Immunotherapy as treatment for Alzheimer's disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized pathologically by the deposition of beta-amyloid (A beta)-containing extracellular neuritic plaques, intracellular neurofibrillary tangles and neuronal loss. Much evidence supports the hypothesis that A beta peptide aggregation contributes to AD pathogenesis, however, currently approved therapeutic treatments do nothing to stop or reverse A beta deposition. The success of active and passive anti-A beta immunotherapies in both preventing and clearing parenchymal amyloid in transgenic mouse models led to the initiation of an active anti-A beta vaccination (AN1792) trial in human patients with mild-to-moderate AD, but was prematurely halted when 6% of inoculated patients developed aseptic meningoencephalitis. Autopsy results from the brains of four individuals treated with AN1792 revealed decreased plaque burden in select brain areas, as well as T-cell lymphocytes in three of the patients. Furthermore, antibody responders showed some improvement in memory task measures. These findings indicated that anti-A beta therapy might still be a viable option for the treatment of AD, if potentially harmful proinflammatory processes can be avoided. Over the past 6 years, this target has led to the development of novel experimental immunization strategies, including selective A beta epitope targeting, antibody and adjuvant modifications, as well as alternative routes and mechanisms of vaccine delivery, to generate anti-A beta antibodies that selectively target and remove specific A beta species without evoking autoimmunity. Results from the passive vaccination AD clinical trials that are currently underway will provide invaluable information about both the effectiveness of newly improved anti-A beta vaccines in clinical treatment, as well as the role of the A beta peptide in the pathogenesis of the disease.
Hawkes
Cheryl A
CA
Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada. cheryla.hawkes@utoronto.ca
McLaurin
Joanne
J
D000544:Alzheimer Disease / Q000276:immunology* / Q000628:therapy*; D023582:Alzheimer Vaccines / Q000276:immunology / Q000627:therapeutic use; D016229:Amyloid beta-Peptides / Q000276:immunology; D000818:Animals; D006801:Humans; D007167:Immunotherapy / Q000379:methods* / Q000639:trends; D010446:Peptide Fragments / Q000276:immunology
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)