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...

We have previously shown that chronic treatment with the monoclonal antibody m266, which is specific for amyloid beta-peptide (Abeta), increases plasma concentrations of Abeta and reduces Abeta burden in the PDAPP transgenic mouse model of Alzheimer's disease (AD). We now report that administration of m266 to PDAPP mice can rapidly reverse memory deficits in both an object recognition task and a holeboard learning and memory task, but without altering brain Abeta burden. We also found that an Abeta/antibody complex was present in both the plasma and the cerebrospinal fluid of m266-treated mice. Our data indicate that passive immunization with this anti-Abeta monoclonal antibody can very rapidly reverse memory impairment in certain learning and memory tasks in the PDAPP mouse model of AD, owing perhaps to enhanced peripheral clearance and (or) sequestration of a soluble brain Abeta species.

The complement system is part of the innate immune response responsible for removing pathogens and cellular debris, in addition to helping to refine CNS neuronal connections via microglia-mediated pruning of inappropriate synapses during brain development. However, less is known about the role of complement during normal aging. Here, we studied the role of the central complement component, C3, in synaptic health and aging. We examined behavior as well as electrophysiological, synaptic, and neuronal changes in the brains of C3-deficient male mice (C3 KO) compared with age-, strain-, and gender-matched C57BL/6J (wild-type, WT) control mice at postnatal day 30, 4 months, and 16 months of age. We found the following: (1) region-specific and age-dependent synapse loss in aged WT mice that was not observed in C3 KO mice; (2) age-dependent neuron loss in hippocampal CA3 (but not in CA1) that followed synapse loss in aged WT mice, neither of which were observed in aged C3 KO mice; and (3) significantly enhanced LTP and cognition and less anxiety in aged C3 KO mice compared with aged WT mice. Importantly, CA3 synaptic puncta were similar between WT and C3 KO mice at P30. Together, our results suggest a novel and prominent role for complement protein C3 in mediating aged-related and region-specific changes in synaptic function and plasticity in the aging brain.