8 August 2010. Antibodies to synthetic Aβ oligomers, or “globulomers,” improve cognition in a mouse model of Alzheimer disease, according to a paper in yesterday’s Journal of Neuroscience. Scientists led by Heinz Hillen and Ulrich Ebert at Abbot, Ludwigshafen, Germany, previously made the globulomers in an attempt to identify antibody epitopes that are specific to toxic forms of Aβ. As first reported from the 2005 Society for Neuroscience meeting at Washington, DC, N-terminal-truncated fragments of Aβ (Aβ20-42) form globulomers that blocked long-term potentiation, which is essential for learning and memory. The globs of Aβ also generated oligomer-selective antibodies (see ARF related news story). Unlike some other antibodies to Aβ oligomers, globulomer antibodies did not bind monomeric Aβ, its precursor protein, Aβ fibrils, or oligomers of other proteins such as α-synuclein. Now, the researchers show that passive and active vaccination against the globulomers protects mice against cognitive decline.
Hillen and colleagues report that the best of the antibodies, A-887755, protects cultured hippocampal neurons against Aβ toxicity, enhancing post-synaptic potentials in the presence of globulomers. In vivo, active immunization with the Aβ globulomers themselves proved beneficial to transgenic APP mice carrying the London mutation (APP/L). The researchers injected six-week-old animals with the globulomers, and three months later the mice performed as well as wild-type controls in a novel object recognition task. In contrast, untreated APP/L mice, or mice immunized with Aβ42, were impaired. Passive vaccination also appeared successful, the Abbott team claims. In 4.5-month-old APP/L mice, three weekly intraperitoneal injections of A-887755 reversed deficits in novel object recognition and rescued spatial memory impairment as judged by distance swum to the hidden platform in the Morris water maze.
It is not clear whether these globulomers have a natural counterpart. That A-887755 protects APP/L mice against cognitive loss and also recognizes Aβ species in extracts from human brain (see ARF related news story) argues, at the least, for the presence of an epitope shared by naturally occurring oligomers and these synthetic ones, the authors suggest. They contend that globulomer-directed immunotherapy may prove superior to other immune-based approaches because A-887755 will not be neutralized by non-toxic Aβ monomers, which are continually produced, and will not increase the risk of inflammatory responses that occurs when antibodies target fibrillar Aβ. “Strictly Aβ oligomer-specific monoclonal antibodies such as A-887755 that are devoid of any monomer or fibril binding will be extremely helpful tools to fully evaluate the therapeutic potential of Aβ oligomer-selective immunotherapy,” write the authors. Abbott is currently pursuing immunotherapy strategies for Alzheimer disease, but the programs are in early-stage development, according to a company spokesperson.—Tom Fagan.
Hillen H, Barghorn S, Striebinger A, Labkovsky B, Muller R, Nimmrich V, Nolte MW, Perez-Cruz C, van der Auwera I, van Leuven F, van Gaalen M, Bespalov AY, Schoemaker H, Sullivan JP, Ebert U. Generation and therapeutic efficacy of highly oligomer-specific beta-amyloid antibodies. Journal of Neuroscience 2010 August 4;30:10369-10379. Abstract