Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo

One of the most clinically advanced forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloid beta protein (A beta)(1-7), but how this may prevent cognitive impairment is unclear(8-13). We hypothesized that antibodies to A beta could exert a beneficial action by directly neutralizing potentially synaptotoxic soluble A beta species(14-16) in the brain. Intracerebroventricular injection of naturally secreted human A beta inhibited long-term potentiation (LTP), a correlate of learning and memory(17), in rat hippocampus in vivo but a monoclonal antibody to A beta completely prevented the inhibition of LTP when injected after A beta. Size fractionation showed that A beta oligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an A beta antibody again prevented such inhibition. Active immunization against A beta was partially effective, and the effects correlated positively with levels of antibodies to A beta oligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble A beta oligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease.