Alzheimer's disease immunotherapy: from in vitro amyloid immunomodulation to in vivo vaccination.

Site-directed antibodies which modulate conformation of amyloid-beta peptide (Abeta) became the theoretical basis of the immunological approach for treatment of Alzheimer's disease (AD). Indeed, antibodies towards the EFRH sequence, located between amino acids 3-6 of the N-terminal region of Abeta, found to be a key position in modulation of Abeta conformation, prevent formation of fibrillar Abeta and dissolve already formed amyloid plaques. The performance of anti-Abeta antibodies in transgenic mice models of AD showed they are delivered to the central nervous system (CNS), preventing and/or dissolving Abeta. Moreover, these antibodies protected the mice from learning and age-related memory deficits. Development of such antibodies via active and/or passive immunization against Abeta peptide fragments has been proposed for AD immunotherapeutic strategies. Experimental active immunization with fibrillar Abeta 1-42 in hu-mans was stopped in phase II clinical trials due to unexpected neuroinflammatory manifestations. In spite of the fact that it will take considerable effort to establish a suitable immunization procedure, these results clearly strengthen the hypothesis that Abeta plays a central role in AD, stimulating a new area for development of Alzheimer's immunotherapeutics.