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From the Roberts Center,*
Haldeman Laboratory, and Civin
Laboratory for Alzheimer's Research, Sun Health Research Institute,
Sun City, Arizona; Phenogenex,
La Jolla,
California; and Elan Pharmaceuticals,
South
San Francisco, California
We have characterized amyloid ß peptide (Aß) concentration, Aß deposition, paired helical filament formation, cerebrovascular amyloid angiopathy, apolipoprotein E (ApoE) allotype, and synaptophysin concentration in entorhinal cortex and superior frontal gyrus of normal elderly control (ND) patients, Alzheimer's disease (AD) patients, and high pathology control (HPC) patients who meet pathological criteria for AD but show no synapse loss or overt antemortem symptoms of dementia. The measures of Aß deposition, Aß-immunoreactive plaques with and without cores, thioflavin histofluorescent plaques, and concentrations of insoluble Aß, failed to distinguish HPC from AD patients and were poor correlates of synaptic change. By contrast, concentrations of soluble Aß clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss. Further investigation revealed that Aß40, whether in soluble or insoluble form, was a particularly useful measure for classifying ND, HPC, and AD patients compared with Aß42. Aß40 is known to be elevated in cerebrovascular amyloid deposits, and Aß40 (but not Aß42) levels, cerebrovascular amyloid angiopathy, and ApoE4 allele frequency were all highly correlated with each other. Although paired helical filaments in the form of neurofibrillary tangles or a penumbra of neurites surrounding amyloid cores also distinguished HPC from AD patients, they were less robust predictors of synapse change compared with soluble Aß, particularly soluble Aß40. Previous experiments attempting to relate Aß deposition to the neurodegeneration that underlies AD dementia may have failed because they assayed the classical, visible forms of the molecule, insoluble neuropil plaques, rather than the soluble, unseen forms of the molecule.
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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]
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 M. Townsend, G. M. Shankar, T. Mehta, D. M. Walsh, and D. J. Selkoe Effects of secreted oligomers of amyloid {beta}-protein on hippocampal synaptic plasticity: a potent role for trimers J. Physiol., April 15, 2006; 572(2): 477 - 492. [Abstract] [Full Text] [PDF]
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 S. Akhondzadeh and S. H. Abbasi Herbal medicine in the treatment of Alzheimer's disease American Journal of Alzheimer's Disease and Other Dementias, March 1, 2006; 21(2): 113 - 118. [Abstract] [PDF]
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E. B. Lee, L. Z. Leng, B. Zhang, L. Kwong, J. Q. Trojanowski, T. Abel, and V. M.-Y. Lee Targeting Amyloid-beta Peptide (Abeta) Oligomers by Passive Immunization with a Conformation-selective Monoclonal Antibody Improves Learning and Memory in Abeta Precursor Protein (APP) Transgenic Mice J. Biol. Chem., February 17, 2006; 281(7): 4292 - 4299. [Abstract] [Full Text] [PDF]
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J.-P. Guo, T. Arai, J. Miklossy, and P. L. McGeer From the Cover: Abeta and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer's disease PNAS, February 7, 2006; 103(6): 1953 - 1958. [Abstract] [Full Text] [PDF]
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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]
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 C. G. Glabe and R. Kayed Common structure and toxic function of amyloid oligomers implies a common mechanism of pathogenesis Neurology, January 24, 2006; 66(1_suppl_1): S74 - S78. [Abstract] [Full Text] [PDF]
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A. Fifre, I. Sponne, V. Koziel, B. Kriem, F. T. Y. Potin, B. E. Bihain, J.-L. Olivier, T. Oster, and T. Pillot Microtubule-associated Protein MAP1A, MAP1B, and MAP2 Proteolysis during Soluble Amyloid {beta}-Peptide-induced Neuronal Apoptosis: SYNERGISTIC INVOLVEMENT OF CALPAIN AND CASPASE-3 J. Biol. Chem., January 6, 2006; 281(1): 229 - 240. [Abstract] [Full Text] [PDF]
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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]
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A. Piccini, C. Russo, A. Gliozzi, A. Relini, A. Vitali, R. Borghi, L. Giliberto, A. Armirotti, C. D'Arrigo, A. Bachi, et al. {beta}-Amyloid Is Different in Normal Aging and in Alzheimer Disease J. Biol. Chem., October 7, 2005; 280(40): 34186 - 34192. [Abstract] [Full Text] [PDF]
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M. Buttini, E. Masliah, R. Barbour, H. Grajeda, R. Motter, K. Johnson-Wood, K. Khan, P. Seubert, S. Freedman, D. Schenk, et al. {beta}-Amyloid Immunotherapy Prevents Synaptic Degeneration in a Mouse Model of Alzheimer's Disease J. Neurosci., October 5, 2005; 25(40): 9096 - 9101. [Abstract] [Full Text] [PDF]
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T. A. Comery, R. L. Martone, S. Aschmies, K. P. Atchison, G. Diamantidis, X. Gong, H. Zhou, A. F. Kreft, M. N. Pangalos, J. Sonnenberg-Reines, et al. Acute {gamma}-Secretase Inhibition Improves Contextual Fear Conditioning in the Tg2576 Mouse Model of Alzheimer's Disease J. Neurosci., September 28, 2005; 25(39): 8898 - 8902. [Abstract] [Full Text] [PDF]
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B. L. Kelly, R. Vassar, and A. Ferreira {beta}-Amyloid-induced Dynamin 1 Depletion in Hippocampal Neurons: A POTENTIAL MECHANISM FOR EARLY COGNITIVE DECLINE IN ALZHEIMER DISEASE J. Biol. Chem., September 9, 2005; 280(36): 31746 - 31753. [Abstract] [Full Text] [PDF]
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B. P.F. Rutten, N. M. Van der Kolk, S. Schafer, M. A.M.J. van Zandvoort, T. A. Bayer, H. W.M. Steinbusch, and C. Schmitz Age-Related Loss of Synaptophysin Immunoreactive Presynaptic Boutons within the Hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L Transgenic Mice Am. J. Pathol., July 1, 2005; 167(1): 161 - 173. [Abstract] [Full Text] [PDF]
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 J. P. Tyszkiewicz and Z. Yan {beta}-Amyloid Peptides Impair PKC-Dependent Functions of Metabotropic Glutamate Receptors in Prefrontal Cortical Neurons J Neurophysiol, June 1, 2005; 93(6): 3102 - 3111. [Abstract] [Full Text] [PDF]
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A. Demuro, E. Mina, R. Kayed, S. C. Milton, I. Parker, and C. G. Glabe Calcium Dysregulation and Membrane Disruption as a Ubiquitous Neurotoxic Mechanism of Soluble Amyloid Oligomers J. Biol. Chem., April 29, 2005; 280(17): 17294 - 17300. [Abstract] [Full Text] [PDF]
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D. M. Walsh, M. Townsend, M. B. Podlisny, G. M. Shankar, J. V. Fadeeva, O. E. Agnaf, D. M. Hartley, and D. J. Selkoe Certain Inhibitors of Synthetic Amyloid {beta}-Peptide (A{beta}) Fibrillogenesis Block Oligomerization of Natural A{beta} and Thereby Rescue Long-Term Potentiation J. Neurosci., March 9, 2005; 25(10): 2455 - 2462. [Abstract] [Full Text] [PDF]
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E. O. Lee, J. L. Kang, and Y. H. Chong The Amyloid-{beta} Peptide Suppresses Transforming Growth Factor-{beta}1-induced Matrix Metalloproteinase-2 Production via Smad7 Expression in Human Monocytic THP-1 Cells J. Biol. Chem., March 4, 2005; 280(9): 7845 - 7853. [Abstract] [Full Text] [PDF]
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M. Wogulis, S. Wright, D. Cunningham, T. Chilcote, K. Powell, and R. E. Rydel Nucleation-Dependent Polymerization Is an Essential Component of Amyloid-Mediated Neuronal Cell Death J. Neurosci., February 2, 2005; 25(5): 1071 - 1080. [Abstract] [Full Text] [PDF]
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K. H. Gylys, J. A. Fein, F. Yang, D. J. Wiley, C. A. Miller, and G. M. Cole Synaptic Changes in Alzheimer's Disease: Increased Amyloid-{beta} and Gliosis in Surviving Terminals Is Accompanied by Decreased PSD-95 Fluorescence Am. J. Pathol., November 1, 2004; 165(5): 1809 - 1817. [Abstract] [Full Text] [PDF]
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J. Ghiso, M. Shayo, M. Calero, D. Ng, Y. Tomidokoro, S. Gandy, A. Rostagno, and B. Frangione Systemic Catabolism of Alzheimer's A{beta}40 and A{beta}42 J. Biol. Chem., October 29, 2004; 279(44): 45897 - 45908. [Abstract] [Full Text] [PDF]
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P. Coleman, H. Federoff, and R. Kurlan A focus on the synapse for neuroprotection in Alzheimer disease and other dementias Neurology, October 12, 2004; 63(7): 1155 - 1162. [Abstract] [Full Text] [PDF]
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G. D. Ciccotosto, D. Tew, C. C. Curtain, D. Smith, D. Carrington, C. L. Masters, A. I. Bush, R. A. Cherny, R. Cappai, and K. J. Barnham Enhanced Toxicity and Cellular Binding of a Modified Amyloid {beta} Peptide with a Methionine to Valine Substitution J. Biol. Chem., October 8, 2004; 279(41): 42528 - 42534. [Abstract] [Full Text] [PDF]
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F. G. DE FELICE, M. N. N. VIEIRA, L. M. SARAIVA, J. D. FIGUEROA-VILLAR, J. GARCIA-ABREU, R. LIU, L. CHANG, W. L. KLEIN, and S. T. FERREIRA Targeting the neurotoxic species in Alzheimer's disease: inhibitors of A{beta} oligomerization FASEB J, September 1, 2004; 18(12): 1366 - 1372. [Abstract] [Full Text] [PDF]
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L. Tong, R. Balazs, P. L. Thornton, and C. W. Cotman {beta}-Amyloid Peptide at Sublethal Concentrations Downregulates Brain-Derived Neurotrophic Factor Functions in Cultured Cortical Neurons J. Neurosci., July 28, 2004; 24(30): 6799 - 6809. [Abstract] [Full Text] [PDF]
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C.-C. Wu, F. Chawla, D. Games, R. E. Rydel, S. Freedman, D. Schenk, W. G. Young, J. H. Morrison, and F. E. Bloom Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: Digital morphometric analyses PNAS, May 4, 2004; 101(18): 7141 - 7146. [Abstract] [Full Text] [PDF]
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I. Greeve, D. Kretzschmar, J.-A. Tschape, A. Beyn, C. Brellinger, M. Schweizer, R. M. Nitsch, and R. Reifegerste Age-Dependent Neurodegeneration and Alzheimer-Amyloid Plaque Formation in Transgenic Drosophila J. Neurosci., April 21, 2004; 24(16): 3899 - 3906. [Abstract] [Full Text] [PDF]
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T. Kawarabayashi, M. Shoji, L. H. Younkin, L. Wen-Lang, D. W. Dickson, T. Murakami, E. Matsubara, K. Abe, K. H. Ashe, and S. G. Younkin Dimeric Amyloid {beta} Protein Rapidly Accumulates in Lipid Rafts followed by Apolipoprotein E and Phosphorylated Tau Accumulation in the Tg2576 Mouse Model of Alzheimer's Disease J. Neurosci., April 14, 2004; 24(15): 3801 - 3809. [Abstract] [Full Text] [PDF]
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W. Farris, S. Mansourian, M. A. Leissring, E. A. Eckman, L. Bertram, C. B. Eckman, R. E. Tanzi, and D. J. Selkoe Partial Loss-of-Function Mutations in Insulin-Degrading Enzyme that Induce Diabetes also Impair Degradation of Amyloid {beta}-Protein Am. J. Pathol., April 1, 2004; 164(4): 1425 - 1434. [Abstract] [Full Text] [PDF]
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Z. Suo, M. Wu, B. A. Citron, G. T. Wong, and B. W. Festoff Abnormality of G-Protein-Coupled Receptor Kinases at Prodromal and Early Stages of Alzheimer's Disease: An Association with Early {beta}-Amyloid Accumulation J. Neurosci., March 31, 2004; 24(13): 3444 - 3452. [Abstract] [Full Text] [PDF]
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A. L. Friedlich, J.-Y. Lee, T. van Groen, R. A. Cherny, I. Volitakis, T. B. Cole, R. D. Palmiter, J.-Y. Koh, and A. I. Bush Neuronal Zinc Exchange with the Blood Vessel Wall Promotes Cerebral Amyloid Angiopathy in an Animal Model of Alzheimer's Disease J. Neurosci., March 31, 2004; 24(13): 3453 - 3459. [Abstract] [Full Text] [PDF]
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R. A. Nixon Niemann-Pick Type C Disease and Alzheimer's Disease: The APP-Endosome Connection Fattens Up Am. J. Pathol., March 1, 2004; 164(3): 757 - 761. [Abstract] [Full Text] [PDF]
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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): 991 - 998. [Abstract] [Full Text] [PDF]
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C. V. Zerbinatti, D. F. Wozniak, J. Cirrito, J. A. Cam, H. Osaka, K. R. Bales, M. Zhuo, S. M. Paul, D. M. Holtzman, and G. Bu Increased soluble amyloid-{beta} peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein PNAS, January 27, 2004; 101(4): 1075 - 1080. [Abstract] [Full Text] [PDF]
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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; 64(5): 1160 - 1168. [Abstract] [Full Text] [PDF]
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J. G. Richards, G. A. Higgins, A.-M. Ouagazzal, L. Ozmen, J. N. C. Kew, B. Bohrmann, P. Malherbe, M. Brockhaus, H. Loetscher, C. Czech, et al. PS2APP Transgenic Mice, Coexpressing hPS2mut and hAPPswe, Show Age-Related Cognitive Deficits Associated with Discrete Brain Amyloid Deposition and Inflammation J. Neurosci., October 1, 2003; 23(26): 8989 - 9003. [Abstract] [Full Text] [PDF]
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J. J. Dougherty, J. Wu, and R. A. Nichols {beta}-Amyloid Regulation of Presynaptic Nicotinic Receptors in Rat Hippocampus and Neocortex J. Neurosci., July 30, 2003; 23(17): 6740 - 6747. [Abstract] [Full Text] [PDF]
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E. Masliah, M. Alford, A. Adame, E. Rockenstein, D. Galasko, D. Salmon, L. A. Hansen, and L. J. Thal A{beta}1-42 promotes cholinergic sprouting in patients with AD and Lewy body variant of AD Neurology, July 22, 2003; 61(2): 206 - 211. [Abstract] [Full Text] [PDF]
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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] [Full Text] [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; 300(5618): 486 - 489. [Abstract] [Full Text] [PDF]
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W. Farris, S. Mansourian, Y. Chang, L. Lindsley, E. A. Eckman, M. P. Frosch, C. B. Eckman, R. E. Tanzi, D. J. Selkoe, and S. Guenette Insulin-degrading enzyme regulates the levels of insulin, amyloid beta -protein, and the beta -amyloid precursor protein intracellular domain in vivo PNAS, April 1, 2003; 100(7): 4162 - 4167. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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J. M. Redwine, B. Kosofsky, R. E. Jacobs, D. Games, J. F. Reilly, J. H. Morrison, W. G. Young, and F. E. Bloom Dentate gyrus volume is reduced before onset of plaque formation in PDAPP mice: A magnetic resonance microscopy and stereologic analysis PNAS, February 4, 2003; 100(3): 1381 - 1386. [Abstract] [Full Text] [PDF]
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I. Sponne, A. Fifre, B. Drouet, C. Klein, V. Koziel, M. Pincon-Raymond, J.-L. Olivier, J. Chambaz, and T. Pillot Apoptotic Neuronal Cell Death Induced by the Non-fibrillar Amyloid-beta Peptide Proceeds through an Early Reactive Oxygen Species-dependent Cytoskeleton Perturbation J. Biol. Chem., January 24, 2003; 278(5): 3437 - 3445. [Abstract] [Full Text] [PDF]
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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; 22(24): 10539 - 10548. [Abstract] [Full Text] [PDF]
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D. J. Selkoe Alzheimer's Disease Is a Synaptic Failure Science, October 25, 2002; 298(5594): 789 - 791. [Abstract] [Full Text] [PDF]
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M. H. Mohajeri, K. Saini, J. G. Schultz, M. A. Wollmer, C. Hock, and R. M. Nitsch Passive Immunization against beta -Amyloid Peptide Protects Central Nervous System (CNS) Neurons from Increased Vulnerability Associated with an Alzheimer's Disease-causing Mutation J. Biol. Chem., August 30, 2002; 277(36): 33012 - 33017. [Abstract] [Full Text] [PDF]
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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; 277(35): 32046 - 32053. [Abstract] [Full Text] [PDF]
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A. Delacourte, N. Sergeant, D. Champain, A. Wattez, C.-A. Maurage, F. Lebert, F. Pasquier, and J.-P. David Nonoverlapping but synergetic tau and APP pathologies in sporadic Alzheimer's disease Neurology, August 13, 2002; 59(3): 398 - 407. [Abstract] [Full Text] [PDF]
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A. I. Bush and R. E. Tanzi The galvanization of beta -amyloid in Alzheimer's disease PNAS, May 28, 2002; 99(11): 7317 - 7319. [Full Text] [PDF]
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M. C. Sugarman, T. R. Yamasaki, S. Oddo, J. C. Echegoyen, M. P. Murphy, T. E. Golde, M. Jannatipour, M. A. Leissring, and F. M. LaFerla Inclusion body myositis-like phenotype induced by transgenic overexpression of beta APP in skeletal muscle PNAS, April 30, 2002; 99(9): 6334 - 6339. [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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E. Masliah, M. Mallory, M. Alford, R. DeTeresa, L.A. Hansen, D.W. McKeel Jr., and J.C. Morris Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease Neurology, January 9, 2001; 56(1): 127 - 129. [Abstract] [Full Text] [PDF]
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L. Mucke, G.-Q. Yu, L. McConlogue, E. M. Rockenstein, C. R. Abraham, and E. Masliah Astroglial Expression of Human {{alpha}}1-Antichymotrypsin Enhances Alzheimer-like Pathology in Amyloid Protein Precursor Transgenic Mice Am. J. Pathol., December 1, 2000; 157(6): 2003 - 2010. [Abstract] [Full Text] [PDF]
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I. Dewachter, J. Van Dorpe, L. Smeijers, M. Gilis, C. Kuiperi, I. Laenen, N. Caluwaerts, D. Moechars, F. Checler, H. Vanderstichele, et al. Aging Increased Amyloid Peptide and Caused Amyloid Plaques in Brain of Old APP/V717I Transgenic Mice by a Different Mechanism than Mutant Presenilin1 J. Neurosci., September 1, 2000; 20(17): 6452 - 6458. [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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Y.-M. Kuo, T. A. Kokjohn, M. D. Watson, A. S. Woods, R. J. Cotter, L. I. Sue, W. M. Kalback, M. R. Emmerling, T. G. Beach, and A. E. Roher Elevated A{beta}42 in Skeletal Muscle of Alzheimer Disease Patients Suggests Peripheral Alterations of A{beta}PP Metabolism Am. J. Pathol., March 1, 2000; 156(3): 797 - 805. [Abstract] [Full Text] [PDF]
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Y.-M. Kuo, T. A. Kokjohn, T. G. Beach, L. I. Sue, D. Brune, J. C. Lopez, W. M. Kalback, D. Abramowski, C. Sturchler-Pierrat, M. Staufenbiel, et al. Comparative Analysis of Amyloid-beta Chemical Structure and Amyloid Plaque Morphology of Transgenic Mouse and Alzheimer's Disease Brains J. Biol. Chem., April 13, 2001; 276(16): 12991 - 12998. [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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