Anti-Aβ antibodies incapable of reducing cerebral Aβ oligomers fail to attenuate spatial reference memory deficits in J20 mice

Neurobiology of Disease

Cynthia A. Lemere¹  Brian O'Nuallain²  Frédérique Bard³  Wen Liu⁴  Dominic M. Walsh⁴  Jessica M. Mc Donald⁴  Alexandra J. Mably⁴  Jean-Cosme Dodart⁵ 

[1] Development 700 Gateway Boulevard, South San Francisco, CA 94080, United States;Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, United States;;Janssen Alzheimer Immunotherapy Research &Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, United States;NeuroBehaviour Laboratory Core, Harvard NeuroDiscovery Center, 77 Avenue Louis Pasteur, Boston, MA 02115, United States;

关键词: Alzheimer's disease;    Amyloid β-protein;    Immunotherapy;    Oligomers;    APP transgenic mice;   

DOI  :  

来源: DOAJ

【 摘 要 】

Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer's disease (AD). A leading hypothesis proposes that a small amphipathic fragment of APP, the amyloid β-protein (Aβ), self-associates to form soluble assemblies loosely referred to as “oligomers” and that these are primary mediators of synaptic dysfunction. As such, Aβ, and specifically Aβ oligomers, are targets for disease modifying therapies. Currently, the most advanced experimental treatment for AD relies on the use of anti-Aβ antibodies. In this study, we tested the ability of the monomer-preferring antibody, m266 and a novel aggregate-preferring antibody, 1C22, to attenuate spatial reference memory impairments in J20 mice. Chronic treatment with m266 resulted in a ~70-fold increase in Aβ detected in the bloodstream, and a ~50% increase in water-soluble brain Aβ — and in both cases Aβ was bound to m266. In contrast, 1C22 increased the levels of free Aβ in the bloodstream, and bound to amyloid deposits in J20 brain. However, neither 1C22 nor m266 attenuated the cognitive deficits evident in 12 month old J20 mice. Moreover, both antibodies failed to alter the levels of soluble Aβ oligomers in J20 brain. These results suggest that Aβ oligomers may mediate the behavioral deficits seen in J20 mice and highlight the need for the development of aggregate-preferring antibodies that can reach the brain in sufficient levels to neutralize bioactive Aβ oligomers.Aside from the lack of positive effect of m266 and 1C22 on cognition, a substantial number of deaths occurred in m266- and 1C22-immunized J20 mice. These fatalities were specific to anti-Aβ antibodies and to the J20 mouse line since treatment of wild type or PDAPP mice with these antibodies did not cause any deaths. These and other recent results indicate that J20 mice are particularly susceptible to targeting of the APP/Aβ/tau axis. Notwithstanding the specificity of fatalities for J20 mice, it is worrying that the murine precursor (m266) of a lead experimental therapeutic, Solanezumab, did not engage with putatively pathogenic Aβ oligomers.

【 授权许可】

Unknown