ABSTRACT
Alzheimer’s disease (AD) is the most com m on form o f dementia and afflicts -15-20 million people worldwide. Currently, there is no effective cure. Research efforts over the past decade have dem onstrated that amyloid-beta protein (Aß), a small peptide generated from its large precursor protein, the amyloid precursor protein (APP), plays a central role in AD pathogenesis, thus leading to the development o f therapies aimed at lowering Aß levels in the brain. O ne such strategy involves using Aß immunotherapy, either by direct Aß peptide vaccination or passive transfer o f Aß-specific antibodies, to modulate Aß levels in the central nervous system (CNS). Here, we provide an overview o f such immune-based studies in wildtype (W T) mice and transgenic (tg) mouse models o f AD, as well as those in humans. Aß im m unization in APP tg mice has proven effective in lowering cerebral Aß levels, including plaque deposition, w ith the caveat that the earlier it is given, the better. Prevention o f and improvement in behavior deficits normally seen in APP tg mice has been shown following both active and passive Aß im munization. Various im m unization protocols have been tested in both W T and tg mice and are described here. Three proposed mechanisms for the Aß-lowering, behavioral improvement effects o f the Aß vaccine are discussed and include: disaggregation of Aß fibrillar aggregates and prevention o f soluble Aß to form fibrils, Fc-mediated microglial phagocytosis o f Aß, and a shift in efflux o f Aß from CNS to the periphery. Following clinical safety trials, a large Phase Ha clinical Aß vaccine trial in AD patients was initiated in the USA and Europe in late 2001. T he dosing was stopped on March 1, 2002, due to adverse CNS reactions in -5% o f patients. We speculate here about the possible causes for such adverse effects and provide a culm ination o f ideas from many researchers towards the future o f Aß im m unotherapy for the prevention and treatm ent o f AD. It is with optimism that we proceed.
