, 2001). Then we used the scheme described above (see Figure 4) to assign a color to each voxel according to the projection of its category model weights into the PC space (for separate PC ABT 888 maps, see Figure S4). The results are shown in Figures 7A and 7C for two subjects (corresponding maps for other subjects are shown in Figure S5). (Readers who wish to explore these maps in detail, and examine the category selectivity of each voxel, may do so by going to http://gallantlab.org/semanticmovies.) These maps reveal that the semantic space is represented in broad gradients that are distributed across much of anterior visual

cortex (some of these gradients are shown schematically in Figure S6). In inferior temporal cortex, regions of animal (yellow) and human representation (green and blue-green) run along the inferior temporal sulcus (ITS). Both the fusiform face area and occipital face area lie within the region of human representation, but the surrounding region of animal representation was previously unknown. In a gradient that runs from the ITS toward the middle temporal sulcus, human representation gives way to Pifithrin-�� nmr animal representation, which then gives way to representation of human action, athletes, and outdoor spaces (red and red-green). The dorsal part

of the gradient contains the extrastriate body area and area MT+/V5 and also responds strongly to motion (positive on the first PC, see Figures 7B and 7D). In medial occipitotemporal cortex, a region of vehicle (pink) and landscape (purple) representation sits astride the collateral sulcus. This region, which contains the PPA, lies at one end of a long gradient that runs across medial parietal cortex. Toward RSC and along the PrCu, the representational gradient shifts toward buildings

(blue-indigo) and landscapes (purple). Mannose-binding protein-associated serine protease This gradient continues forward along the superior bank of the intraparietal sulcus as far as the posterior end of the cingulate sulcus while shifting representation toward geography (purple-red) and human action (red). This long gradient encompasses both the dorsal and ventral visual pathways (Ungerleider and Mishkin, 1982) in one unbroken band of cortex that represents a continuum of semantic categories related to vehicles, buildings, landscapes, geography, and human actions. This map also reveals that visual semantic categories are well represented outside of occipital cortex. In parietal cortex, an anterior-posterior gradient from animal (yellow) to landscape (purple) representation is located in the posterior bank of the postcentral sulcus (PoCeS). This is consistent with earlier reports that movies of hand movements evoke responses in the PoCeS (Buccino et al., 2001; Hasson et al., 2004) and may reflect learned associations between visual and somatosensory stimuli. In frontal cortex, a region of human action and athlete representation (red) is located at the posterior end of the superior frontal sulcus (SFS).

, 2008; Renn et al., 1999), and regulate circadian behaviors and sleep in rodents (VIP) ( Hu et al., 2011; Maywood et al., 2007). Thus, conserved molecular mechanisms are employed

to regulate arousal and quiescence in developmentally programmed, metabolically driven, and circadian behavioral states. If lethargus is a sleep-like state, as previously proposed (Raizen et al., 2008; Van Buskirk and Sternberg, 2007), one would expect that disrupting quiescence during lethargus would be deleterious. Contrary to this notion, the fertility and development of npr-1 mutants were not grossly altered, indicating that locomotion quiescence during lethargus is not essential for normal development or molting. These results do not ABT-888 price exclude the idea that quiescence during lethargus has significant effects on health in native environments (where conditions are more variable). How are arousal peptides functionally coupled to circadian and developmental cycles? VIP and PDF are expressed in central clock neurons: selleck compound rat VIP in the suprachiasmatic nucleus (SCN) of the hypothalamus, fly PDF in LNv neurons, and worm PDF in the

RMG circuit (Helfrich-Förster, 1995; Maywood et al., 2007). Rhythmic changes in pdf mRNA levels were not observed in the Drosophila circadian and C. elegans molting cycles ( Janssen et al., 2009; Park and Hall, 1998). Instead, PDF-1 secretion was dramatically reduced during lethargus. Inhibition of PDF-1 secretion and inhibition of locomotion during lethargus were both abolished in npr-1 mutants. Thus, altered PDF-1 secretion provides a cellular mechanism for coupling changes Mannose-binding protein-associated serine protease in locomotor activity to the molting cycle. How is PDF-1 secretion inhibited during lethargus? In npr-1 mutants, pheromone and oxygen responses mediated

by the RMG circuit are enhanced ( Cheung et al., 2005; Gray et al., 2004; Macosko et al., 2009), and we observed a corresponding enhancement of PDF-1 secretion. Similarly, inactivation and restoration of TAX-4 CNG channel expression in the RMG circuit was accompanied by parallel changes in PDF-1 secretion. Based on these results, we propose that RMG circuit activity is diminished during lethargus, thereby inhibiting PDF-1 secretion. Consistent with this idea, forced depolarization of ASH neurons expressing PDF-1 was sufficient to arouse locomotion during lethargus. How do central clock neurons engender rhythmic behaviors? A great deal is known about how the activity and expression profile of central clock neurons are regulated. Much less is known about how clock neurons dictate circadian behaviors. In C. elegans, responsiveness to several sensory cues is reduced during lethargus. In particular, touch sensitivity and touch-evoked calcium transients in the touch neurons are decreased during lethargus ( Raizen et al., 2008; Schwarz et al., 2011; Singh et al., 2011). Our results provide a cellular mechanism for these effects.

Each agent had a fixed probability of predicting the asset’s movement accurately (Figure 2A), although this was not told to the subjects. As a result, the agents’ forecasting performance was independent of the asset’s performance. The asset increased or decreased in value on any particular trial with a drifting probability (Figure 2B). Subjects’

payoffs depended on the quality of their predictions, and not on the performance of the asset: every trial subjects won $1 for correct guesses and lost $1 for incorrect ones. See the Experimental Procedures for details. We assumed that subjects learned about the asset using a Bayesian model that allowed for estimates of the probability of price changes to evolve stochastically with changing Nutlin-3 in vivo degrees of volatility. This part of the model is based on previous related work on Bayesian learning about reward likelihood (Behrens et al., 2007, Behrens et al., 2008 and Boorman et al., 2011). The model described in the Supplemental Information (available online) learned to effectively track

the performance of the asset, as shown in Figure 2B (Table S1). Furthermore, on average, it successfully predicted 80.0% (SE, 2.0%) of subjects’ asset predictions and dramatically outperformed Linsitinib price a standard reinforcement-learning algorithm with a Rescorla Wagner update rule (Rescorla and Wagner, 1972) that allowed for subject-specific learning rates (see Table S1 and Supplemental Information for details). We considered four natural classes of behavioral models according to which participants might form and update beliefs about the agents’ expertise (see Experimental Procedures

and Supplemental Information for formal descriptions). All of the models assumed that subjects used information about agents’ performance to update beliefs about their ability using Bayesian updating. The models differed on the information that they used to carry out the updates, and on the timing of those updates within a trial. First, we and considered a full model of the problem, given the information communicated to subjects, which uses Bayes rule to represent the joint probability distribution for the unknowns (i.e., the asset predictability and an agent’s ability), given past observations of asset outcomes and correct and incorrect guesses. This model predicts that subjects learn about the asset and agents together, on the basis of both past asset outcomes and the past performance of agents. This model would represent an optimal approach for a setting in which these two parameters fully governed agent performance.

Problematic alcohol use was screened with the Alcohol Use Disorders Identification Test-Consumption (Bush et al., 1998). The stop signal task consisted of four trial

types: go trials, stop trials and two types of control trials to contrast successful and failed stop trials. Go trials required the subjects to perform a two-choice reaction time task in which subjects had to react as quickly as possible to an airplane appearing on the screen by a button press with their right index finger (airplane flying to the right) or their left index finger BKM120 (airplane flying to the left). In stop trials, a cross appeared on the airplane requiring inhibition of the response. In the control trials for successful stops, the airplane appeared with the cross already superimposed with no delay, essentially constituting a nogo trial ( Heslenfeld and

Oosterlaan, 2003 and Band and van Boxtel, 1999). We reasoned that by controlling for stimulus complexity and the absence of a motor response in these successful stop control trials, only neural activation related to active response inhibition would be isolated. In the control trials for failed stops, the cross appeared after the subject had responded (whereas in failed stop signal trials, the stop signal was presented before the response of the subject), controlling for stimulus complexity and the presence of a motor response. This allowed us to isolate brain regions associated with conflict and error monitoring ( Heslenfeld and Oosterlaan, 2003). We used a staircase tracking algorithm that dynamically adjusted stop signal delay, ensuring successful Selleckchem Capmatinib performance in approximately 50% of the stop trials across subjects and groups ( Osman et al., 1986). A fixation sign was presented for 500 ms and immediately 3-mercaptopyruvate sulfurtransferase followed by the go stimulus, which was presented for 1000 ms. Stop signal duration depended on its delay and ended

at the same time as the go signal. This was followed by an intertrial interval varying between 3 and 8 s (mean 3.5 s). A total of 360 trials were presented, divided over three blocks of 120 trials, lasting 7 min each. There were 245 go trials, 45 stop trials, 23 control trials for successful stop trials (in which the stop signal was presented 16 ms before go stimulus onset) and 47 control trials for failed stop trials (23 trials with a stop signal delay after the subject’s response that equaled the mean RT of subjects for that run and 24 trials with a stop signal appearing directly after the subject had responded). The stop signal task was practiced outside the scanner. SSRT was calculated by subtracting mean stop signal delay from mean RT to go stimuli. MR scans were acquired with a 3.0 Tesla Intera full-body MRI scanner (Philips Medical Systems, Best, The Netherlands) with a phased array SENSE RF 6-channel receiver head coil. Thirty-five axial slices (voxel size 3 mm × 3 mm × 3 mm, interslice gap 0.

This Slaughterhouse is under the control of the Institute of Agricultural and Forest Defense of Espírito Santo (“Instituto de Defesa Agropecuária e Florestal do Espírito Santo” – IDAF) and was registered in the State Inspection System (“Sistema de Inspeção Estadual”) under No. 080. Fragments of approximately 2 cm2 were collected from the surface and internal areas free of lesions of right lobule because the largest number of lesions was observed in this lobule. The biliary vesicle and bile were also collected to diagnosis

of eggs of the parasite. The patent infection was confirmed by presence of parasites in bile duct, eggs in the bile and macroscopic lesions and the results were summary in Table 2. The livers of four uninfected cattle (3 females and 1 male)

were obtained after slaughter at the Curvelo Slaughterhouse (“Abatedouro Everolimus research buy de Curvelo”), in the state of Minas Gerais (MG), which is an F. hepatica-free zone. After removal, the liver fragments were immersed separately in 15-ml Falcon tubes containing 5 ml of TRIzol® reagent (Invitrogen™ Life Technologies, Brasil). Then, the samples were stored in liquid nitrogen and transported to the Laboratory of Cell Biology and Biotechnological OSI-744 manufacturer Innovation at the Ezequiel Dias Foundation (“Fundação Ezequiel Dias” – FUNED, Brazil), where total RNA extractions were performed. The fragments of liver tissues were ground with a mortar and pestle and liquid nitrogen, and 1 ml of TRIzol® reagent was subsequently added and the RNA extraction following conformed manufacture instructions. The concentration and quality of the RNA preparation was estimated by readings in a spectrophotometer (Nanovue PlusTM) at 260 and 280 nm, and the calculations of the 260/280 nm ratios

were obtained. The primer pairs for gene expression analysis of the IFN-γ, IL-4, IL-10 genes and the constitutively expressed GAPDH gene in the liver tissue of cattle were designed based on sequences from the literature (Table 1) (Waldvogel et al., 2004, Konnai et al., 2003 and Buza et al., 2004). The GAPDH gene was used to normalize the gene expression data. The primers were synthesized by Invitrogen™ Life Technologies, MycoClean Mycoplasma Removal Kit Brazil. The Kit SuperScript® III, Platinum® 129 SYBR Green One-Step qRT-PCR (Invitrogen™ Life Technologies, Brazil) was used for the qRT-PCR reaction. The following reagents were used for each reaction: 0.2 μl of SuperScript® III RT/Platinum®Taq Mix with RNase (RNase OUT) included, 5 μl of SYBR® 132 Green Reaction Buffer Mix, 1 μl of forward primer, 1 μl of reverse primer, 0.02 μl of ROX, 0.28 μl of DEPC treated water and 2.5 μl of the RNA sample. 134 The amplifications were performed in triplicate.

By comparison, the interpretation of anatomical connections using GdDOTA-CTB is simpler; it has all the properties of a classic neural tracer, without requiring animal sacrifice. Presumably, future applications of the GdDOTA-CTB approach (perhaps in combination with other MRI-based techniques, such as DTI, resting state fMRI, and/or MEMRI) will furnish a much richer in vivo diagram of brain circuitry. At a practical level, this MR-visible tracer can be used to target anatomically connected regions, using electrophysiological microelectrodes and/or serial tracer injections. More generally, this in vivo approach can reveal changes

occurring during plasticity induced by normal or abnormal physiology (e.g., axonal pruning or sprouting), in both central SKI-606 in vivo and peripheral nervous systems (Rakic et al., 1986, LaMantia and Rakic, 1990, Wu and Kaas, 2000, Wu and Kaas, 2002, Raff et al., 2002, Medana and Esiri, 2003 and Prince et al., 2009). GdDOTA-CTB was made

in-house using commercially available products. The detailed synthesis procedures are described in the Supplemental Information. Gd-Albumin was purchased commercially (Biopal Inc, Worcester, MA; cat# P-00P01-100) and was lyophilized and rediluted in double distilled water to a final concentration of 30% in protein and 65 mM in Gd solution. Forty-one adult Sprague-Dawley rats (280–350 g) were used in these experiments (29 injected with GdDOTA-CTB, 4 GdDOTA injections, 3 Gd-Albumin injections, 1 saline injection, and 4 MnCl2 injections). Selleckchem Vorinostat In experiments #1–3, a total of 24

rats received unilateral intracortical injections of GdDOTA-CTB into area S1, and Adenosine 1 received saline injection into area S1. In experiment #4, 4 rats received injections of GdDOTA in area S1 and 3 received injections of Gd-Albumin in S1. In experiment #5, we compared injections of manganese chloride (MnCl2; n = 4) with GdDOTA-CTB to measure diffusion and transport dynamics in both the S1 injection site and the thalamic transport zones. In experiment #6, 4 additional rats received a unilateral injection of GdDOTA-CTB in the nostril cavity (n = 2) or the OB (n = 2). One additional rat was scanned for 14 hr ex vivo, 7 days after an S1 injection of GdDOTA-CTB. All experiments were performed in compliance with guidelines set by the ACUC of the NINDS, NIH. Surgical details and procedures regarding the injections are given in Supplemental Information. Animals were imaged prior to injection (“baseline”), and immediately (1–2 hr) after injection, on days 1–7 postinjection, and at longer intervals for up to 2 months postinjection. Four animals were imaged for 7–10 days postinjection, then sacrificed for histology. GdDOTA alone was injected into the S1 forepaw, using the same coordinates as in the GdDOTA-CTB experiments. MRI data were acquired at the baseline, immediately after injection, and every 12 hr until day 2. The last image was acquired on day 5 postinjection.

, 2003), well above normal elevations in [Ca2+]i used for cell signaling. We observed that there were no calcium signals detected in astrocytes when 10 mM K+ was bath applied (Figure S5), ruling out [Ca2+]i as the trigger in these experiments. These data indicate that functional sAC protein,

which is expressed in astrocytes in this region of the brain, produces cAMP when HCO3− entry is triggered by high [K+]ext. Glycogen in the brain is only stored selleck inhibitor in astrocytes (Brown, 2004; Brown et al., 2005; Magistretti, 2006) and some neurotransmitters such as vasoactive intestinal peptide, noradrenaline, and adenosine promote astrocytic glycogenolysis in the brain (Sorg and Magistretti, 1991). In addition, glycogenolysis in brain tissue was previously reported to

be promoted by high [K+]ext (Hof et al., 1988) through an unknown mechanism. Because astrocytes do not express the enzyme glucose-6-phosphatase (Brown and Ransom, 2007; Dringen and Hamprecht, 1993; Magistretti et al., 1993), they cannot generate free glucose from glycogen; therefore, in astrocytes, glycogen breakdown induced by increased cAMP (Pellerin et al., 2007) results in pyruvate, followed by lactate. We tested the hypothesis that sAC was responsible for coupling K+ increases to glycogen breakdown in astrocytes and for the production and release of lactate. Raising [K+]ext to 10 mM for 30 min significantly reduced cellular glycogen levels (26.7% ± 6.5%, n = 6, p < 0.001; Figure 4A) compared to control condition (2.5 mM K+: 100%, n = 6). This effect was significantly inhibited by the sAC inhibitor see more 2-OH (90.5% ± 10.6%, n = 6, p < 0.001; Figure 4A) but not by the tmAC antagonist DDA (32.7% ± 7.5%, n = 5, p > 0.05; Figure 4A). Levetiracetam Superfusate measurements of lactate release revealed that brain slices exposed to high [K+]ext showed elevated lactate levels (2.5 mM K+: 30.7 ± 3.1 μM, n = 7; 10 mM K+: 69.0 ±

5.2 μM, n = 6, p < 0.001; Figure 4B), which were blocked by 2-OH (32.1 ± 3.6 μM, n = 6, p < 0.001) and KH7 (26.7 ± 7.2 μM, n = 4, p < 0.001; Figure 4B) but not by DDA (61.3 ± 9.6 μM, n = 6, p > 0.05; Figure 4B). Furthermore, the increase in lactate by high [K+]ext was dose dependent with applications of 2.5, 5, 7.5, and 10 mM K+ (Figure 4C). We verified and extended these findings by taking direct measurements of the time course of lactate release from brain slices using a lactate enzyme-based electrode. An immediate and transient increase of lactate was induced by 5 mM [K+]ext and subsequent addition of 10 mM [K+]ext led to a further augmentation, demonstrating dose dependency and rapid efflux of lactate when [K+]ext changes (n = 3; Figure 4D). Finally, we confirmed the role of glycolysis in the production of lactate from glycogen using the glycolytic inhibitor iodoacetate (IA, 200 μM) and the lactate dehydrogenase (LDH) inhibitor oxamate (2.5 mM) (Gordon et al., 2008; Pellerin and Magistretti, 2004; Takano et al., 2007).

Similar to that in hippocampal synapses, several lines of evidence suggested that genetic elimination of RIMs interfered with the coupling between Ca2+ channels and transmitter release (Table 1). First, the presynaptic Ca2+ channel density was reduced. Because the gating properties of Ca2+ channels were unchanged, this suggests a reduction in the density of presynaptic Ca2+ channel proteins (see Kaeser et al., 2011). Second, the intrinsic Ca2+ sensitivity of transmitter release measured by Ca2+ uncaging was diminished. Third, the amplitude of the Ca2+ concentration transient at the Ca2+ sensor,

estimated from a comparison of synaptic data and uncaging data, was altered, again consistent selleck products with a loosening of the coupling between Ca2+ channels and Ca2+ sensors of exocytosis. The results (Kaeser et al., 2011 and Han et al., 2011) converge on the conclusion that RIMs change the coupling between Ca2+ channels and transmitter

release. However, the paper of Han et al. (2011), and in particular another extensive study by Deng et al. (2011), suggests that this is only one side of Alectinib mw the coin. At both the hippocampal synapses and the calyx of Held, the size of the releasable pool of synaptic vesicles is reduced in the RIM double knockout mouse. In the hippocampal synapses, pool size was measured by application of hypertonic sucrose solution (Deng et al., 2011). At the calyx of Held, the size of the readily releasable pool was elegantly probed in Ca2+ uncaging experiments (Han et al., 2011). Based on serial

electron microscopy analysis of calyx synapses, Han et al. suggest a reduction in the number of docked vesicles in RIM-deficient synapses. Thus, a docking deficit may underlie the reduction in pool size. In contrast, in the hippocampal synapses, genetic elimination of RIM appears to involve Munc13, a classical priming factor (Betz et al., 2001). This suggests that RIM regulates pool size via effects on priming. How do the different domains of RIM mediate these diverse functions? For the tethering function of RIM, rescue experiments suggest that both the PDZ domain and DNA ligase the proline-rich domain of RIM are necessary and sufficient for the effects (Kaeser et al., 2011). In contrast, the Rab3 binding domain seems to be dispensable. Because the proline-rich region of RIM represents the site of interaction with RIM-BPs (Hibino et al., 2002), the results suggest that a tripartite complex of RIMs, RIM-BPs, and Ca2+ channels is formed during tethering (Figure 1). For the priming function, the Zn2+ finger domain of RIM is necessary and sufficient (Deng et al., 2011). Because this site interacts with Munc13, this suggests that the effects on priming are mediated by Munc13 (Betz et al., 2001).

Corrected optical density readings were calculated by subtracting the plate background reading. Antibodies specific for M. haemolytica were measured at week 2, 6, 10 and 12 with an in-house ELISA at the laboratory of MSD Animal

Health (Boxmeer, Netherlands). Microtitre plates were coated with M. haemolytica antigen. Serum was diluted and incubated and bound antibodies were detected after incubation with an anti-bovine serum-peroxidase conjugate as previously described ( Assié et al., 2009). At weeks 8 and 12, blood samples from a subset of calves (six randomly selected animals from each group) were collected into heparinized tubes. Peripheral blood mononuclear cells (PBMC) were isolated by centrifuging over Histopaque (Sigma) and recovered in RPMI 1640 medium (supplemented with 10% heat-inactivated foetal calf serum, 100 U/ml penicillin, 100 μg/ml streptomycin, 2 mM l-glutamine). Viable cells were counted by Trypan blue exclusion buy Trametinib and resuspended at a concentration of 1 × 106 cells/ml. One millilitre of this suspension was added in duplicate to a 24-well plate. Cells were stimulated with F. hepatica excretory-secretory antigen (ES; 10 μg/ml), lipopolysaccharide (LPS; Escherichia coli 0111:B4,

Selleck FK228 Alexis; 5 μg/ml) as a bacterial antigen and toll-like receptor ligand 7/8 (TLRL; Resiquimod R848, Invivogen; 1 mg/ml) as a viral antigen. Medium and Con A (Sigma; 5 μg/ml) were used as negative and positive controls, respectively. Cell cultures were incubated for 72 h at 37 °C before supernatants were collected and stored at −20 °C for cytokine analysis. Cytokine levels were measured using commercially available

ELISA kits, or antibody pairs. Interleukin 4 (IL-4) was measured using a kit from Pierce Biotechnology in accordance with the manufacturer’s guidelines. Transforming growth factor beta (TGF-β) was measured using a human ELISA (Promega) as previously described ( Abbott et al., 2005). Nitric oxide (NO) was measured using the Griess Reagent Kit (Promega). Interleukin 10 (IL-10) and Interferon gamma (IFN-γ) were measured using commercially available isothipendyl antibody pairs as previously described ( Flynn and Mulcahy, 2008). Regression procedures were employed to comparatively assess the effect of liver fluke infection status on each of the vaccination, biochemical and cytokine variables, over a 12-week period. Prior to the analysis, the stability of the variance for each parameter was assessed, and where normality was not identified, a transformation step was applied (log transformed for PI-3 and BRSV SNT as well as GLDH and square root transformed for GGT variables). In the case of IFN-γ and BRSV, where the variance for these dependent variables could not be stabilised, a non-parametric quartile (median 50) regression model was applied. In addition, a pre-infection comparison of all variables was carried out using an independent student t-test to ensure a group effect was not present prior to commencement of the trial.

We have previously demonstrated that chronic treatment with 3D6 significantly increases the incidence of microhemorrhage (Racke et al., 2005). In this study, we again observed

a dramatic increase in microhemorrhage with 3D6 treatment (p < 0.001) (Figure 4C). Significantly, the 3D6-dependent exacerbation of microhemorrhage occurred even in the absence of plaque lowering. In contrast, treatment with either mE8-IgG1 or mE8-IgG2a did not significantly increase microhemorrhage, even though these Aβp3-x antibodies were able to reduce LY294002 deposited Aβ. These results demonstrate that treatment with the Aβp3-x antibodies in aged PDAPP mice with maximal plaque loads was able to reduce existing deposited Aβ without CAA-related microhemorrhage liability. To investigate whether the Aβp3-x antibody mE8-IgG2a would be efficacious at preventing plaque deposition, we performed a study in 5.5-month-old PDAPP mice, an age before ABT-888 mouse the initiation of Aβ deposition, with the following antibodies: negative control antibody (IgG2a), 3D6, and mE8-IgG2a. A time zero group and an additional parallel untreated group of transgenic mice were incorporated in

the study to determine the time course of deposition. As expected, the time zero animals (5.5 months of age) lacked deposited Aβ42 (Figure 5C). In hippocampus, a dramatic accumulation of deposited Aβ42 occurred throughout the study period (∼45-fold) with the majority depositing during the latter 2 months of the study (∼80% between months 10.5 and 12.5). Consistent with previous reports for similar N-terminal antibodies, treatment

with 3D6 resulted in a significant ∼68% decrease of hippocampal Aβ42 (p < 0.001) as compared to the control IgG, although levels were higher than the untreated animals sacrificed at 10.5 months of age. The mE8-IgG2a treatment resulted in a nonsignificant ∼30% decrease in Aβ42 as compared to the control until IgG-treated mice. Similar results were observed in the cortical extracts from these mice (Figure 5D). These results demonstrate that while the phagocytic mechanism of the Aβp3-x antibody is able to clear deposited Aβ, it is less effective at preventing Aβ42 deposition in young PDAPP mice. In contrast, the N-terminal antibody 3D6, which binds soluble and insoluble Aβ, reveals an opposite pattern of efficacy (no clearance of established plaque and strong prevention of deposition), thereby suggesting that the major mechanism of action for these two antibodies is different. We sought to determine the mechanism of action responsible for the differential effects on plaque lowering observed for the Aβp3-x and 3D6 antibodies by performing in vivo target engagement studies.