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