S2-02-05: Anti-abeta antibodies in Alzheimer's disease mouse models

Abstract

The pioneering work of Schenk and colleagues demonstrated the therapeutic potential of generating an antibody response capable of recognizing Abeta and Abeta amyloid. Indeed, dozens of studies now show that in mouse models of AD antibodies to Abeta can attenuate Abeta deposition and plaque associated pathologies (e.g. gliosis) and reverse behavioral deficits in these mice. Despite initial setbacks multiple active and passive Abeta immunotherapy trials are now being tested humans. Both active immunizations with fibrillar or Abeta or fragments of Abeta and passive immunization with anti-Abeta antibodies have been evaluated in mouse models of AD. Endpoints have included Abeta deposition, gliosis, behavioral alterations, and levels of Abeta and antibody in various brain, CSF and plasma. Numerous studies consistently demonstrate that active or passive immunotherapy suppresses Abeta deposition in mouse models of AD. Though diffuse plaques may be cleared by immunotherapy, it is controversial as to whether compact plaques are cleared. In mice only rare side effects have been reported. To date there is no consensus as to mechanisms of action, ideal target epitope, or whether an antibody is truly needed. Our work suggests that efficacy is related to target epitope, is dependent on the levels of Abeta deposition at the time of initiation of therapy, and cannot be easily explained by most of the postulated mechanisms. Novel strategies targetting amyloid versus Abeta will be presented. Abeta immunotherapy remains a promising approach for the treatment of AD. Late stage trials of passive immunotherapy are underway in humans. Though mouse models may be helpful in evaluating the potential efficacy of a given Abeta immunotherapy, they may not be useful in predicting possible side effects. Even in mice the efficacy of immunotherapy is limited with respect to certain endpoints when treatment is initiated in mice with AD like amyloid loads. Further understanding of the mechanisms underlying efficacy are likely to be needed in order to develop an optimized immunologic approach to targeting Abeta in AD.