Chapter 6: Immunotherapeutic Strategies Towards Treatment of Alzheimer's Disease

Treatment of Alzheimer's disease (AD) by recruiting an immune response against beta-amyloid (Aβ) was suggested by findings that monoclonal antibodies against synthetic Aβ peptide can keep the peptides from aggregating into neurotoxic fibrils and can dissolve already formed amyloid. Active and passive immunization studies in transgenic mice models of AD show that antibodies against Aβ peptide are effective in reducing Aβ levels and plaque pathology, as well as attenuating cognitive deficits in animal models of AD sometimes associated with adverse reactions. Although the causative role of Aβ peptide in AD pathogenesis is well-established, it is less clear whether Aβ, deposited as amyloid or some other less well-characterized Aβ soluble assembly, initiates the cascade eventually leading to neuronal death and dysfunction. In view of this debate, decreasing Aβ production from its precursor protein APP is a logical step to intervene. Here we describe a new approach to reduce Aβ peptide formation, based on blocking the β-secretase cleavage site of APP using antibodies which interfere with APP-BACE interaction. It is not yet clear if the various strategies for mobilizing the immune system will end up being a treatment to prevent or to treat AD. However, immunotherapy has clearly strengthened the hypothesis that Aβ peptide plays a central role in AD and has stimulated a new area for development of Alzheimer's therapeutics and for their further evaluation in renewed human phase clinical trials.