Glucagon-Like Peptide-1 Receptor Agonists and Brain Vascular Function.

Prevention of cardiovascular events and regression of atherosclerotic changes are the primary aims of preventive cardiovascular medicine. Arterial thrombosis is caused by endothelial dysfunction, which disrupts vascular haemostasis. Glucagon-like peptide 1 (GLP-1) receptor agonists have been initially used as glucose lowering agents, but over time have been used for other indications due to their cardiorenal benefit, as well as their benefit in the regression of atherosclerosis process.

Increased Levels of Coagulation Factor XI in Plasma Are Related to Alzheimer's Disease Diagnosis.

Background: Alzheimer's disease is a complex disorder of unclear etiology that develops in the elderly population. It is a debilitating, progressive neurodegeneration for which disease-modifying therapies do not exist. Previous studies have suggested that, for a subset of patients, dysregulation in hemostasis might be one of the molecular mechanisms that ultimately leads to the development of neurodegeneration resulting in cognitive decline that represents the most prominent symptomatic characteristic of Alzheimer's disease.

SOMAscan-based proteomic measurements of plasma brain natriuretic peptide are decreased in mild cognitive impairment and in Alzheimer's dementia patients.

Alzheimer's disease represents the most common age-related neurodegenerative disorder and a leading cause of progressive cognitive impairment. Predicting cognitive decline is challenging but would be invaluable in an increasingly aging population which also experiences a rising cardiovascular risk. In order to examine whether plasma measurements of one of the established biomarkers of heart failure, brain natriuretic peptide (BNP), reflect a decline in cognitive function, associated with Alzheimer's disease neurodegeneration, BNP levels were analysed, by using a novel assay called a SOMAscan, in 1.

The Notch intracellular domain represses CRE-dependent transcription.

Members of the cyclic-AMP response-element binding protein (CREB) transcription factor family regulate the expression of genes needed for long-term memory formation. Loss of Notch impairs long-term, but not short-term, memory in flies and mammals. We investigated if the Notch-1 (N1) exerts an effect on CREB-dependent gene transcription.

Prostate-derived sterile 20-like kinases (PSKs/TAOKs) phosphorylate tau protein and are activated in tangle-bearing neurons in Alzheimer disease.

In Alzheimer disease (AD), the microtubule-associated protein tau is highly phosphorylated and aggregates into characteristic neurofibrillary tangles. Prostate-derived sterile 20-like kinases (PSKs/TAOKs) 1 and 2, members of the sterile 20 family of kinases, have been shown to regulate microtubule stability and organization. Here we show that tau is a good substrate for PSK1 and PSK2 phosphorylation with mass spectrometric analysis of phosphorylated tau revealing more than 40 tau residues as targets of these kinases.

Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway.

Although the mechanism of Aβ action in the pathogenesis of Alzheimer's disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aβ neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aβ/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aβ toxicity and DKK1 upregulation and, conversely, Aβ increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1.

The metalloprotease meprin β generates amino terminal-truncated amyloid β peptide species.

The amyloid β (Aβ) peptide, which is abundantly found in the brains of patients suffering from Alzheimer disease, is central in the pathogenesis of this disease. Therefore, to understand the processing of the amyloid precursor protein (APP) is of critical importance. Recently, we demonstrated that the metalloprotease meprin β cleaves APP and liberates soluble N-terminal APP (N-APP) fragments.

Plasma biomarkers of brain atrophy in Alzheimer's disease.

Peripheral biomarkers of Alzheimer's disease (AD) reflecting early neuropathological change are critical to the development of treatments for this condition. The most widely used indicator of AD pathology in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with brain atrophy in AD.

Metalloprotease meprin beta generates nontoxic N-terminal amyloid precursor protein fragments in vivo.

Identification of physiologically relevant substrates is still the most challenging part in protease research for understanding the biological activity of these enzymes. The zinc-dependent metalloprotease meprin β is known to be expressed in many tissues with functions in health and disease. Here, we demonstrate unique interactions between meprin β and the amyloid precursor protein (APP).

β-Amyloid precursor protein and tau protein levels are differently regulated in human cerebellum compared to brain regions vulnerable to Alzheimer's type neurodegeneration.

It is well established that the human brain exhibits regional variability in its vulnerability to Alzheimer's disease (AD) pathology. We set out to determine if this regional vulnerability is reflected in the expression pattern, or processing, of two key proteins involved in AD pathology, the β-amyloid precursor protein (APP) and tau, by immunoblotting. Our data demonstrate that APP processing and APP protein levels are not different between AD patients and healthy, age-matched subjects, but that levels of mature APP are greatly reduced in cerebellum compared to regions of the brain most vulnerable to AD, entorhinal cortex and hippocampus.

Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease.

Context: Blood-based analytes may be indicators of pathological processes in Alzheimer disease (AD).

Objective: To identify plasma proteins associated with AD pathology using a combined proteomic and neuroimaging approach.

Design: Discovery-phase proteomics to identify plasma proteins associated with correlates of AD pathology.

Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice.

As impaired insulin signalling (IIS) is a risk factor for Alzheimer's disease we crossed mice (Tg2576) over-expressing human amyloid precursor protein (APP), with insulin receptor substrate 2 null (Irs2(-/-)) mice which develop insulin resistance. The resulting Tg2576/Irs2(-/-) animals had increased tau phosphorylation but a paradoxical amelioration of Abeta pathology. An increase of the Abeta binding protein transthyretin suggests that increased clearance of Abeta underlies the reduction in plaques.

High aldosterone-to-renin variants of CYP11B2 and pregnancy outcome.

Background: Increased aldosterone concentrations and volume expansion of normal pregnancies are hallmarks of normal pregnancies and blunted in pre-eclampsia. Accordingly, we hypothesized an active mineralocorticoid system to protect from pre-eclampsia.

Methods: In pregnant women (normotensive n = 44; pre-eclamptic n = 48), blood pressure, urinary tetrahydro-aldosterone excretion and activating polymorphisms (SF-1 site and intron 2) of the aldosterone synthase gene (CYP11B2) were determined; 185 non-pregnant normotensive individuals served as control.

Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding.

Background: Shedding of the Alzheimer amyloid precursor protein (APP) ectodomain can be accelerated by phorbol esters, compounds that act via protein kinase C (PKC) or through unconventional phorbol-binding proteins such as Munc13-1. We have previously demonstrated that application of phorbol esters or purified PKC potentiates budding of APP-bearing secretory vesicles at the trans-Golgi network (TGN) and toward the plasma membrane where APP becomes a substrate for enzymes responsible for shedding, known collectively as alpha-secretase(s). However, molecular identification of the presumptive "phospho-state-sensitive modulators of ectodomain shedding" (PMES) responsible for regulated shedding has been challenging.

11beta-Hydroxysteroid dehydrogenase type 2 in pregnancy and preeclampsia.

Cortisol availability is controlled by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which inactivates cortisol in cortisone, unable to bind to the glucocorticoid receptor. The 11beta-HSD2 enzyme activity limits either intracellular cortisol concentrations or within the uteroplacental compartment the transfer of cortisol into the fetal circulation. Mechanisms, by which 11beta-HSD2 activity is controlled, include transcriptional control, posttranscriptional modifications of 11beta-HSD2 transcript half-life, epigenetic regulation via methylation of genomic DNA and direct inhibition of enzymatic activity.

Proteome-based plasma biomarkers for Alzheimer's disease.

Alzheimer's disease is a common and devastating disease for which there is no readily available biomarker to aid diagnosis or to monitor disease progression. Biomarkers have been sought in CSF but no previous study has used two-dimensional gel electrophoresis coupled with mass spectrometry to seek biomarkers in peripheral tissue. We performed a case-control study of plasma using this proteomics approach to identify proteins that differ in the disease state relative to aged controls.

Evidence for compromised aldosterone synthase enzyme activity in preeclampsia.

Background: In normal pregnancy, an increased aldosterone (Aldo) concentration coincides with volume expansion. In preeclampsia, Aldo levels are low despite intravascular volume depletion. The present investigation aimed to characterize the compromised Aldo synthesis in preeclampsia, and to identify the molecular basis hereof.

Lack of association between the levels of the low-density lipoprotein receptor-related protein (LRP) and either Alzheimer dementia or LRP exon 3 genotype.

The low-density lipoprotein receptor-related protein (LRP), which interacts with the Alzheimer disease (AD) beta-amyloid precursor protein (APP), represents an important pathway in AD pathology. LRP-mediated receptor pathways appear to regulate both the production and the clearance of amyloid beta-protein (Abeta), a principal neuropathological product in AD. Several conflicting studies have examined levels of LRP in AD brains, as well as the relationship between the LRP exon 3 (C766T) polymorphism and LRP levels and/or disease susceptibility.

Angiotensin II regulates 11beta-hydroxysteroid dehydrogenase type 2 via AT2 receptors.

Background: In preeclampsia, cortisol degradation by the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) is compromised, which enhances intracellular cortisol availability. This leads to vasoconstriction and renal sodium retention with volume expansion, thus increasing blood pressure. An augmented availability of angiotensin II (Ang II) predisposes to preeclampsia.

Overexpression and poly-ubiquitylation of the DEAD-box RNA helicase p68 in colorectal tumours.

The DEAD box RNA helicase, p68, is upregulated in exponentially growing cells and shows cell cycle-dependent changes in nuclear localization. Although some other DEAD box proteins have been implicated in cancer, there have been no reports of any link between p68 status and carcinogenesis. In the present study we have analysed specimens from 50 patients with colorectal adenocarcinomas, including cases in which an adenomatous polyp was also present, by immunohistochemistry and Western blotting.

Fluid Shear Stress Reduces 11ss-Hydroxysteroid Dehydrogenase Type 2.

-In pregnancy, invading trophoblasts represent the inner vascular border of maternal spiral arteries and are exposed to elevated shear stress (ss) in hypertensive disorders. Intracellular cortisol availability is regulated by 11ss-hydroxysteroid dehydrogenases (11ss-HSDs), thus determining body fluid volume and vascular responses. The impact of ss on 11ss-HSD2 activity was studied in the human JEG-3 cell line, a model for trophoblasts.

The nuclear DEAD box RNA helicase p68 interacts with the nucleolar protein fibrillarin and colocalizes specifically in nascent nucleoli during telophase.

The DEAD box protein, p68, is an established RNA-dependent ATPase and RNA helicase in vitro, but neither the physiological function of this protein nor the macromolecules with which it interacts are known. Using a yeast two-hybrid screen, we identified the nucleolar protein, fibrillarin, as a protein that interacts with p68. Coimmunoprecipitation experiments confirmed that p68 and fibrillarin can form complexes in cellular extracts, and deletion analysis identified regions in each protein responsible for mediating the interaction.

Substitution of a conserved amino acid residue alters the ligand binding properties of peroxisome proliferator activated receptors.

Mutation of glutamic acid 282 of PPARalpha to glycine has been shown to result in an increased EC(50) for a wide variety of PPAR activating compounds. This has suggested that mutant receptor has a reduced ability to bind ligand. In this study we show that this mutation reduces the affinity of mPPARalpha and hPPARgamma for the fluorescent fatty acid, cis-parinaric acid and that the mutant hPPARgamma protein has a reduced affinity for the radiolabelled compound, SB236636.