Alzheimer's disease and immunotherapy.
Site-directed antibodies which modulate conformation of beta-amyloid peptide 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 Alzheimer's AbetaP, found to be a key position in protein conformation modulation, suppress formation of beta-amyloid and dissolve already formed fibrillar amyloid. The performance of anti-beta-amyloid antibodies in transgenic mice models of AD showed they are delivered to the central nervous system (CNS), preventing and dissolving beta-amyloid plaques. Moreover, these antibodies protected the mice from learning and age-related memory deficits. Naturally occurring anti-AbetaP antibodies have been found in human CSF and in the plasma of healthy individuals, but were significantly lower in AD patients, suggesting that AD may be an immunodeficient disorder. Active and/or passive immunization against beta-amyloid peptide has been proposed as a method for preventing and/or treating Alzheimer's disease. Experimental active immunization with Abeta 1-42 in humans was stopped in phase II clinical trials due to unexpected neuroinflammatory manifestations. Antibodies generated with this first-generation vaccine might not have the desired therapeutic properties to target the "correct" mechanism, however, new clinical approaches are now under consideration. Immunotherapy represents fascinating ways to test the amyloid hypothesis and offers genuine opportunities for AD treatment, but requires careful antigen and antibody selection to maximize efficacy and minimize adverse events.
Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat Aviv, Tel-Aviv, P.O. Box 69978, Israel. beka@post.tau.ac.il
Beka
B
Solomon
D000544:Alzheimer Disease / Q000628:therapy*; D000818:Animals; D006801:Humans; D007167:Immunotherapy