Neutralization of Soluble, Synaptotoxic Amyloid β Species by Antibodies Is Epitope Specific

被引:53
作者
Zago, Wagner [1 ]
Buttini, Manuel [1 ]
Comery, Thomas A. [2 ]
Nishioka, Christopher [1 ]
Gardai, Shyra J. [1 ]
Seubert, Peter [1 ]
Games, Dora [1 ]
Bard, Frederique [1 ]
Schenk, Dale [1 ]
Kinney, Gene G. [1 ]
机构
[1] Janssen Alzheimer Immunotherapy Res & Dev, San Francisco, CA 94080 USA
[2] Pfizer Global Res & Dev, Groton, CT 06340 USA
关键词
ALZHEIMERS-DISEASE; A-BETA; MOUSE MODEL; TAU-HYPERPHOSPHORYLATION; DIFFUSIBLE LIGANDS; OLIGOMERS; IMMUNOTHERAPY; IMMUNIZATION; PEPTIDE; NEUROPATHOLOGY;
D O I
10.1523/JNEUROSCI.1676-11.2012
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Several anti-amyloid beta (A beta) antibodies are under evaluation for the treatment of Alzheimer's disease (AD). Clinical studies using the N-terminal-directed anti-A beta antibody bapineuzumab have demonstrated reduced brain PET-Pittsburg-B signals, suggesting the reduction of A beta plaques, and reduced levels of total and phosphorylated tau protein in the CSF of treated AD patients. Preclinical studies using 3D6 (the murine form of bapineuzumab) have demonstrated resolution of A beta plaque and vascular burdens, neuritic dystrophy, and preservation of synaptic density in the transgenic APP mouse models. In contrast, few studies have evaluated the direct interaction of this antibody with synaptotoxic soluble A beta species. In the current report, we demonstrated that 3D6 binds to soluble, synaptotoxic assemblies of A beta(1-42) and prevents multiple downstream functional consequences in rat hippocampal neurons including changes in glutamate AMPA receptor trafficking, AD-type tau phosphorylation, and loss of dendritic spines. In vivo, we further demonstrated that 3D6 prevents synaptic loss and acutely reverses the behavioral deficit in the contextual fear conditioning task in transgenic mouse models of AD, two endpoints thought to be linked to synaptotoxic soluble A beta moieties. Importantly C-terminal anti-A beta antibodies were ineffective on these endpoints. These results, taken with prior studies, suggest that N-terminal anti-A beta antibodies effectively interact with both soluble and insoluble forms of A beta and therefore appear particularly well suited for testing the A beta hypothesis of AD.
引用
收藏
页码:2696 / 2702
页数:7
相关论文
共 29 条
[1]   Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease [J].
Bard, F ;
Cannon, C ;
Barbour, R ;
Burke, RL ;
Games, D ;
Grajeda, H ;
Guido, T ;
Hu, K ;
Huang, JP ;
Johnson-Wood, K ;
Khan, K ;
Kholodenko, D ;
Lee, M ;
Lieberburg, I ;
Motter, R ;
Nguyen, M ;
Soriano, F ;
Vasquez, N ;
Weiss, K ;
Welch, B ;
Seubert, P ;
Schenk, D ;
Yednock, T .
NATURE MEDICINE, 2000, 6 (08) :916-919
[2]   Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer's disease-like neuropathology [J].
Bard, F ;
Barbour, R ;
Cannon, C ;
Carretto, R ;
Fox, M ;
Games, D ;
Guido, T ;
Hoenow, K ;
Hu, K ;
Johnson-Wood, K ;
Khan, K ;
Kholodenko, D ;
Lee, C ;
Lee, M ;
Motter, R ;
Nguyen, M ;
Reed, A ;
Schenk, D ;
Tang, P ;
Vasquez, N ;
Seubert, P ;
Yednock, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (04) :2023-2028
[3]   Structural Correlates of Antibodies Associated with Acute Reversal of Amyloid β-related Behavioral Deficits in a Mouse Model of Alzheimer Disease [J].
Basi, Guriqbal S. ;
Feinberg, Hadar ;
Oshidari, Farshid ;
Anderson, John ;
Barbour, Robin ;
Baker, Jeanne ;
Comery, Thomas A. ;
Diep, Linnea ;
Gill, Davinder ;
Johnson-Wood, Kelly ;
Goel, Amita ;
Grantcharova, Katerina ;
Lee, Mike ;
Li, Jingzhi ;
Partridge, Anthony ;
Griswold-Prenner, Irene ;
Piot, Nicolas ;
Walker, Don ;
Widom, Angela ;
Pangalos, Menelas N. ;
Seubert, Peter ;
Jacobsen, J. Steven ;
Schenk, Dale ;
Weis, William I. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (05) :3417-3427
[4]   A Single Ascending Dose Study of Bapineuzumab in Patients With Alzheimer Disease [J].
Black, Ronald S. ;
Sperling, Reisa A. ;
Safrstein, Beth ;
Motter, Ruth N. ;
Pallay, Allan ;
Nichols, Alice ;
Grundman, Michael .
ALZHEIMER DISEASE & ASSOCIATED DISORDERS, 2010, 24 (02) :198-203
[5]  
Blennow K, 2010, ALZH ASS INT C ALZH
[6]   β-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer's disease [J].
Buttini, M ;
Masliah, E ;
Barbour, R ;
Grajeda, H ;
Motter, R ;
Johnson-Wood, K ;
Khan, K ;
Seubert, P ;
Freedman, S ;
Schenk, D ;
Games, D .
JOURNAL OF NEUROSCIENCE, 2005, 25 (40) :9096-9101
[7]   Dynamin-dependent endocytosis of ionotropic glutamate receptors [J].
Carroll, RC ;
Beattie, EC ;
Xia, HH ;
Lüscher, C ;
Altschuler, Y ;
Nicoli, RA ;
Malenka, RC ;
von Zastrow, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (24) :14112-14117
[8]   The role of amyloid-beta derived diffusible ligands (ADDLs) in Alzheimer's disease [J].
Catalano, Susan M. ;
Dodson, Elizabeth C. ;
Henze, Darrell A. ;
Joyce, Joseph G. ;
Krafft, Grant A. ;
Kinney, Gene G. .
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2006, 6 (06) :597-608
[9]   Acute γ-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer's disease [J].
Comery, TA ;
Martone, RL ;
Aschmies, S ;
Atchison, KP ;
Diamantidis, G ;
Gong, XH ;
Zhou, H ;
Kreft, AF ;
Pangalos, MN ;
Sonnenberg-Reines, J ;
Jacobsen, JS ;
Marquis, KL .
JOURNAL OF NEUROSCIENCE, 2005, 25 (39) :8898-8902
[10]   Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers [J].
De Felice, Fernanda G. ;
Wu, Diana ;
Lambert, Mary P. ;
Fernandez, Sara J. ;
Velasco, Pauline T. ;
Lacor, Pascale N. ;
Bigio, Eileen H. ;
Jerecic, Jasna ;
Acton, Paul J. ;
Shughrue, Paul J. ;
Chen-Dodson, Elizabeth ;
Kinney, Gene G. ;
Klein, William L. .
NEUROBIOLOGY OF AGING, 2008, 29 (09) :1334-1347