42 research outputs found
Destruxin E Decreases Beta-Amyloid Generation by Reducing Colocalization of Beta-Amyloid-Cleaving Enzyme 1 and Beta-Amyloid Protein Precursor
Alzheimer-disease-associated beta-amyloid (A beta) is produced by sequential endoproteolysis of beta-amyloid protein precursor (beta APP): the extracellular portion is shed by cleavage in the juxtamembrane region by beta-amyloid-cleaving enzyme (BACE)/beta-secretase, after which it is cleaved by presenilin (PS)/gamma-secretase near the middle of the transmembrane domain. Thus, inhibition of either of the secretases reduces A beta generation and is a fundamental strategy for the development of drugs to prevent Alzheimer disease. However, it is not clear how small compounds reduce A beta production without inhibition of the secretases. Such compounds are expected to avoid some of the side effects of secretase inhibitors. Here, we report that destruxin E (Dx-E), a natural cyclic hexadepsipeptide, reduces A beta generation without affecting BACE or PS/gamma-secretase activity. In agreement with this, Dx-E did not inhibit Notch signaling. We found that Dx-E decreases colocalization of BACE1 and beta APP, which reduces beta-cleavage of beta APP. Therefore, the data demonstrate that Dx-E represents a novel A beta-reducing process which could have fewer side effects than secretase inhibitors. Copyright (C) 2009 S. Karger AG, Base
Influence of procedures for preparation of bacterial cultures on the interlaboratory variability of data in Ames test. 2: Shaking conditions for cultivation of bacteria
Generation of three induced pluripotent stem cell (iPSC) lines from a multiple endocrine neoplasia type 1 (MEN1) patient and three iPSC lines from an unaffected relative of the patient
Coloration of Glass due to Copper Incorporated into Glass Surface by Ion Exchange. Effect of Al_2O_3 Component in Glass
Semi-Automated Biomarker Discovery from Pharmacodynamic Effects on EEG in ADHD Rodent Models
Abstract We propose a novel semi-automatic approach to design biomarkers for capturing pharmacodynamic effects induced by pharmacological agents on the spectral power of electroencephalography (EEG) recordings. We apply this methodology to investigate the pharmacodynamic effects of methylphenidate (MPH) and atomoxetine (ATX) on attention deficit/hyperactivity disorder (ADHD), using rodent models. We inject the two agents into the spontaneously hypertensive rat (SHR) model of ADHD, the Wistar-Kyoto rat (WKY), and the Wistar rat (WIS), and record their EEG patterns. To assess individual EEG patterns quantitatively, we use an integrated methodological approach, which consists of calculating the mean, slope and intercept parameters of temporal records of EEG spectral power using a smoothing filter, outlier truncation, and linear regression. We apply Fisher discriminant analysis (FDA) to identify dominant discriminants to be heuristically consolidated into several new composite biomarkers. Results of the analysis of variance (ANOVA) and t-test show benefits in pharmacodynamic parameters, especially the slope parameter. Composite biomarker evaluation confirms their validity for genetic model stratification and the effects of the pharmacological agents used. The methodology proposed is of generic use as an approach to investigating thoroughly the dynamics of the EEG spectral power
Macrophage colony stimulating factor is associated with excretion of amyloid-β peptides from cerebrospinal fluid to peripheral blood
Deglycosylated anti-amyloid beta antibodies induce amyloid beta sequestration with reduced microglial phagocytosis and cytokine release
Accumulation of amyloid beta (Abeta) is a pathological hallmark of Alzheimer\u27s disease, and lowering Abeta is a promising therapeutic approach. Intact anti-Abeta antibodies reduce brain Abeta through two pathways: enhanced microglial phagocytosis and Abeta transfer from the brain to the periphery (Abeta sequestration). While activation of microglia, which is essential for microglial phagocytosis, is necessarily accompanied by undesired neuroinflammatory events, the capacity for sequestration does not seem to be linked to such effects. We and other groups have found that simple Abeta binding agents are sufficient to reduce brain Abeta through the sequestration pathway. In this study, we aimed to eliminate potentially deleterious immune activation from antibodies without affecting the ability to induce sequestration. The glycan portion of immunoglobulin is critically involved in interactions with immune effectors including the Fc receptor and complement c1q; deglycosylation eliminates these interactions, while antigen (Abeta)-binding affinity is maintained. In this study, we investigated whether deglycosylated anti-Abeta antibodies reduce microglial phagocytosis and neuroinflammation without altering the capacity to induce Abeta sequestration. Deglycosylated antibodies maintained Abeta binding affinity. Deglycosylated antibodies did not enhance Abeta phagocytosis or cytokine release in primary cultured microglia, whereas intact antibodies did so significantly. Intravenous injection of deglycosylated antibodies elevated plasma Abeta levels and induced Abeta sequestration to a similar or greater degree compared with intact antibodies in an Alzheimer\u27s transgenic mouse model without or with Abeta plaque pathology. We conclude that deglycosylated antibodies effectively induced Abeta sequestration without provoking neuroinflammation; thus, these deglycosylated antibodies may be optimal for sequestration therapy for Alzheimer\u27s disease
Semagacestat Is a Pseudo-Inhibitor of γ-Secretase
γ-secretase inhibitors (GSI) are drugs developed to decrease amyloid-β peptide (Aβ) production by inhibiting intramembranous cleavage of β-amyloid protein precursor (βAPP). However, a large phase 3 trial of semagacestat, a potential non-transition state analog (non-TSA) GSI, in patients with Alzheimer’s disease (AD) was terminated due to unexpected aggravation of cognitive deficits and side effects. Here, we show that some semagacestat effects are clearly different from a phenotype caused by a loss of function of presenilins, core proteins in the γ-secretase complex. Semagacestat increases intracellular byproduct peptides, produced along with Aβ through serial γ-cleavage of βAPP, as well as intracellular long Aβ species, in cell-based and in vivo studies of AD model mice. Other potential non-TSA GSIs, but not L685,458, a TSA GSI, have similar effects. Furthermore, semagacestat inhibits release of de novo intramembranous γ-byproducts to the soluble space. Thus, semagacestat is a pseudo-GSI, and therefore, the semagacestat clinical trial did not truly test the Aβ hypothesis