Active immunization with the amyloid ␤ (A␤) peptide has been shown to decrease brain A␤ deposition in transgenic mouse models of Alzheimer's disease and certain peripherally administered anti-A␤ antibodies were shown to mimic this effect. In exploring factors that alter A␤ metabolism and clearance, we found that a monoclonal antibody (m266) directed against the central domain of A␤ was able to bind and completely sequester plasma A␤. Peripheral administration of m266 to PDAPP transgenic mice, in which A␤ is generated specifically within the central nervous system (CNS), results in a rapid 1,000-fold increase in plasma A␤, due, in part, to a change in A␤ equilibrium between the CNS and plasma. Although peripheral administration of m266 to PDAPP mice markedly reduces A␤ deposition, m266 did not bind to A␤ deposits in the brain. Thus, m266 appears to reduce brain A␤ burden by altering CNS and plasma A␤ clearance.A bundant evidence suggests that a key event in Alzheimer's disease (AD) pathogenesis is the conversion of the amyloid ␤ (A␤) peptide from soluble to aggregated forms in the brain. A␤, the principal proteinaceous component of plaque core and cerebrovascular amyloid, is composed of aggregates of the 4-kDa A␤ peptide (1). A␤ is predominantly 40-42 aa in length and is a normal, soluble proteolytic product of the amyloid precursor protein (APP), a large integral membrane protein expressed at high levels in the brain (2). Studies of mutations in APP and the presenilins, which cause early-onset, autosomal dominant, familial AD have revealed one common molecular consequence; they all increase A␤ production or increase the ratio of A␤ 42 ͞ A␤ 40 (3-6). Because A␤ 42 is more prone to aggregate, this appears to increase the probability that A␤ aggregation, amyloid deposition, and other downstream consequences will ensue, resulting in AD neuropathology.Production of A␤ via APP processing, however, is not the only factor that can influence the probability of A␤ deposition. Evidence has accumulated that indicates that factors regulating A␤ catabolism (7), clearance (8, 9), and aggregation (10) are also critical in regulating A␤ metabolism. For example, the 4 allele of apolipoprotein E (apoE) is a major AD risk factor, and apoE plays an important role in A␤ deposition (11). In vitro and in vivo studies indicate that apoE does not appear to play a role in A␤ production per se but influences A␤ clearance, aggregation, conformation, and toxicity (10-17). Other A␤ binding proteins may have similar or distinct effects (10). The transport of exogenous A␤ between the central nervous system (CNS) and plasma also may regulate brain A␤ levels (9). Recent studies have demonstrated that exogenous A␤ 40 is rapidly transported from cerebrospinal fluid (CSF) to plasma with an elimination half-life from brain of Յ30 min (8, 9). Because ''physiological'' A␤-binding proteins (e.g., apoJ͞apoE) can influence the transport͞flux of A␤ between CNS and͞or plasma (9, 18, 19), we became interested in whether exogenous A␤ binding molecules might b...

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The deposition of amyloid-beta (Abeta) peptides into amyloid plaques precedes the cognitive dysfunction of Alzheimer's disease (AD) by years. Biomarkers indicative of brain amyloid burden could be useful for identifying individuals at high risk for developing AD. As in AD in humans, baseline plasma Abeta levels in a transgenic mouse model of AD did not correlate with brain amyloid burden. However, after peripheral administration of a monoclonal antibody to Abeta (m266), we observed a rapid increase in plasma Abeta and the magnitude of this increase was highly correlated with amyloid burden in the hippocampus and cortex. This method may be useful for quantifying brain amyloid burden in patients at risk for or those who have been diagnosed with AD.

We quantified the amount of amyloid ␤-peptide (A␤) immunoreactivity as well as amyloid deposits in a large cohort of transgenic mice overexpressing the V717F human amyloid precursor protein (APP V717F؉/؊ TG mice) with no, one, or two mouse apolipoprotein E (Apoe) alleles at various ages. Remarkably, no amyloid deposits were found in any brain region of APP V717F؉/؊ Apoe ؊/؊ TG mice as old as 22 mo of age, whereas age-matched APP V717F ؉/؊ Apoe ؉/؊ and Apoe ؉/؉ TG mice display abundant amyloid deposition. The amount of A␤ immunoreactivity in the hippocampus was also markedly reduced in an Apoe gene dose-dependent manner (Apoe ؉/؉ > Apoe ؉/؊ Ͼ Ͼ Apoe ؊/؊ ), and no A␤ immunoreactivity was detected in the cerebral cortex of APP V717F؉/؊ Apoe ؊/؊ TG mice at any of the time points examined. The absence of apolipoprotein E protein (apoE) dramatically reduced the amount of both A␤1-40 and A␤1-42 immunoreactive deposits as well as the resulting astrogliosis and microgliosis normally observed in APP V717F TG mice. ApoE immunoreactivity was detected in a subset of A␤ immunoreactive deposits and in virtually all thioflavine-Sfluorescent amyloid deposits. Because the absence of apoE alters neither the transcription or translation of the APP V717F transgene nor its processing to A␤ peptide(s), we postulate that apoE promotes both the deposition and fibrillization of A␤, ultimately affecting clearance of protease-resistant A␤/apoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathological hallmarks of Alzheimer's disease.