The Guinea Pig as a model for sporadic Alzheimer's Disease (AD): the impact of cholesterol intake on expression of AD-related genes

Extent: 12p.We investigated the guinea pig, Cavia porcellus, as a model for Alzheimer’s disease (AD), both in terms of the conservation of genes involved in AD and the regulatory responses of these to a known AD risk factor - high cholesterol intake. Unlike rats and mice, guinea pigs possess an Aβ peptide sequence identical to human Aβ. Consistent with the commonality between cardiovascular and AD risk factors in humans, we saw that a high cholesterol diet leads to up-regulation of BACE1 (β-secretase) transcription and down-regulation of ADAM10 (α-secretase) transcription which should increase release of Aβ from APP. Significantly, guinea pigs possess isoforms of AD-related genes found in humans but not present in mice or rats. For example, we discovered that the truncated PS2V isoform of human PSEN2, that is found at raised levels in AD brains and that increases γ-secretase activity and Aβ synthesis, is not uniquely human or aberrant as previously believed. We show that PS2V formation is up-regulated by hypoxia and a high-cholesterol diet while, consistent with observations in humans, Aβ concentrations are raised in some brain regions but not others. Also like humans, but unlike mice, the guinea pig gene encoding tau, MAPT, encodes isoforms with both three and four microtubule binding domains, and cholesterol alters the ratio of these isoforms. We conclude that AD-related genes are highly conserved and more similar to human than the rat or mouse. Guinea pigs represent a superior rodent model for analysis of the impact of dietary factors such as cholesterol on the regulation of AD-related genes.Mathew J. Sharman, Seyyed H. Moussavi Nik, Mengqi M. Chen, Daniel Ong, Linda Wijaya, Simon M. Laws, Kevin Taddei, Morgan Newman, Michael Lardelli, Ralph N. Martins, Giuseppe Verdil

Megalin/LRP2 Expression Is Induced by Peroxisome Proliferator-Activated Receptor -Alpha and -Gamma: Implications for PPARs' Roles in Renal Function

BACKGROUND: Megalin is a large endocytic receptor with relevant functions during development and adult life. It is expressed at the apical surface of several epithelial cell types, including proximal tubule cells (PTCs) in the kidney, where it internalizes apolipoproteins, vitamins and hormones with their corresponding carrier proteins and signaling molecules. Despite the important physiological roles of megalin little is known about the regulation of its expression. By analyzing the human megalin promoter, we found three response elements for the peroxisomal proliferator-activated receptor (PPAR). The objective of this study was to test whether megalin expression is regulated by the PPARs. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of epithelial cell lines with PPARα or PPARγ ligands increased megalin mRNA and protein expression. The stimulation of megalin mRNA expression was blocked by the addition of specific PPARα or PPARγ antagonists. Furthermore, PPAR bound to three PPAR response elements located in the megalin promoter, as shown by EMSA, and PPARα and its agonist activated a luciferase construct containing a portion of the megalin promoter and the first response element. Accordingly, the activation of PPARα and PPARγ enhanced megalin expression in mouse kidney. As previously observed, high concentrations of bovine serum albumin (BSA) decreased megalin in PTCs in vitro; however, PTCs pretreated with PPARα and PPARγ agonists avoided this BSA-mediated reduction of megalin expression. Finally, we found that megalin expression was significantly inhibited in the PTCs of rats that were injected with BSA to induce tubulointerstitial damage and proteinuria. Treatment of these rats with PPARγ agonists counteracted the reduction in megalin expression and the proteinuria induced by BSA. CONCLUSIONS: PPARα/γ and their agonists positively control megalin expression. This regulation could have an important impact on several megalin-mediated physiological processes and on pathophysiologies such as chronic kidney disease associated with diabetes and hypertension, in which megalin expression is impaired

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Introduction: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. Methods: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Results: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P 0.72. Furthermore, [TIMP- 2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. Conclusions: Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI

Deux nouvelles espèces de

De nouveaux taxa de Puces, seulement connus par le mâle, sont ajoutés à la faune chilio-andine. Il s’agit de représentants du sousgenre Neornipsyllus, inféodé aux Oiseaux, essentiellement Passériformes. D. (N.) huinayensis sp. n., est, inter alia, caractérisé par la disposition des fortes soies du télomère ; D. (N.) tapaculensis sp. n. montre un tergite X (ou proctiger) original pour l’Ordre entier par sa forme et sa chetotaxie en grande partie formée de soies bifides

Deux nouvelles espèces de Dasypsyllus (Siphonaptera : Ceratophyllidae) au Chili

De nouveaux taxa de Puces, seulement connus par le mâle, sont ajoutés à la faune chilio-andine. Il s’agit de représentants du sousgenre Neornipsyllus, inféodé aux Oiseaux, essentiellement Passériformes. D. (N.) huinayensis sp. n., est, inter alia, caractérisé par la disposition des fortes soies du télomère ; D. (N.) tapaculensis sp. n. montre un tergite X (ou proctiger) original pour l’Ordre entier par sa forme et sa chetotaxie en grande partie formée de soies bifides

Philodryas chamissonis (Reptilia: Squamata: Colubridae) preys on the arboreal marsupial Dromiciops gliroides (Mammalia: Microbiotheria: Microbiotheriidae)

Philodryas chamissonis, the Chilean long-tailed snake, is a diurnal predator mainly of Liolaemus lizards, but also of amphibians, birds, rodents and juvenile rabbits. Dromiciops gliroides (Colocolo opossum) is an arboreal marsupial endemic of temperate rainforest of southern South America. Little information is available about this marsupial's biology and ecology. Here we report the predation of one Colocolo opossum by an adult female P. chamissonis in a mixed Nothofagus forest, composed mainly by N. dombeyi, N. glauca and N. alpina trees, in the "Huemules de Niblinto" National Reserve, Nevados de Chillán, Chile. Since these two species have different activity and habitat use patterns, we discuss how this encounter may have occurred. Although it could just have been an opportunistic event, this finding provides insights into the different components of food chains in forest ecosystems of Chile

Philodryas chamissonis (Reptilia: Squamata: Colubridae) preys on the arboreal marsupial Dromiciops gliroides (Mammalia: Microbiotheria: Microbiotheriidae)

Philodryas chamissonis, the Chilean long-tailed snake, is a diurnal predator mainly of Liolaemus lizards, but also of amphibians, birds, rodents and juvenile rabbits. Dromiciops gliroides (Colocolo opossum) is an arboreal marsupial endemic of temperate rainforest of southern South America. Little information is available about this marsupial's biology and ecology. Here we report the predation of one Colocolo opossum by an adult female P. chamissonis in a mixed Nothofagus forest, composed mainly by N. dombeyi, N. glauca and N. alpina trees, in the "Huemules de Niblinto" National Reserve, Nevados de Chillán, Chile. Since these two species have different activity and habitat use patterns, we discuss how this encounter may have occurred. Although it could just have been an opportunistic event, this finding provides insights into the different components of food chains in forest ecosystems of Chile

High-resolution X-ray Diffraction Beamline At The Lnls For The Study Of Charge, Orbital And Magnetic Structures.

A high-resolution X-ray diffraction beamline at the Brazilian Synchrotron Light Laboratory (LNLS) has been commissioned for the study of crystalline magnetic materials. The beamline optics is based on a Rh-coated vertical-focusing X-ray mirror and a sagittal-focusing double-crystal monochromator. The primary instrument is a six-circle diffractometer equipped with energy and polarization analysers and a closed-cycle He cryostat. The beamline source is a bending magnet of the 1.37 GeV storage ring of the LNLS, delivering approximately 4 x 10(10) photons s(-1) at 8 keV at the sample position. Resonant and non-resonant scattering are the main techniques used to study charge, orbital and magnetic structures. Examples of magnetic scattering in Ho and NiO single crystals, as well as orbital ordering in manganites thin films, are presented.10430-