Amyloidßprotein immunotherapy neutralizes Aßoligomers 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 amyloidßprotein (Aß), but how this may prevent cognitive impairment is unclear. We hypothesized that antibodies to Aßcould exert a beneficial action by directly neutralizing potentially synaptotoxic soluble Aßspecies in the brain. Intracerebroventricular injection of naturally secreted human Aßinhibited long-term potentiation (LTP), a correlate of learning and memory, in rat hippocampus in vivo but a monoclonal antibody to Aßcompletely prevented the inhibition of LTP when injected after Aß. Size fractionation showed that Aßoligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an Aßantibody again prevented such inhibition. Active immunization against Aßwas partially effective, and the effects correlated positively with levels of antibodies to Aßoligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble Aßoligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease. [ABSTRACT FROM AUTHOR]