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

Site-directed antibodies which modulate conformation of amyloid-β peptide (Aβ) 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 Aβ, found to be a key position in modulation of Aβ conformation, prevent formation of fibrillar Aβ and dissolve already formed amyloid plaques. The performance of anti-Aβ antibodies in transgenic mice models of AD showed they are delivered to the central nervous system (CNS), preventing and/or dissolving Aβ. Moreover, these antibodies protected the mice from learning and age-related memory deficits. Development of such antibodies via active and/or passive immunization against Aβ peptide fragments has been proposed for AD immunotherapeutic strategies. Experimental active immunization with fibrillar Aβ 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 Aβ plays a central role in AD, stimulating a new area for development of Alzheimer's immunotherapeutics.