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

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