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.

When administered intracerebroventricularly to mice performing various learning tasks involving either short-term or long-term memory, secreted forms of the ␤-amyloid precursor protein (APP s 751 and APP s 695 ) have potent memory-enhancing effects and block learning deficits induced by scopolamine. The memory-enhancing effects of APP s were observed over a wide range of extremely low doses (0.05-5,000 pg intracerebroventricularly), blocked by anti-APP s antisera, and observed when APP s was administered either after the first training session in a visual discrimination or a lever-press learning task or before the acquisition trial in an object recognition task. APP s had no effect on motor performance or exploratory activity. APP s 695 and APP s 751were equally effective in the object recognition task, suggesting that the memory-enhancing effect of APP s does not require the Kunitz protease inhibitor domain. These data suggest an important role for APP s s on memory processes.Alzheimer's disease (AD) is the most common cause of progressive cognitive decline and dementia in aged humans. The deposition of the ␤-amyloid peptide(s) (A␤) in extracellular neuritic plaques of AD patients is an early and invariant feature of this neurodegenerative disorder (1). A␤ is derived from a large membrane-spanning ␤-amyloid precursor protein (APP), encoded by a single gene located on chromosome 21. Alternative splicing of this gene in humans leads to three major isoforms, either lacking (APP 695 ) or containing (APP 751 and APP 770 ) a Kunitz protease inhibitor domain. APP 695 is selectively expressed in the brain, whereas APP 751 and APP 770 also are abundantly expressed in peripheral tissues. Proteolytic processing of APPs at the N-and C-termini by ␤-and ␥-secretases leads to the production of A␤ (2). An alternative cleavage by ␣-secretase(s) within the A␤ domain of APPs generates secreted N-terminal products, the secreted APPs (APP s s) (2). The normal physiological functions of APPs and secreted derivatives are still poorly understood. However, neurotrophic as well as neuroprotective actions have been reported for both APP s 751 and APP s 695 (3-6). Recent behavioral studies have shown that intracerebroventricular (i.c.v.) administration of anti-APPs antisera results in memory impairment in rats performing a passive avoidance task (7,8). Further, the induction of long-term potentiation in hippocampal slices is associated with increased APP s synthesis and secretion (9). These data suggest that APP s s may be involved in learning and memory processes. In the present study, we investigated whether APP s 751 and APP s 695 have memoryenhancing actions when directly administered to mice performing various learning tasks and to mice rendered amnestic by administering the anticholinergic drug scopolamine.

PDAPP transgenic mice have been shown to develop age dependently much of the cerebral histopathology associated with Alzheimer's disease. PDAPP mice (3-10 months old) were tested in a battery of memory tasks to determine whether they develop memory-behavioral deficits and whether these deficits occur before or after amyloid deposition. PDAPP mice manifest robust impairments in a radial-maze spatial discrimination task at all ages tested. Mild deficits were observed in a barpress learning task in 3-month-old PDAPP mice. In contrast, PDAPP mice show an age-dependent decrease in spontaneous object-recognition performance that appears to be severe at ages when amyloid deposition is known to occur. Thus, the PDAPP mouse shows severe deficits in the radial maze well before amyloid plaque deposition, whereas object-recognition performance decreases with age and may be associated with amyloid deposition.

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The purpose of the present study was to design an object recognition task in mice and characterize the effects of scopolamine in this paradigm. This task consisted of exposing mice for 6 or 10 min to an object in an open field (trial 1) and, after a delay (1-24 h), testing mice for 10 min with the object and a novel object (trial 2). Mice explored the novel object more than the familiar object as the inter-trial delay decreased and/or the duration of trial 1 increased. Administration of scopolamine (0.3, 1 and 3 mg kg-1, s.c.) before trial 1 reduced recognition performance on trial 2 after a 3 h inter-trial delay and induced other behavioural effects, including an increase in locomotor activity on trial 1. Methylscopolamine (1 mg kg-1) had no effect on recognition performance. The present results show that this task is a useful model to test recognition memory in mice and that blocking the central cholinergic system impairs this form of memory.

Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the 4 allele increasing and the 2 allele decreasing risk for developing AD. ApoE has been shown to influence brain amyloid-␤ peptide (A␤) and amyloid burden, both in humans and in transgenic mice. Here we show that direct intracerebral administration of lentiviral vectors expressing the three common human apoE isoforms differentially alters hippocampal A␤ and amyloid burden in the PDAPP mouse model of AD. Expression of apoE4 in the absence of mouse apoE increases hippocampal A␤ 1-42 levels and amyloid burden. By contrast, expression of apoE2, even in the presence of mouse apoE, markedly reduces hippocampal A␤ burden. Our data demonstrate rapid apoE isoform-dependent effects on brain A␤ burden in a mouse model of AD. Gene delivery of apoE2 may prevent or reduce brain A␤ burden and the subsequent development of neuritic plaques.amyloid plaques ͉ gene therapy A lzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of cognitive function and is associated with a characteristic neuropathology, including amyloid plaques, neurofibrillary tangles, synaptic loss, and neurodegeneration. Mutations in several genes, including the presenilins 1 and 2 and the amyloid precursor protein (APP) gene, have been shown to cause rare autosomal dominant forms of AD (1-3). Moreover, mutations of these genes have been shown to alter normal processing of APP to the 4-kDa amyloid-␤ peptide(s) (A␤), A␤ 1-40 or A␤ . AD mutations either increase production or alter the ratio of these peptides, which accumulate in the extracellular space to form amyloid-containing neuritic plaques. The apolipoprotein E (apoE) gene is a major risk factor for late-onset AD with the 4 allele increasing and the 2 allele decreasing the morbid risk for developing AD (4). Individuals carrying one or two 4 alleles develop AD at a younger age and have higher amyloid-plaque burden compared with individuals carrying two 3 alleles (5-8). In fact, several studies have demonstrated higher brain A␤ burden in elderly nondemented individuals carrying one or two 4 alleles, suggesting that apoE4 somehow contributes to A␤ deposition and brain amyloid burden (9, 10). Genetic epidemiological studies also suggest a protective role for the 2 allele, which in some studies has been shown to reduce the risk of AD by Ϸ50% (11).ApoE is a 34-kDa lipid-binding protein produced primarily in the liver, which functions in the transport of triglycerides and cholesterol (12). ApoE is also abundantly expressed in the brain, primarily in astrocytes and microglia, where it has been postulated to play a role in neuronal plasticity and synaptogenesis (13-17). How apoE contributes to AD pathogenesis is, however, as yet unclear. We and others have shown that apoE facilitates A␤ fibrillogenesis and deposition in vitro and in vivo and͞or participates in the clearance and degradation of A␤ in brain (18)(19)(20)(21)(22)(23).In the present study, we investigated whethe...