G. Glabe, and J. Busciglio
A Role for Synaptic Zinc in Activity-Dependent A{beta} Oligomer Formation and Accumulation at Excitatory Synapses
J. Neurosci.,
April 1, 2009;
29(13):
4004 - 4015.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Koffie, M. Meyer-Luehmann, T. Hashimoto, K. W. Adams, M. L. Mielke, M. Garcia-Alloza, K. D. Micheva, S. J. Smith, M. L. Kim, V. M. Lee, et al.
Oligomeric amyloid {beta} associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques
PNAS,
March 10, 2009;
106(10):
4012 - 4017.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Nishitsuji, T. Tomiyama, K. Ishibashi, K. Ito, R. Teraoka, M. P. Lambert, W. L. Klein, and H. Mori
The E693{Delta} Mutation in Amyloid Precursor Protein Increases Intracellular Accumulation of Amyloid {beta} Oligomers and Causes Endoplasmic Reticulum Stress-Induced Apoptosis in Cultured Cells
Am. J. Pathol.,
March 1, 2009;
174(3):
957 - 969.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. J. Meilandt, M. Cisse, K. Ho, T. Wu, L. A. Esposito, K. Scearce-Levie, I. H. Cheng, G.-Q. Yu, and L. Mucke
Neprilysin Overexpression Inhibits Plaque Formation But Fails to Reduce Pathogenic A{beta} Oligomers and Associated Cognitive Deficits in Human Amyloid Precursor Protein Transgenic Mice
J. Neurosci.,
February 18, 2009;
29(7):
1977 - 1986.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. G. De Felice, M. N. N. Vieira, T. R. Bomfim, H. Decker, P. T. Velasco, M. P. Lambert, K. L. Viola, W.-Q. Zhao, S. T. Ferreira, and W. L. Klein
From the Cover: Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of A{beta} oligomers
PNAS,
February 10, 2009;
106(6):
1971 - 1976.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Bravo, M. Arimon, J. J. Valle-Delgado, R. Garcia, N. Durany, S. Castel, M. Cruz, S. Ventura, and X. Fernandez-Busquets
Sulfated Polysaccharides Promote the Assembly of Amyloid {beta}1-42 Peptide into Stable Fibrils of Reduced Cytotoxicity
J. Biol. Chem.,
November 21, 2008;
283(47):
32471 - 32483.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Jimenez, D. Baglietto-Vargas, C. Caballero, I. Moreno-Gonzalez, M. Torres, R. Sanchez-Varo, D. Ruano, M. Vizuete, A. Gutierrez, and J. Vitorica
Inflammatory Response in the Hippocampus of PS1M146L/APP751SL Mouse Model of Alzheimer's Disease: Age-Dependent Switch in the Microglial Phenotype from Alternative to Classic
J. Neurosci.,
November 5, 2008;
28(45):
11650 - 11661.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. G. Glabe
Structural Classification of Toxic Amyloid Oligomers
J. Biol. Chem.,
October 31, 2008;
283(44):
29639 - 29643.
[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]
|
|
|
|
|
|
|
J. A. Fein, S. Sokolow, C. A. Miller, H. V. Vinters, F. Yang, G. M. Cole, and K. H. Gylys
Co-Localization of Amyloid Beta and Tau Pathology in Alzheimer's Disease Synaptosomes
Am. J. Pathol.,
June 1, 2008;
172(6):
1683 - 1692.
[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]
|
|
|
|
|
|
|
R. Williamson, A. Usardi, D. P. Hanger, and B. H. Anderton
Membrane-bound {beta}-amyloid oligomers are recruited into lipid rafts by a fyn-dependent mechanism
FASEB J,
May 1, 2008;
22(5):
1552 - 1559.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. A. Kotilinek, M. A. Westerman, Q. Wang, K. Panizzon, G. P. Lim, A. Simonyi, S. Lesne, A. Falinska, L. H. Younkin, S. G. Younkin, et al.
Cyclooxygenase-2 inhibition improves amyloid-{beta}-mediated suppression of memory and synaptic plasticity
Brain,
March 1, 2008;
131(3):
651 - 664.
[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]
|
|
|
|
|
|
|
W.-Q. Zhao, F. G. De Felice, S. Fernandez, H. Chen, M. P. Lambert, M. J. Quon, G. A. Krafft, and W. L. Klein
Amyloid beta oligomers induce impairment of neuronal insulin receptors
FASEB J,
January 1, 2008;
22(1):
246 - 260.
[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]
|
|
|
|
|
|
|
M. Stefani
Generic Cell Dysfunction in Neurodegenerative Disorders: Role of Surfaces in Early Protein Misfolding, Aggregation, and Aggregate Cytotoxicity
Neuroscientist,
October 1, 2007;
13(5):
519 - 531.
[Abstract]
[PDF]
|
|
|
|
|
|
|
T. L. Spires-Jones, M. Meyer-Luehmann, J. D. Osetek, P. B. Jones, E. A. Stern, B. J. Bacskai, and B. T. Hyman
Impaired Spine Stability Underlies Plaque-Related Spine Loss in an Alzheimer's Disease Mouse Model
Am. J. Pathol.,
October 1, 2007;
171(4):
1304 - 1311.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. H. Ashe
A Tale about Tau
N. Engl. J. Med.,
August 30, 2007;
357(9):
933 - 935.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Tchantchou, Y. Xu, Y. Wu, Y. Christen, and Y. Luo
EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer's disease
FASEB J,
August 1, 2007;
21(10):
2400 - 2408.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. G. Farias, A. S. Valles, M. Colombres, J. A. Godoy, E. M. Toledo, R. J. Lukas, F. J. Barrantes, and N. C. Inestrosa
Wnt-7a Induces Presynaptic Colocalization of {alpha}7-Nicotinic Acetylcholine Receptors and Adenomatous Polyposis Coli in Hippocampal Neurons
J. Neurosci.,
May 16, 2007;
27(20):
5313 - 5325.
[Abstract]
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
E. Marcello, F. Gardoni, D. Mauceri, S. Romorini, A. Jeromin, R. Epis, B. Borroni, F. Cattabeni, C. Sala, A. Padovani, et al.
Synapse-Associated Protein-97 Mediates {alpha}-Secretase ADAM10 Trafficking and Promotes Its Activity
J. Neurosci.,
February 14, 2007;
27(7):
1682 - 1691.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Yamamoto, E. Matsubara, S. Maeda, H. Minagawa, A. Takashima, W. Maruyama, M. Michikawa, and K. Yanagisawa
A Ganglioside-induced Toxic Soluble Abeta Assembly: ITS ENHANCED FORMATION FROM AbetaBEARING THE ARCTIC MUTATION
J. Biol. Chem.,
January 26, 2007;
282(4):
2646 - 2655.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. N. Lacor, M. C. Buniel, P. W. Furlow, A. Sanz Clemente, P. T. Velasco, M. Wood, K. L. Viola, and W. L. Klein
A{beta} Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease
J. Neurosci.,
January 24, 2007;
27(4):
796 - 807.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Drachman
Aging of the brain, entropy, and Alzheimer disease
Neurology,
October 24, 2006;
67(8):
1340 - 1352.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Rui, P. Tiwari, Z. Xie, and J. Q. Zheng
Acute Impairment of Mitochondrial Trafficking by beta-Amyloid Peptides in Hippocampal Neurons
J. Neurosci.,
October 11, 2006;
26(41):
10480 - 10487.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. F. Lippa
An Individualized Approach to Treatment for Alzheimer's Disease, Pick's Disease, and Other Dementias.
American Journal of Alzheimer's Disease and Other Dementias,
October 1, 2006;
21(5):
354 - 359.
[Abstract]
[PDF]
|
|
|
|
|
|
|
G. M. Shaked, M. P. Kummer, D. C. Lu, V. Galvan, D. E. Bredesen, and E. H. Koo
A{beta} induces cell death by direct interaction with its cognate extracellular domain on APP (APP 597-624)
FASEB J,
June 1, 2006;
20(8):
1254 - 1256.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Deshpande, E. Mina, C. Glabe, and J. Busciglio
Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons.
J. Neurosci.,
May 31, 2006;
26(22):
6011 - 6018.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. R. Thal, E. Capetillo-Zarate, K. Del Tredici, and H. Braak
The Development of Amyloid beta Protein Deposits in the Aged Brain
Sci. Aging Knowl. Environ.,
March 8, 2006;
2006(6):
re1 - re1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. H. Chang, M. J. Savage, D. G. Flood, J. M. Thomas, R. B. Levy, V. Mahadomrongkul, T. Shirao, C. Aoki, and P. T. Huerta
AMPA receptor downscaling at the onset of Alzheimer's disease pathology in double knockin mice
PNAS,
February 28, 2006;
103(9):
3410 - 3415.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-H. Lee, H. J. Kim, J.-H. Lee, H.-J. Cho, J. Kim, K. C. Chung, S. Jung, and S. R. Paik
Dequalinium-induced Protofibril Formation of {alpha}-Synuclein
J. Biol. Chem.,
February 10, 2006;
281(6):
3463 - 3472.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. Singer and N. N. Dewji
Evidence that Perutz's double-beta-stranded subunit structure for beta-amyloids also applies to their channel-forming structures in membranes
PNAS,
January 31, 2006;
103(5):
1546 - 1550.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Oddo, A. Caccamo, L. Tran, M. P. Lambert, C. G. Glabe, W. L. Klein, and F. M. LaFerla
Temporal Profile of Amyloid-beta (Abeta) Oligomerization in an in Vivo Model of Alzheimer Disease: A LINK BETWEEN Abeta AND TAU PATHOLOGY
J. Biol. Chem.,
January 20, 2006;
281(3):
1599 - 1604.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Santos, R. A. Quintanilla, A. Toro, R. Grandy, M. C. Dinamarca, J. A. Godoy, and N. C. Inestrosa
Peroxisomal Proliferation Protects from {beta}-Amyloid Neurodegeneration
J. Biol. Chem.,
December 9, 2005;
280(49):
41057 - 41068.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Roselli, M. Tirard, J. Lu, P. Hutzler, P. Lamberti, P. Livrea, M. Morabito, and O. F. X. Almeida
Soluble {beta}-Amyloid1-40 Induces NMDA-Dependent Degradation of Postsynaptic Density-95 at Glutamatergic Synapses
J. Neurosci.,
November 30, 2005;
25(48):
11061 - 11070.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Ferrao-Gonzales, B. K. Robbs, V. H. Moreau, A. Ferreira, L. Juliano, A. P. Valente, F. C. L. Almeida, J. L. Silva, and D. Foguel
Controlling {beta}-Amyloid Oligomerization by the Use of Naphthalene Sulfonates: TRAPPING LOW MOLECULAR WEIGHT OLIGOMERIC SPECIES
J. Biol. Chem.,
October 14, 2005;
280(41):
34747 - 34754.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. S. Espeseth, M. Xu, Q. Huang, C. A. Coburn, K. L. G. Jones, M. Ferrer, P. D. Zuck, B. Strulovici, E. A. Price, G. Wu, et al.
Compounds That Bind APP and Inhibit A{beta} Processing in Vitro Suggest a Novel Approach to Alzheimer Disease Therapeutics
J. Biol. Chem.,
May 6, 2005;
280(18):
17792 - 17797.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
