The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer disease

Investigators studying the primary culprit responsible for Alzheimer disease have, for the past two decades, primarily focused on amyloid-beta (Abeta). Here, we put Abeta on trial and review evidence amassed by the prosecution that implicate Abeta and also consider arguments and evidence gathered by the defense team who are convinced of the innocence of their client. As in all trials, the arguments provided by the prosecution and defense revolve around the same evidence, with opposing interpretations. Below, we present a brief synopsis of the trial for you, the jury, to decide the verdict. Amyloid-beta: guilty or not-guilty?     

LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival

Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects young adults. Available therapies can inhibit the inflammatory component of MS but do not suppress progressive clinical disability. An alternative approach would be to inhibit mechanisms that drive the neuropathology of MS, which often includes the death of oligodendrocytes, the cells responsible for myelinating the CNS. Identification of molecular mechanisms that mediate the stress response of oligodendrocytes to optimize their survival would serve this need. This study shows that the neurotrophic cytokine leukemia inhibitory factor (LIF) directly prevents oligodendrocyte death in animal models of MS. We also demonstrate that this therapeutic effect complements endogenous LIF receptor signaling, which already serves to limit oligodendrocyte loss during immune attack. Our results provide a novel approach for the treatment of MS.     

Differential sorting and fate of endocytosed GPI-anchored proteins

In this paper, we studied the fate of endocytosed glycosylphosphatidyl inositol anchored proteins (GPI- APs) in mammalian cells, using aerolysin, a bacterial toxin that binds to the GPI anchor, as a probe. We find that GPI-APs are transported down the endocytic pathway to reducing late endosomes in BHK cells, using biochemical, morphological and functional approaches. We also find that this transport correlates with the association to raft-like membranes and thus that lipid rafts are present in late endosomes (in addition to the Golgi and the plasma membrane). In marked contrast, endocytosed GPI-APs reach the recycling endosome in CHO cells and this transport correlates with a decreased raft association. GPI-APs are, however, diverted from the recycling endosome and routed to late endosomes in CHO cells, when their raft association is increased by clustering seven or less GPI-APs with an aerolysin mutant. We conclude that the different endocytic routes followed by GPI-APs in different cell types depend on the residence time of GPI-APs in lipid rafts, and hence that raft partitioning regulates GPI-APs sorting in the endocytic pathway.     

Cross-site differences in foraging behavior of white-faced capuchins (Cebus capucinus)

Researchers have identified a variety of cross-site differences in the foraging behavior of free-ranging great apes, most notably among chimpanzees (Pan troglodytes) and more recently orangutans (Pongo pygmaeus), that are not due to obvious genetic or ecological differences. These differences are often referred to as "traditions." What is not known is whether this high level of interpopulation variation in behavior is limited to hominoids. In this study, we use long-term data from three Costa Rican field sites that are geographically close and similar ecologically to identify potential foraging traditions in white-faced capuchins (Cebus capucinus). Foraging traditions are predicted in Cebus because of many behavioral and morphological convergences between this genus and the great apes. The processing techniques used for the same food species were compared across sites, and all differences found were classified as present, habitual, or customary. Proximity data were also analyzed to determine if social learning mechanisms could explain variation in foraging behavior. Of the 61 foods compared, we found that 20 of them are processed differently by capuchins across sites. The differences involve pound, rub, tap, "fulcrum," "leaf-wrap," and "army ant following." For most of the differences with enough data to analyze, the average proximity score of the "matched" dyads (two individuals within a group who shared a "different" processing technique) was statistically higher than the average proximity score of the remaining "unmatched" dyads.     

Differential regulation of glutamate receptors in Alzheimer's disease

Selective neurodegeneration is a prominent feature in Alzheimer's disease; however, the mechanism of neuronal death is still unclear. Nonetheless, the topographical distribution of different types of receptors is thought to contribute to the regional selective nature of neuronal degeneration. Specifically, since glutamatergic transmission is severely altered by the early degeneration of cortico-cortical connections and hippocampal projections in Alzheimer's disease, we suspect that glutamate receptors may play a new role in the pathophysiology of disease. Here we review the salient aspects of glutamate receptor expression in Alzheimer's disease and how their differential regulation can contribute to the selective neurodegeneration seen in the disease. Additionally, we assess the potential therapeutic value of glutamate receptors as a target for drug intervention in Alzheimer's disease.     

A proteomic approach for identification of secreted proteins during the differentiation of 3T3-L1 preadipocytes to adipocytes

We have undertaken a systematic proteomic approach to purify and identify secreted factors that are differentially expressed in preadipocytes versus adipocytes. Using one-dimensional gel electrophoresis combined with nanoelectrospray tandem mass spectrometry, proteins that were specifically secreted by 3T3-L1 preadipocytes or adipocytes were identified. In addition to a number of previously reported molecules that are up- or down-regulated during this differentiation process (adipsin, adipocyte complement-related protein 30 kDa, complement C3, and fibronectin), we identified four secreted molecules that have not been shown previously to be expressed differentially during the process of adipogenesis. Pigment epithelium-derived factor, a soluble molecule with potent antiangiogenic properties, was found to be highly secreted by preadipocytes but not adipocytes. Conversely, we found hippocampal cholinergic neurostimulating peptide, neutrophil gelatinase-associated lipocalin, and haptoglobin to be expressed highly by mature adipocytes. We also used liquid chromatography-based separation followed by automated tandem mass spectrometry to identify proteins secreted by mature adipocytes. Several additional secreted proteins including resistin, secreted acidic cysteine-rich glycoprotein/osteonectin, stromal cell-derived factor-1, cystatin C, gelsolin, and matrix metalloprotease-2 were identified by this method. To our knowledge, this is the first study to identify several novel secreted proteins by adipocytes by a proteomic approach using mass spectrometry.     

Modeling possible cooling-water intake system impacts on Ohio River fish populations

To assess the possible impacts caused by cooling-water intake system entrainment and impingement losses, populations of six target fish species near power plants on the Ohio River were modeled. A Leslie matrix model was constructed to allow an evaluation of bluegill, freshwater drum, emerald shiner, gizzard shad, sauger, and white bass populations within five river pools. Site-specific information on fish abundance and length-frequency distribution was obtained from long-term Ohio River Ecological Research Program and Ohio River Sanitation Commission (ORSANCO) electrofishing monitoring programs. Entrainment and impingement data were obtained from 316(b) demonstrations previously completed at eight Ohio River power plants. The model was first run under a scenario representative of current conditions, which included fish losses due to entrainment and impingement. The model was then rerun with these losses added back into the populations, representative of what would happen if all entrainment and impingement losses were eliminated. The model was run to represent a 50-year time period, which is a typical life span for an Ohio River coal-fired power plant. Percent changes between populations modeled with and without entrainment and impingement losses in each pool were compared to the mean interannual coefficient of variation (CV), a measure of normal fish population variability. In 6 of the 22 scenarios of fish species and river pools that were evaluated (6 species x 5 river pools, minus 8 species/river pool combinations that could not be evaluated due to insufficient fish data), the projected fish population change was greater than the expected variability of the existing fish population, indicating a possible adverse environmental impact. Given the number of other variables affecting fish populations and the conservative modeling approach, which assumed 100% mortality for all entrained fish and eggs, it was concluded that the likelihood of impact was by no means assured, even in these six cases. It was concluded that in most cases, current entrainment and impingement losses at six Ohio River power plants have little or no effect at the population level.     

Habitat partitioning in a community of darters in the Elk River, West Virginia

Microhabitat use and habitat partitioning for 10 darter species (Percidae: Etheostomatini) were studied by direct observation (snorkeling) at five sites in the Elk River drainage, West Virginia, U.S.A. We used canonical discriminant analysis and univariate tests to determine microhabitat variables that were important in segregating species. Darter species were segregated by depth, substrate size, and water velocity. In addition, Percina typically occurred in the water column, whereas species of Etheostoma were benthic and segregated by occurring under, between, and on top of rocks.