Amyloid Precursor Protein and Proinflammatory Changes Are Regulated in Brain and Adipose Tissue in a Murine Model of High Fat Diet-Induced Obesity

Background: Middle age obesity is recognized as a risk factor for Alzheimer’s disease (AD) although a mechanistic linkage remains unclear. Based upon the fact that obese adipose tissue and AD brains are both areas of proinflammatory change, a possible common event is chronic inflammation. Since an autosomal dominant form of AD is associated with mutations in the gene coding for the ubiquitously expressed transmembrane protein, amyloid precursor protein (APP) and recent evidence demonstrates increased APP levels in adipose tissue during obesity it is feasible that APP serves some function in both disease conditions. Methodology/Principal Findings: To determine whether diet-induced obesity produced proinflammatory changes and altered APP expression in brain versus adipose tissue, 6 week old C57BL6/J mice were maintained on a control or high fat diet for 22 weeks. Protein levels and cell-specific APP expression along with markers of inflammation and immune cell activation were compared between hippocampus, abdominal subcutaneous fat and visceral pericardial fat. APP stimulation-dependent changes in macrophage and adipocyte culture phenotype were examined for comparison to the in vivo changes. Conclusions/Significance: Adipose tissue and brain from high fat diet fed animals demonstrated increased TNF-a and microglial and macrophage activation. Both brains and adipose tissue also had elevated APP levels localizing to neurons and macrophage/adipocytes, respectively. APP agonist antibody stimulation of macrophage cultures increased specific cytokin

Plasma biomarkers of depressive symptoms in older adults

The pathophysiology of negative affect states in older adults is complex, and a host of central nervous system and peripheral systemic mechanisms may play primary or contributing roles. We conducted an unbiased analysis of 146 plasma analytes in a multiplex biochemical biomarker study in relation to number of depressive symptoms endorsed by 566 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) at their baseline and 1-year assessments. Analytes that were most highly associated with depressive symptoms included hepatocyte growth factor, insulin polypeptides, pregnancy-associated plasma protein-A and vascular endothelial growth factor. Separate regression models assessed contributions of past history of psychiatric illness, antidepressant or other psychotropic medicine, apolipoprotein E genotype, body mass index, serum glucose and cerebrospinal fluid (CSF) τ and amyloid levels, and none of these values significantly attenuated the main effects of the candidate analyte levels for depressive symptoms score. Ensemble machine learning with Random Forests found good accuracy (∼80%) in classifying groups with and without depressive symptoms. These data begin to identify biochemical biomarkers of depressive symptoms in older adults that may be useful in investigations of pathophysiological mechanisms of depression in aging and neurodegenerative dementias and as targets of novel treatment approaches

APOE and Alzheimer disease: a major gene with semi-dominant inheritance

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease

Excavating in breccia: new methods developed at the Benzú rockshelter

Excavators examining breccia deposits are faced with the prospect of extracting finds from a material akin to concrete. Nevertheless such deposits are sometimes the only witness of early Palaeolithic occupation. Our inventive authors put aside the hammers, acids and explosives of earlier days, and used quarry techniques to cut the breccia into small blocks, which they then freed from their finds in the laboratory, using tools developed in palaeontology. As a result, they gathered a huge harvest of stone tools, bones and shells. It all goes to show that archaeological excavation is an exercise of infinite variety: to every problem, its solution; to every terrain, its method

In situ Raman characterization of minerals and degradation processes in a variety of cultural and geological heritage sites

Wetest the capabilities of in situ Raman spectroscopy for non-destructive analysis of degradation processes in invaluable masterpieces, as well as for the characterization of minerals and prehistoric rock-art in caves. To this end, we have studied the mechanism of decay suffered by the 15th-century limestone sculptures that decorate the retro-choir of Burgos Cathedral (N Spain). In situ Raman probe detected hydrated sulfate and nitrateminerals on the sculptures, which are responsible for the decay of the original limestone. In addition, in situ Raman analyses were performed on unique speleothems in El Soplao Cave (Cantabria, N Spain) and in the Gruta de las Maravillas (Aracena, SWSpain). Unusual cavemineralswere detected in El Soplao Cave, such as hydromagnesite (Mg5(CO3)4(OH)2·4H2O), as well as ferromanganese oxides in the black biogenic speleothems recently discovered in this cavern. In the Gruta de las Maravillas, gypsum (CaSO4·2H2O) was identified for the first time, as part of the oldest cave materials, so providing additional evidence of hypogenic mechanisms that occurred in this cave during earlier stages of its formation. Finally, we present preliminary analyses of several cave paintings in the renowned “Polychrome Hall” of Altamira Cave (Cantabria, N. Spain). Hematite (Fe2O3) is the most abundant mineral phase, which provides the characteristic ochre-reddish color to the Altamira bison and deer paintings. Thus, portable Raman spectroscopy is demonstrated to be an analytical technique compatible with preserving our cultural and natural heritage, since the analysis does not require physical contact between the Raman head and the analyzed items

Progesterone significantly enhances the mobility of boar spermatozoa

Progesterone released from the cumulus cells of the oocyte causes a number of physiological responses in human sperm cells including hyperactivation, acrosome reaction and chemotaxis. We employed a validated sperm mobility assay, which involves measuring the ability of sperm to penetrate an inert cell separation solution over time, to assess the ability of progesterone to enhance the mobility of boar spermatozoa. Cells maximally penetrate the solution over 50 minutes. 100nM progesterone significantly (P = 0.01) increased the mobility of non-capacitated sperm cells causing a doubling in the rate at which the cells penetrated through the cell separation solution (control half maximal penetration rate [Km] = 18.0±2.2; +100nM progesterone Km = 8.8±0.8min). Similarly, capacitated cells penetrated at a rate (Km = 19.2±3.0 min) not significantly different from non-capacitated cells and 100nM progesterone also significantly increased the rate of penetration of capacitated cells (Km = 9.5±1.0 min, P<0.05). The T-type voltage gated calcium channel blocker mibefradil (30mM) significantly inhibited both the control and progesterone enhanced mobility in non-capacitated and capacitated sperm. Only capacitated cells showed a significant increase in the acrosome reaction in response to 100nM progesterone (control non-reacted = 75±4%, +100nM progesterone non-reacted = 47±10%). Western blot analysis confirmed that there was an increase in the total protein tyrosine phosphorylation levels in capacitated cells. In conclusion, we have demonstrated that 100nM progesterone accelerates the mobility of boar sperm cells through an inert cell separation solution in an extracellular calcium dependent manner

Speleogenesi e speleotemi di opale della Cueva Guacamaya, Auyan Tepui, Gran Sabana, Venezuela

La Cueva Guacamaya, esplorata nel marzo 2009 dall’elicotterista Raul Arias, è la più vasta cavità a sviluppo orizzontale conosciuta nel massiccio quarzitico dell’Auyan Tepui, nella Gran Sabana Venezuelana. A differenza delle altre cavità esplorate nell’area in precedenti esplorazioni dell’Associazione La Venta, questa grotta presenta morfologie peculiari, sviluppandosi lungo un sottile interstrato di ossidi e argille che interrompe la serie quarzitica della Formazione Mataui. La presenza di speleotemi di opale, di svariate forme e dimensioni notevoli, unite alla presenza di infiorescenze di gesso, per la prima volta segnalate in ambiente quarzitico in tale abbondanza, fanno di questa cavità un’interessante oggetto di studio sia per gli aspetti mineralogici, sia per un futuro progetto di datazione e geochimica degli speleotemi di opale.In March 2009 the Guacamaya cave was discovered on the Auyan Tepui by the helicopter pilot Raul Arias. It represents one of the longest caves explored on this table mountain, the only one known today with a complete horizontal development, comparable with those of the Brewer Cave System, in the Chimantha Tepui (the world largest sandstone cave). This cave presents typical morphologies, developed along an evident interbed of oxides, amorphous silica and clay interposed between hard quartzitic massive banks. In the walls around this layer, a variety of opal speleothems, of unusual dimensions and shapes, together with gypsum flowers and crusts have been documented. This preliminary study focuses on the general morphology of the cave conduits and on the mineralogical compositions and features of the opal-gypsum speleothems