Hypercholesterolemia and 27-Hydroxycholesterol Increase S100A8 and RAGE Expression in the Brain: a Link Between Cholesterol, Alarmins, and Neurodegeneration.

Alterations in cholesterol metabolism in the brain have a major role in the physiology of Alzheimer's disease (AD). Oxysterols are cholesterol metabolites with multiple implications in memory functions and in neurodegeneration. Previous studies have shown detrimental effects of cholesterol metabolites in neurons, but its effect in glial cells is unknown.

Spectroscopic analysis of corrosion products in a bronze cauldron from the Late Iberian Iron Age.

Selected bronze fragments unearthed at Cerro de la Cruz (Almedinilla, southern Spain) were analyzed to determine the chemical composition of the corrosion products formed on their surface. The fragments came from a large bronze cauldron used in an Iberian village that was devastated in the mid II century BCE - possibly around 141 BCE. The fragments were analyzed by using various instrumental techniques including electron scanning microscopy coupled to energy dispersive X-ray spectroscopy (SEM-EDS), X-ray fluorescence (XRF) spectroscopy, and also by X-ray diffraction (XRD) and micro-Raman spectroscopy.

27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation.

Hypercholesterolemia is associated with cognitively deteriorated states. Here, we show that excess 27-hydroxycholesterol (27-OH), a cholesterol metabolite passing from the circulation into the brain, reduced in vivo brain glucose uptake, GLUT4 expression, and spatial memory. Furthermore, patients exhibiting higher 27-OH levels had reduced F-fluorodeoxyglucose uptake.

Angiotensin II type-2 receptor stimulation induces neuronal VEGF synthesis after cerebral ischemia.

Intense efforts are being undertaken to understand the pathobiology of ischemia and to develop novel and effective treatments. Angiotensin II type 2 receptor (AT2R) is related with a beneficial role in neurodegenerative disorders, including ischemia. However, the underlying molecular mechanism remains elusive.

Raman microspectroscopic analysis of decorative pigments from the Roman villa of El Ruedo (Almedinilla, Spain).

In this work, we analysed the preparatory layer and paintings in the hypocaustum of the Roman villa of El Ruedo (Almedinilla, southern Spain). The specimens studied were from the III and IV centuries. Raman microscopy was for the first time used here to examine Roman pictures in the south of the Iberian peninsula.

27-hydroxycholesterol mediates negative effects of dietary cholesterol on cognition in mice.

In spite of the fact that cholesterol does not pass the blood-brain barrier, treatment of mice with dietary cholesterol causes significant effects on a number of genes in the brain and in addition a memory impairment. We have suggested that these effects are mediated by 27-hydroxycholesterol, which is able to pass the blood-brain barrier. To test this hypothesis we utilized Cyp27-/- mice lacking 27-hydroxycholesterol.

Estradiol and Progesterone Administration After pMCAO Stimulates the Neurological Recovery and Reduces the Detrimental Effect of Ischemia Mainly in Hippocampus.

Epidemiological studies have suggested a differential response, males versus female, in stroke incidence and prognosis. These divergences in brain response after damage are based mostly on hormonal differences. To date, estradiol and progesterone administered independently have demonstrated neuroprotection after ischemia in animal models.

Thioredoxin-80 is a product of alpha-secretase cleavage that inhibits amyloid-beta aggregation and is decreased in Alzheimer's disease brain.

Thioredoxin-1 (Trx1) is an endogenous dithiol reductant and antioxidant that was shown to be decreased in Alzheimer's disease (AD) neurons. A truncated form of Trx1, thioredoxin 80 (Trx80), was reported to be secreted from monocytes having cytokine activity. Here, we show that Trx80 is present in human brain in an aggregated form.

side-chain-oxidized oxysterols upregulate ACE2 and Mas receptor in rat primary neurons.

Background: Disturbances in cholesterol metabolism have been associated with hypertension and Alzheimer's disease (AD). We recently reported increased angiotensin-converting enzyme (ACE) activity and angiotensinogen (AGT) levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment and AD. ACE activity positively correlated with plasma and CSF 27-hydroxycholesterol (27-OH) levels, an oxysterol that passes to the brain from the blood.

Estrogen protects against amyloid-β toxicity by estrogen receptor α-mediated inhibition of Daxx translocation.

Estrogen was shown to promote neuronal survival against several neurotoxic insults including β-amyloid (Aβ). The proposed mechanism includes the activation of the mitogen activated protein kinase/extracellular signal-regulated kinase (Mapk/Erk), phosphatidylinositol 3-kinase/Akt pathways and the upregulation of antiapoptotic proteins. On the other hand, Aβ neurotoxicity depends on the activation of apoptosis signal-regulating kinase 1 (Ask1), and both Ask1 activity and Aβ toxicity are inhibited by thioredoxin-1 (Trx1).

Side chain-oxidized oxysterols regulate the brain renin-angiotensin system through a liver X receptor-dependent mechanism.

Disturbances in cholesterol metabolism have been associated with hypertension and neurodegenerative disorders. Because cholesterol metabolism in the brain is efficiently separated from plasma cholesterol by the blood-brain barrier (BBB), it is an unsolved paradox how high blood cholesterol can cause an effect in the brain. Here, we discuss the possibility that cholesterol metabolites permeable to the BBB might account for these effects.

Plasma cholesterol and risk for late-onset Alzheimer's disease.

Alzheimer's disease (AD), the most common cause of dementia, is a progressive neurodegenerative disorder affecting millions of people worldwide. AD has a multifactorial origin, resulting from an interaction between genetic susceptibility and environmental risk factors. Genetic, epidemiological, experimental and clinical data strongly suggest that the metabolism of cholesterol has an important role in AD pathogenesis.

Upregulation of brain renin angiotensin system by 27-hydroxycholesterol in Alzheimer's disease.

In spite of the fact that cholesterol does not pass the blood-brain barrier, hypercholesterolemia has been linked to increase Alzheimer's disease (AD) risk. Hypertension is another risk factor and angiotensin converting enzyme (ACE) activity is known to be increased in AD. Furthermore, a lower incidence of AD has been reported in patients taking anti-hypertensive drugs.

Cholinergic hypofunction impairs memory acquisition possibly through hippocampal Arc and BDNF downregulation.

Recent evidence suggests that activity-regulated cytoskeleton associated protein (Arc) and brain-derived neurotrophic factor (BDNF) are key players in the cellular mechanisms that trigger synaptic changes and memory consolidation. Cholinergic deafferentiation of hippocampus has been largely shown to induce memory impairments in different behavioral tasks. However, the mechanisms underlying cholinergic-induced memory formation remain unclear.

Influence of residue 22 on the folding, aggregation profile, and toxicity of the Alzheimer's amyloid beta peptide.

Several biophysical techniques have been used to determine differences in the aggregation profile (i.e., the secondary structure, aggregation propensity, dynamics, and morphology of amyloid structures) and the effects on cell viability of three variants of the amyloid beta peptide involved in Alzheimer's disease.

Impaired long term memory consolidation in transgenic mice overexpressing the human soluble form of IL-1ra in the brain.

Interleukin-1 (IL-1) is expressed following LTP induction and is required for long-term memory consolidation. We demonstrate that the long-term, but not short-term memory is impaired in a transgenic mouse strain overexpressing the human soluble interleukin-1 receptor antagonist (hsIL-1ra) in the brain. Overexpression of IL-1ra was found to reduce the basal as well as the novelty-induced upregulation of activity-regulated cytoskeleton-associated protein (Arc) in the dentate gyrus and in the retrosplenial cortex.

Parkin-mediated ubiquitination regulates phospholipase C-gamma1.

Mutations in parkin cause autosomal recessive forms of Parkinson's disease (PD), with an early age of onset and similar pathological phenotype to the idiopathic disease. Parkin has been identified as an E3 ubiquitin ligase that mediates different types of ubiquitination, which has made the search for substrates an intriguing possibility to identify pathological mechanisms linked to PD. In this study, we present PLCgamma1 as a novel substrate for parkin.

Activity-regulated cytoskeleton-associated protein in rodent brain is down-regulated by high fat diet in vivo and by 27-hydroxycholesterol in vitro.

Growing evidence strongly suggests that high fat diet (HFD) has an important role in some neurodegenerative disorders, including Alzheimer's disease (AD). To identify new cellular pathways linking hypercholesterolemia and neurodegeneration, we analyzed the effects of HFD on gene expression in mouse brain. Using cDNA microarrays and real time RT-PCR, we found that HFD has a mild, but significant effect on the expression of several genes.

A chemogenomic screening of sulfanilamide-hypersensitive Saccharomyces cerevisiae mutants uncovers ABZ2, the gene encoding a fungal aminodeoxychorismate lyase.

Large-scale phenotypic analyses have proved to be useful strategies in providing functional clues about the uncharacterized yeast genes. We used here a chemogenomic profiling of yeast deletion collections to identify the core of cellular processes challenged by treatment with the p-aminobenzoate/folate antimetabolite sulfanilamide. In addition to sulfanilamide-hypersensitive mutants whose deleted genes can be categorized into a number of groups, including one-carbon related metabolism, vacuole biogenesis and vesicular transport, DNA metabolic and cell cycle processes, and lipid and amino acid metabolism, two uncharacterized open reading frames (YHI9 and YMR289w) were also identified.

The txl1+ gene from Schizosaccharomyces pombe encodes a new thioredoxin-like 1 protein that participates in the antioxidant defence against tert-butyl hydroperoxide.

Yeasts are equipped with several putative single-domain thioredoxins located in different subcellular compartments. However, additional proteins containing thioredoxin domains are also encoded by the yeast genomes as described for mammals and other eukaryotic organisms. We report here the characterization of the fission yeast orthologue thioredoxin-like 1 (txl1(+)), which has been previously identified in mammals.

Purine biosynthesis, riboflavin production, and trophic-phase span are controlled by a Myb-related transcription factor in the fungus Ashbya gossypii.

Ashbya gossypii is a natural riboflavin overproducer used in the industrial production of the vitamin. We have isolated an insertional mutant exhibiting higher levels of riboflavin production than the wild type. DNA analysis of the targeted locus in the mutant strain revealed that a syntenic homolog of the Saccharomyces cerevisiae BAS1 gene, a member of the Myb family of transcription factors, was inactivated.