As described in the “Target of the Month” section of this edition of TherapeuticAdvances, 4 million Americans currently suffer from Alzheimer's disease and experts estimate that 22 million people around the world will be afflicted by 2025. The amyloid hypothesis suggests that the process of beta amyloid protein fibrillogenesis is responsible for triggering a cascade of physiological events that contribute directly to the initiation and progression of Alzheimer's disease. Hence the identification of therapeutic strategies that prevent the accumulation or the toxicity of beta amyloid represents a major target for the pharmaceutical industry. The development of vaccines that allow patients to develop immunity to and removal of beta amyloid has recently received much attention. In particular, Elan and Wyeth were developing AN-1792 (Betabloc), a 42-amino acid form of the beta amyloid peptide. Immunization of transgenic PDAPP mice, a model of Alzheimer's disease, with AN-1792 prevented the development of amyloid plaques, neurite dystrophy and astrogliosis. Alzheimer's disease-like neuropathologies were also reduced. Although AN-1792 was safe in healthy monkeys and also in humans under a phase I setting, further phase II studies were terminated due to inflammatory side-effects on the CNS. Since an immune response to beta amyloid was generated, activities have been ongoing to develop alternative vaccines that are free of side-effects. Of particular interest in this respect is data emerging from a collaboration of researchers at the University of Toronto and the University of Konstanz, Germany. These data demonstrate that injecting protofibrillar amyloid beta peptide 1-42 in a mouse model of Alzheimer's disease, TgCRND8, specifically generates antibodies to peptides 4-10 of amyloid beta peptide. These antibodies prevented beta amyloid fibrillogenesis and toxicity and facilitated the clearance of pre-existing amyloid beta peptide 1-42 fibers. In contrast to amyloid beta peptide 1-42 however, immunization with protofibrillar amyloid beta peptide 1-42 did not cause an inflammatory response in either the central nervous system or the peripheral immune system. This lack of inflammation was related to an absence of T cell activation that is seen following beta peptide 1-42 immunization. It is therefore suggested that targeting peptides 4-10 of amyloid beta peptide either by immunization with protofibrillar amyloid beta peptide 1-42 or through the use of small-molecule mimics may lead to the safe and effective treatment of Alzheimer's disease.

January, 2003

Adapted from McLaurin et al, Nat Med. 2002 Nov;8(11):1263-9