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The Journal of Neuroscience, October 15, 1999, 19(20):8876-8884
Protofibrillar Intermediates of Amyloid -Protein Induce Acute
Electrophysiological Changes and Progressive Neurotoxicity in Cortical
Neurons
Dean M.
Hartley2,
Dominic M.
Walsh2,
Chianping P.
Ye1, 3,
Thekla
Diehl2,
Sara
Vasquez2,
Peter M.
Vassilev1, 3,
David B.
Teplow2, and
Dennis. J.
Selkoe2
1 Department of Neurology and Medicine,
Harvard Medical School, and the 2 Center for
Neurologic Diseases and 3 Division of
Endocrinology, Department of Medicine, Brigham and Women's Hospital,
Boston, Massachusetts 02115
Alzheimer's disease (AD) is a progressive neurodegenerative
disorder that is thought to be caused in part by the age-related accumulation of amyloid -protein (A ). The presence of neuritic plaques containing abundant A -derived amyloid fibrils in AD brain tissue supports the concept that fibril accumulation per se underlies neuronal dysfunction in AD. Recent observations have begun to challenge
this assumption by suggesting that earlier A assemblies formed
during the process of fibrillogenesis may also play a role in AD
pathogenesis. Here, we present the novel finding that protofibrils (PF), metastable intermediates in amyloid fibril formation, can alter
the electrical activity of neurons and cause neuronal loss. Both low
molecular weight A (LMW A ) and PF reproducibly induced toxicity
in mixed brain cultures in a time- and concentration-dependent manner.
No increase in fibril formation during the course of the experiments
was observed by either Congo red binding or electron microscopy,
suggesting that the neurotoxicity of LMW A and PF cannot be
explained by conversion to fibrils. Importantly, protofibrils, but not
LMW A , produced a rapid increase in EPSPs, action potentials, and membrane depolarizations. These data suggest that PF have inherent
biological activity similar to that of mature fibrils. Our results
raise the possibility that the preclinical and early clinical
progression of AD is driven in part by the accumulation of specific
A assembly intermediates formed during the process of fibrillogenesis.
Key words:
Alzheimer; amyloid -protein; neurotoxicity; electrophysiology; fibrillogenesis; neurodegeneration
Copyright © 1999 Society for Neuroscience 0270-6474/99/19208876-09$05.00/0
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N. Iwata, H. Mizukami, K. Shirotani, Y. Takaki, S.-i. Muramatsu, B. Lu, N. P. Gerard, C. Gerard, K. Ozawa, and T. C. Saido
Presynaptic Localization of Neprilysin Contributes to Efficient Clearance of Amyloid-{beta} Peptide in Mouse Brain
J. Neurosci.,
January 28, 2004;
24(4):
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[Abstract]
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M. A. Moss, M. R. Nichols, D. K. Reed, J. H. Hoh, and T. L. Rosenberry
The Peptide KLVFF-K6 Promotes {beta}-Amyloid(1-40) Protofibril Growth by Association but Does Not Alter Protofibril Effects on Cellular Reduction of 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide (MTT)
Mol. Pharmacol.,
November 1, 2003;
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[Abstract]
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J. R. Kim, T. J. Gibson, and R. M. Murphy
Targeted Control of Kinetics of {beta}-Amyloid Self-association by Surface Tension-modifying Peptides
J. Biol. Chem.,
October 17, 2003;
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A. Ferrari, F. Hoerndli, T. Baechi, R. M. Nitsch, and J. Gotz
{beta}-Amyloid Induces Paired Helical Filament-like Tau Filaments in Tissue Culture
J. Biol. Chem.,
October 10, 2003;
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D. D. Mousseau, S. Chapelsky, G. De Crescenzo, M. D. Kirkitadze, J. Magoon, S. Inoue, D. B. Teplow, and M. D. O'Connor-McCourt
A Direct Interaction between Transforming Growth Factor (TGF)-{beta}s and Amyloid-{beta} Protein Affects Fibrillogenesis in a TGF-{beta}Receptor-independent Manner
J. Biol. Chem.,
October 3, 2003;
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J. R. Cirrito, P. C. May, M. A. O'Dell, J. W. Taylor, M. Parsadanian, J. W. Cramer, J. E. Audia, J. S. Nissen, K. R. Bales, S. M. Paul, et al.
In Vivo Assessment of Brain Interstitial Fluid with Microdialysis Reveals Plaque-Associated Changes in Amyloid-{beta} Metabolism and Half-Life
J. Neurosci.,
October 1, 2003;
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H. Hiruma, T. Katakura, S. Takahashi, T. Ichikawa, and T. Kawakami
Glutamate and Amyloid {beta}-Protein Rapidly Inhibit Fast Axonal Transport in Cultured Rat Hippocampal Neurons by Different Mechanisms
J. Neurosci.,
October 1, 2003;
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G. Bitan, S. S. Vollers, and D. B. Teplow
Elucidation of Primary Structure Elements Controlling Early Amyloid {beta}-Protein Oligomerization
J. Biol. Chem.,
September 12, 2003;
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M. Tanaka, Y. Machida, Y. Nishikawa, T. Akagi, T. Hashikawa, T. Fujisawa, and N. Nukina
Expansion of Polyglutamine Induces the Formation of Quasi-aggregate in the Early Stage of Protein Fibrillization
J. Biol. Chem.,
September 5, 2003;
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Y. Gong, L. Chang, K. L. Viola, P. N. Lacor, M. P Lambert, C. E. Finch, G. A. Krafft, and W. L. Klein
Alzheimer's disease-affected brain: Presence of oligomeric A{beta} ligands (ADDLs) suggests a molecular basis for reversible memory loss
PNAS,
September 2, 2003;
100(18):
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[Abstract]
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G. Merlini and V. Bellotti
Molecular Mechanisms of Amyloidosis
N. Engl. J. Med.,
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I. Qahwash, K. L. Weiland, Y. Lu, R. W. Sarver, R. F. Kletzien, and R. Yan
Identification of a Mutant Amyloid Peptide That Predominantly Forms Neurotoxic Protofibrillar Aggregates
J. Biol. Chem.,
June 13, 2003;
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[Abstract]
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M. Hoshi, M. Sato, S. Matsumoto, A. Noguchi, K. Yasutake, N. Yoshida, and K. Sato
Spherical aggregates of {beta}-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3{beta}
PNAS,
May 27, 2003;
100(11):
6370 - 6375.
[Abstract]
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[PDF]
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R. Kayed, E. Head, J. L. Thompson, T. M. McIntire, S. C. Milton, C. W. Cotman, and C. G. Glabe
Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis
Science,
April 18, 2003;
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[Abstract]
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W. B. Stine Jr., K. N. Dahlgren, G. A. Krafft, and M. J. LaDu
In Vitro Characterization of Conditions for Amyloid-beta Peptide Oligomerization and Fibrillogenesis
J. Biol. Chem.,
March 21, 2003;
278(13):
11612 - 11622.
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G. Bitan, M. D. Kirkitadze, A. Lomakin, S. S. Vollers, G. B. Benedek, and D. B. Teplow
Amyloid beta -protein (Abeta ) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways
PNAS,
January 7, 2003;
100(1):
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[Abstract]
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M. Buttini, G.-Q. Yu, K. Shockley, Y. Huang, B. Jones, E. Masliah, M. Mallory, T. Yeo, F. M. Longo, and L. Mucke
Modulation of Alzheimer-Like Synaptic and Cholinergic Deficits in Transgenic Mice by Human Apolipoprotein E Depends on Isoform , Aging, and Overexpression of Amyloid beta Peptides But Not on Plaque Formation
J. Neurosci.,
December 15, 2002;
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H. A. Lashuel, D. M. Hartley, D. Balakhaneh, A. Aggarwal, S. Teichberg, and D. J. E. Callaway
New Class of Inhibitors of Amyloid-beta Fibril Formation. IMPLICATIONS FOR THE MECHANISM OF PATHOGENESIS IN ALZHEIMER'S DISEASE
J. Biol. Chem.,
November 1, 2002;
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D. J. Selkoe
Alzheimer's Disease Is a Synaptic Failure
Science,
October 25, 2002;
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[Abstract]
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L. Hou, I. Kang, R. E. Marchant, and M. G. Zagorski
Methionine 35 Oxidation Reduces Fibril Assembly of the Amyloid Abeta -(1-42) Peptide of Alzheimer's Disease
J. Biol. Chem.,
October 18, 2002;
277(43):
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[Abstract]
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Y. Luo, J. V. Smith, V. Paramasivam, A. Burdick, K. J. Curry, J. P. Buford, I. Khan, W. J. Netzer, H. Xu, and P. Butko
Inhibition of amyloid-beta aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761
PNAS,
September 17, 2002;
99(19):
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[Abstract]
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[PDF]
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Y.-H. Suh and F. Checler
Amyloid Precursor Protein, Presenilins, and alpha -Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease
Pharmacol. Rev.,
September 1, 2002;
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K. N. Dahlgren, A. M. Manelli, W. B. Stine Jr., L. K. Baker, G. A. Krafft, and M. J. LaDu
Oligomeric and Fibrillar Species of Amyloid-beta Peptides Differentially Affect Neuronal Viability
J. Biol. Chem.,
August 23, 2002;
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R. B. DeMattos, M. A. O'dell, M. Parsadanian, J. W. Taylor, J. A. K. Harmony, K. R. Bales, S. M. Paul, B. J. Aronow, and D. M. Holtzman
Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease
PNAS,
August 6, 2002;
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[Abstract]
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K. T. Dineley, K. A. Bell, D. Bui, and J. D. Sweatt
beta -Amyloid Peptide Activates alpha 7 Nicotinic Acetylcholine Receptors Expressed in Xenopus Oocytes
J. Biol. Chem.,
July 5, 2002;
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K. Zou, J.-S. Gong, K. Yanagisawa, and M. Michikawa
A Novel Function of Monomeric Amyloid beta -Protein Serving as an Antioxidant Molecule against Metal-Induced Oxidative Damage
J. Neurosci.,
June 15, 2002;
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K. T. Dineley, X. Xia, D. Bui, J. D. Sweatt, and H. Zheng
Accelerated Plaque Accumulation, Associative Learning Deficits, and Up-regulation of alpha 7 Nicotinic Receptor Protein in Transgenic Mice Co-expressing Mutant Human Presenilin 1 and Amyloid Precursor Proteins
J. Biol. Chem.,
June 14, 2002;
277(25):
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M. A. Westerman, D. Cooper-Blacketer, A. Mariash, L. Kotilinek, T. Kawarabayashi, L. H. Younkin, G. A. Carlson, S. G. Younkin, and K. H. Ashe
The Relationship between Abeta and Memory in the Tg2576 Mouse Model of Alzheimer's Disease
J. Neurosci.,
March 1, 2002;
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[Abstract]
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M. Koistinaho, M. Ort, J. M. Cimadevilla, R. Vondrous, B. Cordell, J. Koistinaho, J. Bures, and L. S. Higgins
Specific spatial learning deficits become severe with age in beta -amyloid precursor protein transgenic mice that harbor diffuse beta -amyloid deposits but do not form plaques
PNAS,
November 20, 2001;
(2001)
261562998.
[Abstract]
[Full Text]
[PDF]
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S. S.-S. Wang, D. L. Rymer, and T. A. Good
Reduction in Cholesterol and Sialic Acid Content Protects Cells from the Toxic Effects of beta -Amyloid Peptides
J. Biol. Chem.,
November 2, 2001;
276(45):
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K. H. Ashe
Learning and Memory in Transgenic Mice Modeling Alzheimer's Disease
Learn. Mem.,
November 1, 2001;
8(6):
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[Abstract]
[Full Text]
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H. LIN, R. BHATIA, and R. LAL
Amyloid {beta} protein forms ion channels: implications for Alzheimer's disease pathophysiology
FASEB J,
November 1, 2001;
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[Abstract]
[Full Text]
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H. YAZAWA, Z.-X. YU, TAKEDA, Y. LE, W. GONG, V. J. FERRANS, J. J. OPPENHEIM, C. C. H. LI, and J. M. WANG
{beta} Amyloid peptide (A{beta}42) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages
FASEB J,
November 1, 2001;
15(13):
2454 - 2462.
[Abstract]
[Full Text]
[PDF]
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W. T. Kimberly, J. B. Zheng, S. Y. Guenette, and D. J. Selkoe
The Intracellular Domain of the beta -Amyloid Precursor Protein Is Stabilized by Fe65 and Translocates to the Nucleus in a Notch-like Manner
J. Biol. Chem.,
October 19, 2001;
276(43):
40288 - 40292.
[Abstract]
[Full Text]
[PDF]
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M. Michikawa, J.-S. Gong, Q.-W. Fan, N. Sawamura, and K. Yanagisawa
A Novel Action of Alzheimer's Amyloid {beta}-Protein (A{beta}): Oligomeric A{beta} Promotes Lipid Release
J. Neurosci.,
September 15, 2001;
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[Abstract]
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K. T. Dineley, M. Westerman, D. Bui, K. Bell, K. H. Ashe, and J. D. Sweatt
{beta}-Amyloid Activates the Mitogen-Activated Protein Kinase Cascade via Hippocampal {alpha}7 Nicotinic Acetylcholine Receptors: In Vitro and In Vivo Mechanisms Related to Alzheimer's Disease
J. Neurosci.,
June 15, 2001;
21(12):
4125 - 4133.
[Abstract]
[Full Text]
[PDF]
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D. J. Selkoe
Alzheimer's Disease: Genes, Proteins, and Therapy
Physiol Rev,
April 1, 2001;
81(2):
741 - 766.
[Abstract]
[Full Text]
[PDF]
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J.-H. Kim, R. Anwyl, Y.-H. Suh, M. B. A. Djamgoz, and M. J. Rowan
Use-Dependent Effects of Amyloidogenic Fragments of {beta}-Amyloid Precursor Protein on Synaptic Plasticity in Rat Hippocampus In Vivo
J. Neurosci.,
February 15, 2001;
21(4):
1327 - 1333.
[Abstract]
[Full Text]
[PDF]
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R. Siman, A. G. Reaume, M. J. Savage, S. Trusko, Y.-G. Lin, R. W. Scott, and D. G. Flood
Presenilin-1 P264L Knock-In Mutation: Differential Effects on Abeta Production, Amyloid Deposition, and Neuronal Vulnerability
J. Neurosci.,
December 1, 2000;
20(23):
8717 - 8726.
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S. Kumar-Singh, C. De Jonghe, M. Cruts, R. Kleinert, R. Wang, M. Mercken, B. De Strooper, H. Vanderstichele, A. Lofgren, I. Vanderhoeven, et al.
Nonfibrillar diffuse amyloid deposition due to a {gamma}42-secretase site mutation points to an essential role for N-truncated A{beta}42 in Alzheimer's disease
Hum. Mol. Genet.,
November 1, 2000;
9(18):
2589 - 2598.
[Abstract]
[Full Text]
[PDF]
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L. Mucke, E. Masliah, G.-Q. Yu, M. Mallory, E. M. Rockenstein, G. Tatsuno, K. Hu, D. Kholodenko, K. Johnson-Wood, and L. McConlogue
High-Level Neuronal Expression of Abeta 1-42 in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation
J. Neurosci.,
June 1, 2000;
20(11):
4050 - 4058.
[Abstract]
[Full Text]
[PDF]
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D. L. Rymer and T. A. Good
The Role of G Protein Activation in the Toxicity of Amyloidogenic Abeta -(1-40), Abeta -(25-35), and Bovine Calcitonin
J. Biol. Chem.,
January 19, 2001;
276(4):
2523 - 2530.
[Abstract]
[Full Text]
[PDF]
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L. Tong, P. L. Thornton, R. Balazs, and C. W. Cotman
beta -Amyloid-(1-42) Impairs Activity-dependent cAMP-response Element-binding Protein Signaling in Neurons at Concentrations in Which Cell Survival Is Not Compromised
J. Biol. Chem.,
May 11, 2001;
276(20):
17301 - 17306.
[Abstract]
[Full Text]
[PDF]
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M. Koistinaho, M. Ort, J. M. Cimadevilla, R. Vondrous, B. Cordell, J. Koistinaho, J. Bures, and L. S. Higgins
Specific spatial learning deficits become severe with age in beta -amyloid precursor protein transgenic mice that harbor diffuse beta -amyloid deposits but do not form plaques
PNAS,
December 4, 2001;
98(25):
14675 - 14680.
[Abstract]
[Full Text]
[PDF]
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