After many years of intense research on the etiology and pathogenesis of Alzheimer's disease (AD), the amyloid #beta# (AB) peptide, the major component of senile plaques, has become a realistic target for developing effective therapies for AD. A recent study showing that simple immunization with the more amyloidogenic 42-aa-long A#beta# peptide (A#beta#42) can reduce AD levels, inhibit the deposition of amyloid onto existing plaques, and clear established senile plaques that are present in brain of a mouse model of AD amyloidosis has raised hopes for a potentially important new therapeutic approach to treat AD (1). This observation surprised the AD community, and the significance of this finding has already resulted in a request for applications of grants initiated by former President Clinton from the National Institute on Aging targeted specifically at providing an understanding of how and why this approach may work as potential therapy for AD. Thus, although the underlying mechanism(s) of A#beta# immunotherapy remain unclear, it has already opened up a whole new area of research to gain insight into why such an approach carl lead to the elimination of amyloid deposits in the brains of transgenic mice that develop AD amyloidosis. In a recent PNAS issue, DeMattos et al. (2) provide mechanistic insights on this remarkable effect. These authors peripherally administered ah anti-A#beta# monoclonal antibody m266 by i.v. injection into transgenic mice (PDAPP) that overexpressed a mutant amyloid precursor protein (APP) in which valine, the normal amino acid residue at position 717, is mutated to phenylalanine, and they showed a dramatic 1,000-fold increase in plasma A#beta# level. Because the plasma levels of A#beta# in the untreated animals were very low and because A#beta# is produced only m the brains of these mice, the authors proposed that m266 in the plasma acts as a "peripheral A#beta# sink" to facilitate the efflux of A#beta# from brain to plasma in the PDAPP mice. They then went on to show that long-term peripheral administration of m266 to PDAPP mice markedly reduces A#beta# burden without the antibody actually crossing the blood brain barrier and binding to A#beta# deposits in the brain. Because recent studies have shown that exogenous 40-aa-long Al8 peptides (A#beta#40) can be transported rapidly from cerebral spinal fluid (CSF) to plasma (3-5), the authors conclude that the likely mechanism to explain why peripherally administered m266 can remove A#beta# deposits from brain is by altering the dynamic equilibrium of Al8 between brain, CSF, and plasma such that a reduction of plasma Al8 can lead to an efflux of brain A#beta# to the CSF and into the circulation.
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