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#29037261   2017/10/17 Save this To Up

Distinct deposition of amyloid-β species in brains with Alzheimer's disease pathology visualized with MALDI imaging mass spectrometry.

Amyloid β (Aβ) deposition in the brain is an early and invariable feature of Alzheimer's disease (AD). The Aβ peptides are composed of about 40 amino acids and are generated from amyloid precursor proteins (APP), by β- and γ-secretases. The distribution of individual Aβ peptides in the brains of aged people, and those suffering from AD and cerebral amyloid angiopathy (CAA), is not fully characterized. We employed the matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) to illustrate the spatial distribution of a broad range of Aβ species in human autopsied brains. With technical advancements such as formic acid pretreatment of frozen autopsied brain samples, we have: i) demonstrated that Aβ1-42 and Aβ1-43 were selectively deposited in senile plaques while full-length Aβ peptides such as Aβ1-36, 1-37, 1-38, 1-39, 1-40, and Aβ1-41 were deposited in leptomeningeal blood vessels. ii) Visualized distinct depositions of N-terminal truncated Aβ40 and Aβ42, including pyroglutamate modified at Glu-3 (N3pE), only with IMS for the first time. iii) Demonstrated that one single amino acid alteration at the C-terminus between Aβ1-42 and Aβ1-41 results in profound changes in their distribution pattern. In vitro, this can be attributed to the difference in the self-aggregation ability amongst Aβ1-40, Aβ1-41, and Aβ1-42. These observations were further confirmed with immunohistochemistry (IHC), using the newly developed anti-Aβ1-41 antibody. Here, distinct depositions of truncated and/or modified C- and N-terminal fragments of Aβs in AD and CAA brains with MALDI-IMS were visualized in a spacio-temporal specific manner. Specifically, Aβ1-41 was detected both with MALDI-IMS and IHC suggesting that a single amino acid alteration at the C-terminus of Aβ results in drastic distribution changes. These results suggest that MALDI-IMS could be used as a standard approach in combination with clinical, genetic, and pathological observations in understanding the pathology of AD and CAA.

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Beta Amyloid (42) ELISA K Beta Amyloid (1 40) ELISA Beta Amyloid (40) ELISA K Beta Amyloid (1 40) ELISA Integrin β1 (CD29) Antib Tissue array of gastric d Liver disease spectrum ti Lung disease spectrum tis Colon disease spectrum ti Rectum disease spectrum ( Kidney disease spectrum ( Breast disease spectrum t

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#28109886   2017/01/22 Save this To Up

Truncated prion protein PrP226* - A structural view on its role in amyloid disease.

In the brain of patients with transmissible spongiform encephalopathies, besides PrP(Sc) aggregates, deposition of truncated PrP molecules was described. Jansen et al. reported two clinical cases with deposition of C-terminally truncated PrP, one of them ending with Tyr226. We have previously described the discovery of monoclonal antibody V5B2 that selectively recognizes this version of the prion protein, which we called PrP226*. Using monoclonal antibody V5B2 we showed that accumulation of PrP226* is characteristic for most types of human and animal TSEs. Its distribution correlates to the distribution of PrP(Sc) aggregates. To gain insight into the structural basis of its presence and distribution in PrP aggregates, we have determined the NMR structure of recombinant PrP226*. The structure of the protein consists of a disordered N-terminal part (residues 90-125) and a structured C-terminal part (residues 126-226). The C-terminal segment consists of four α-helices and a short antiparallel β-sheet. Our model predicts a break in the C-terminal helix and reorganized hydrophobic interactions between helix α3 and β2-α2 loop due to the shorter C-terminus. The structural model gives information on the possible role of the protein in the development of amyloid disease and can serve as a foundation to develop tools for prevention and treatment of prion diseases.

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Beta Amyloid (42) ELISA K Beta Amyloid (1 40) ELISA Beta Amyloid (40) ELISA K Beta Amyloid (1 40) ELISA Goat Anti-Human Prion Pro Toxoplasma gondii GRA8, r FIV Core Ag, recombinant HIV 1 intergase antigen. Human Macrophage Inflamma Human Macrophage Inflamma Mouse Macrophage Inflamma Mouse Macrophage Inflamma

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#28073379   2017/01/11 Save this To Up

Tau passive immunization inhibits not only tau but also Aβ pathology.

Accumulation of hyperphosphorylated tau protein is a histopathological hallmark of Alzheimer's disease (AD) and related tauopathies. Currently, there is no effective treatment available for these progressive neurodegenerative diseases. In recent years, tau immunotherapy has shown great potential in animal models. We report the effect of immunization with tau antibodies 43D against tau 6-18 and 77E9 against tau 184-195 on tau and amyloid-β (Aβ) pathologies and cognition in triple-transgenic (3×Tg)-AD mice at mild to moderate stages of the disease.

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Human dopachrome tautomer Human L-dopachrome tautom ELISA Kit for Dopachrome Taurine CAS Number [107 3 Taurocholic acid, sodium IMCI Immunization grade c IMCI Immunization grade c Immunization grade chick IMBI Immunization grade b Immunization grade bovine Immunization grade porcin IMPI Immunization grade p

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#27437944   2016/07/21 Save this To Up

Neprilysin Inhibits Coagulation through Proteolytic Inactivation of Fibrinogen.

Neprilysin (NEP) is an endogenous protease that degrades a wide range of peptides including amyloid beta (Aβ), the main pathological component of Alzheimer's disease (AD). We have engineered NEP as a potential therapeutic for AD but found in pre-clinical safety testing that this variant increased prothrombin time (PT) and activated partial thromboplastin time (APTT). The objective of the current study was to investigate the effect of wild type NEP and the engineered variant on coagulation and define the mechanism by which this effect is mediated. PT and APTT were measured in cynomolgus monkeys and rats dosed with a human serum albumin fusion with an engineered variant of NEP (HSA-NEPv) as well as in control plasma spiked with wild type or variant enzyme. The coagulation factor targeted by NEP was determined using in vitro prothrombinase, calibrated automated thrombogram (CAT) and fibrin formation assays as well as N-terminal sequencing of fibrinogen treated with the enzyme. We demonstrate that HSA-NEP wild type and HSA-NEPv unexpectedly impaired coagulation, increasing PT and APTT in plasma samples and abolishing fibrin formation from fibrinogen. This effect was mediated through cleavage of the N-termini of the Aα- and Bβ-chains of fibrinogen thereby significantly impairing initiation of fibrin formation by thrombin. Fibrinogen has therefore been identified for the first time as a substrate for NEP wild type suggesting that the enzyme may have a role in regulating fibrin formation. Reductions in NEP levels observed in AD and cerebral amyloid angiopathy may contribute to neurovascular degeneration observed in these conditions.

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#26890761   2016/04/01 Save this To Up

Differential Membrane Toxicity of Amyloid-β Fragments by Pore Forming Mechanisms.

A major characteristic of Alzheimer's disease (AD) is the presence of amyloid-β peptide (Aβ) oligomers and aggregates in the brain. It is known that Aβ oligomers interact with the neuronal membrane and induce perforations that cause an influx of calcium ions and enhance the release of synaptic vesicles leading to a delayed synaptic failure by vesicle depletion. To better understand the mechanism by which Aβ exerts its effect on the plasma membrane, we evaluated three Aβ fragments derived from different regions of Aβ(1-42); Aβ(1-28) from the N-terminal region, Aβ(25-35) from the central region, and Aβ(17-42) from the C-terminal region. The neuronal activities of these fragments were examined with patch clamp, immunofluorescence, transmission electron microscopy, aggregation assays, calcium imaging, and MTT reduction assays. The present results indicate that the fragment Aβ(1-28) contributes to aggregation, an increase in intracellular calcium and synaptotoxicity, but is not involved in membrane perforation; Aβ(25-35) is important for membrane perforation, calcium increase, and synaptotoxicity; and Aβ(17-42) induced mitochondrial toxicity similar to the full length Aβ(1-42), but was unable to induce membrane perforation and calcium increase, supporting the idea that it is less toxic in the non-amyloidogenic pathway.

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BYL-719 Mechanisms: PI3K- MCE Membrane Filter, Pore Epithelial Membrane Anti Epithelial Membrane Anti Epithelial Membrane Anti Amyloid Stain Kit (Congo Amyloid Stain Kit (Congo Jones Stain Kit (For Bas TMB Precipitating Reagen TMB Precipitating Reagen TMB Precipitating Reagen Neo βgal

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#26626428   2015/12/02 Save this To Up

Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X.

Full-length Aβ1-42 and Aβ1-40, N-truncated pyroglutamate Aβ3-42 and Aβ4-42 are major variants in the Alzheimer brain. Aβ4-42 has not been considered as a therapeutic target yet. We demonstrate that the antibody NT4X and its Fab fragment reacting with both the free N-terminus of Aβ4-x and pyroglutamate Aβ3-X mitigated neuron loss in Tg4-42 mice expressing Aβ4-42 and completely rescued spatial reference memory deficits after passive immunization. NT4X and its Fab fragment also rescued working memory deficits in wild type mice induced by intraventricular injection of Aβ4-42. NT4X reduced pyroglutamate Aβ3-x, Aβx-40 and Thioflavin-S positive plaque load after passive immunization of 5XFAD mice. Aβ1-x and Aβx-42 plaque deposits were unchanged. Importantly, for the first time, we demonstrate that passive immunization using the antibody NT4X is therapeutically beneficial in Alzheimer mouse models showing that N-truncated Aβ starting with position four in addition to pyroglutamate Aβ3-x is a relevant target to fight Alzheimer's disease.

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Abeta (1-40 42) | 4D8 | o BCL-XL(Phospho-Ser62) Ant Androgen Receptor (Phosph Androgen Receptor (Phosph BCL XL (Ab 62) Antibody H Androgen Receptor (Ab 650 XPNPEP3 antibody Source R XE7 antibody Source Rabbi XYLB antibody Source Rabb Factor XI antibody Source XRCC3 antibody Source Rab L-xylulose reductase anti

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#26529393   2015/11/04 Save this To Up

N-truncated Aβ2-X starting with position two in sporadic Alzheimer's disease cases and two Alzheimer mouse models.

According to the modified amyloid hypothesis, the key event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid β-peptides (Aβs) in plaques and cerebral blood vessels. Additionally to full-length peptides, a great diversity of N-truncated Aβ variants is derived from the larger amyloid-β protein precursor (AβPP). Vast evidence suggests that Aβx-42 isoforms play an important role in triggering neurodegeneration due to their high abundance, amyloidogenic propensity and toxicity. Although N-truncated Aβ peptides and Aβx-42 species appear to be the crucial players in AD etiology, the Aβ2-X isoforms did not receive much attention yet. The present study is the first to show immunohistochemical evidence of Aβ2-X in cases of AD and its distribution in AβPP/PS1KI and 5XFAD transgenic mouse models using a novel antibody pAB77 that has been developed using Aβ2-14 as antigen. Positive plaques and congophilic amyloid angiopathy (CAA) were observed in AD cases and in both mouse models. While in AD cases, abundant CAA and less pronounced plaque pathology was evident, the two mouse models showed predominantly extracellular Aβ deposits and minor CAA staining. Western blotting and a capillary isoelectric focusing immunoassay demonstrated the high specificity of the antibody pAb77 against Aβ-variants starting with the N-terminal Alanine-2.

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Beta Amyloid (42) ELISA K Beta Amyloid (1 40) ELISA Beta Amyloid (40) ELISA K Beta Amyloid (1 40) ELISA Tissue array of gastric d Liver disease spectrum ti Lung disease spectrum tis Colon disease spectrum ti Rectum disease spectrum ( Kidney disease spectrum ( Breast disease spectrum t Breast disease spectrum t

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#26459115   2015/12/21 Save this To Up

Oxidative stress and mitochondria-mediated cell death mechanisms triggered by the familial Danish dementia ADan amyloid.

Familial Danish Dementia (FDD), an early-onset non-amyloid-β (Aβ) cerebral amyloidosis, is neuropathologically characterized by widespread cerebral amyloid angiopathy, parenchymal amyloid and preamyloid deposits, as well as neurofibrillary degeneration indistinguishable to that seen in Alzheimer's disease (AD). The main amyloid subunit composing FDD lesions, a 34-amino acid de-novo generated peptide ADan, is the direct result of a genetic defect at the 3'-end of the BRI2 gene and the physiologic action of furin-like proteolytic processing at the C-terminal region of the ADan precursor protein. We aimed to study the impact of the FDD mutation, the additional formation of the pyroglutamate (pE) posttranslational modification as well as the relevance of C-terminal truncations -all major components of the heterogeneous FDD deposits- on the structural and neurotoxic properties of the molecule. Our data indicates that whereas the mutation generated a β-sheet-rich hydrophobic ADan subunit of high oligomerization/fibrillization propensity and the pE modification further enhanced these properties, C-terminal truncations had the opposite effect mostly abolishing these features. The potentiation of pro-amyloidogenic properties correlated with the initiation of neuronal cell death mechanisms involving oxidative stress, perturbation of mitochondrial membrane potential, release of mitochondrial cytochrome c, and downstream activation of caspase-mediated apoptotic pathways. The amyloid-induced toxicity was inhibited by targeting specific components of these detrimental cellular pathways, using reactive oxygen scavengers and monoclonal antibodies recognizing the pathological amyloid subunit. Taken together, the data indicate that the FDD mutation and the pE posttranslational modification are both primary elements driving intact ADan into an amyloidogenic/neurotoxic pathway while truncations at the C-terminus eliminate the pro-amyloidogenic characteristics of the molecule, likely reflecting effect of physiologic clearance mechanisms.

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#26452689   2015/11/06 Save this To Up

Isobaric Quantification of Cerebrospinal Fluid Amyloid-β Peptides in Alzheimer's Disease: C-Terminal Truncation Relates to Early Measures of Neurodegeneration.

The amyloid beta (Aβ) peptide is the main constituent of the plaques characteristic of Alzheimer's disease (AD). Measurement of Aβ1-42 in cerebrospinal fluid (CSF) is a valuable marker in AD research, where low levels indicate AD. Although the use of immunoassays measuring Aβ1-38 and Aβ1-40 in addition to Aβ1-42 has increased, quantitative assays of other Aβ peptides remain rarely explored. We recently discovered novel Aβ peptides in CSF using antibodies recognizing the Aβ mid-domain region. Here we have developed a method using both Aβ N-terminal and mid-domain antibodies for immunoprecipitation in combination with isobaric labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for relative quantification of endogenous Aβ peptides in CSF. The developed method was used in a pilot study to produce Aβ peptide profiles from 38 CSF samples. Statistical comparison between CSF samples from 19 AD patients and 19 cognitively healthy controls revealed no significant differences at group level. A significant correlation was found between several larger C-terminally truncated Aβ peptides and protein biomarkers for neuronal damage, particularly prominent in the control group. Comparison of the isobaric quantification with immunoassays measuring Aβ1-38 or Aβ1-40 showed good correlation (r(2) = 0.84 and 0.85, respectively) between the two analysis methods. The developed method could be used to assess disease-modifying therapies directed at Aβ production or degradation.

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Beta Amyloid (42) ELISA K Beta Amyloid (1 40) ELISA Beta Amyloid (40) ELISA K Beta Amyloid (1 40) ELISA Integrin β1 (CD29) Antib Beta Amyloid (40) ELISA K Beta Amyloid (1 42) ELISA Anti 3 DG imidazolone Mon rHIV gp36, soluble Antige rHIV gp41, soluble Antige Nycodenz, non ionic, non Homogenizer for 24 sample

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#26351699   2015/09/23 Save this To Up

Peptide dimer structure in an Aβ(1-42) fibril visualized with cryo-EM.

Alzheimer's disease (AD) is a fatal neurodegenerative disorder in humans and the main cause of dementia in aging societies. The disease is characterized by the aberrant formation of β-amyloid (Aβ) peptide oligomers and fibrils. These structures may damage the brain and give rise to cerebral amyloid angiopathy, neuronal dysfunction, and cellular toxicity. Although the connection between AD and Aβ fibrillation is extensively documented, much is still unknown about the formation of these Aβ aggregates and their structures at the molecular level. Here, we combined electron cryomicroscopy, 3D reconstruction, and integrative structural modeling methods to determine the molecular architecture of a fibril formed by Aβ(1-42), a particularly pathogenic variant of Aβ peptide. Our model reveals that the individual layers of the Aβ fibril are formed by peptide dimers with face-to-face packing. The two peptides forming the dimer possess identical tilde-shaped conformations and interact with each other by packing of their hydrophobic C-terminal β-strands. The peptide C termini are located close to the main fibril axis, where they produce a hydrophobic core and are surrounded by the structurally more flexible and charged segments of the peptide N termini. The observed molecular architecture is compatible with the general chemical properties of Aβ peptide and provides a structural basis for various biological observations that illuminate the molecular underpinnings of AD. Moreover, the structure provides direct evidence for a steric zipper within a fibril formed by full-length Aβ peptide.

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