Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report

Amyloid-beta peptide (Abeta) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Abeta in a transgenic mouse model of AD reduces both age-related accumulation of Abeta in the brain and associated cognitive impairment. Here we present the first analysis of human neuropathology after immunization with Abeta (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Abeta plaques; (ii) those areas of cortex that were devoid of Abeta plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Abeta-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Abeta immunotherapy in mouse models of AD and suggest that the immune response generated against the peptide elicited clearance of Abeta plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9).     

Identification of anti-repressor elements that confer high and stable protein production in mammalian cells

The expression of transgenic proteins is often low and unstable over time, a problem that may be due to integration of the transgene in repressed chromatin. We developed a screening technology to identify genetic elements that efficiently counteract chromatin-associated repression. When these elements were used to flank a transgene, we observed a substantial increase in the number of mammalian cell colonies that expressed the transgenic protein. Expression of the shielded transgene was, in a copy number-dependent fashion, substantially higher than the expression of unprotected transgenes. Also, protein production remained stable over an extended time period. The DNA elements are small, not exceeding 2,100 base pairs (bp), and they are highly conserved between human and mouse, at both the functional and sequence levels. Our results demonstrate the existence of a class of genetic elements that can readily be applied to more efficient transgenic protein production in mammalian cells.     

Enhancement of antidepressant potency by a potentiator of AMPA receptors

1. AMPA receptor potentiators (ARPs) exhibit antidepressant-like activity in preclinical tests (for example, the forced swim test) that are highly predictive of efficacy in humans. Unlike most currently used antidepressants, ARPs do not elevate extracellular levels of biogenic amines (e.g., 5HT, NE) in prefrontal cortex at doses that are active in the forced swim test.2. The present series of experiments examined the effects of combining the ARP, LY 392098, with biogenic amine-based antidepressants in the forced swim test. Male, NIH Swiss mice were placed in a cylinder of water and observed for attempted escape behaviors and immobility.3. LY 392098 dose-dependently decreased immobility as did a range of classical antidepressants. At doses of LY 392098 below those that decreased immobility, this compound significantly increased the potency with which fluoxetine and citalopram (SSRI antidepressants), imipramine (tricyclic antidepressant), duoxetine (norepinephrine/serotonin uptake blocker), nisoxetine (norepinephrine uptake inhibitor), and rolipram (PDE4 inhibitor) decreased immobility in the forced swim test with potency shifts upward of 5-fold (fluoxetine, imipramine, and rolipram). Likewise, ineffective doses of the traditional antidepressants potentiated the effects LY 392098 with shifts in the dose-effect functions that were 10-fold or more for citalopram, fluoxetine, imipramine, and duloxetine.4. Combined with other evidence for a role of AMPA receptors in the efficacy of antidepressants, the current data suggest that the addition of an ARP may augment the activity and perhaps the onset of the therapeutic effects of biogenic amine and second messenger-based antidepressants.     

Density and population structure of owl monkeys (Aotus azarai) in the Argentinean Chaco

Owl monkeys are small monogamous primates ranging over a wide area extending from Panama to the Chaco region of northern Argentina. The Chaco, an alluvial plain covering over one million km2 of Argentina, Bolivia, Brazil, and Paraguay, consists of a mosaic of grasslands, savannas, xeric thorn forests, and gallery forests. The region shows significant seasonal variation in climate, rainfall, and food availability. The goal of this study was to determine the density, size, and structure of a population of Aotus azarai in the seasonal gallery forests of the eastern Argentinean Chaco. Reported population density, as well as group size and composition are based on data collected from 11 groups contacted on approximately 900 occasions, and observed for over 2,000 hours during a three-year period. Group and individual densities were 16 groups/km2 and 64 individuals/km2, respectively. Approximately half of the groups (n = 5) were small groups which had three individuals most of the time and never more than four, whereas the remaining groups were large groups composed of four or five individuals, and sometimes even six or seven individuals. This is the first study of A. azarai based on monitoring of a relatively large number of distinct groups. Our data suggest that owl monkeys in the seasonal subtropical forests of Formosa live at a density as high as those reported for owl monkey populations observed in tropical forests. The data also show that the social groups in the owl monkey population are of comparable size and composition to those characteristic of populations in the tropics.     

Application of conformationally restricted peptidomimetics to modeling the bound conformation of peptide antagonists with the IL-1 receptor

A collection of complementary peptide caricatures that closely mimic low-energy (presumably highly populated) conformations of amino acids of interest would constitute a valuable tool set to study the interactions of small peptide ligands with their biological targets. Our general strategy for the design, synthesis and application of peptidomimetics is presented. An illustration of how structural information from mimetics combined with cutting edge biophysical data can be used to derive a model for the bound conformation of an 11-mer peptide antagonist with the IL-1 receptor is given.     

Rescue of an MMTV transgene by co-integration reveals novel locus control properties of the ovine β-lactoglobulin gene that confer locus commitment to heterogeneous tissues

In an attempt to enhance the frequency and level of expression of a poor-performing MMTV-driven transgene, we co-integrated this construct with the ovine -lactoglobulin (BLG) gene in transgenic mice. Seven lines of transgenic mice possessing co-integrated BLG and MMTV-RZ5 transgenes were compared with 12 lines of mice that possessed only the MMTV-RZ5 construct. Co-integration enhanced the frequency of expression in the mammary gland from two out of 12 lines for the MMTV-RZ5 transgene alone, to five out of seven when co-integrated with BLG. Surprisingly, co-integration also resulted in co-expression of the two transgenes in the salivary gland, lung and spleen in addition to the mammary gland. Furthermore, both transgenes were expressed in virgin animals, and throughout pregnancy and lactation, suggesting that the developmental regulation of the locus follows that of the MMTV-promoter. These findings represent a novel locus control property of the ovine BLG gene that confer s commitment of the locus to the mammary gland, but also to a range of heterogeneous tissues possibly defined by the second promoter at the locus     

Marine bacterioplankton can increase evaporation and gas transfer by metabolizing insoluble surfactants from the air–seawater interface

Hydrophobic surfactants at the air–sea interface can retard evaporative and gaseous exchange between the atmosphere and the ocean. While numerous studies have examined the metabolic role of bacterioneuston at the air–sea interface, the interactions between hydrophobic surfactants and bacterioplankton are not well constrained. A novel experimental design was developed, using Vibrio natriegens and ³H-labelled hexadecanoic acid tracer, to determine how the bacterial metabolism of fatty acids affects evaporative fluxes. In abiotic systems, >92% of the added hexadecanoic acid remained at the air–water interface. In contrast, the presence of V. natriegens cells draws down insoluble hexadecanoic acid from the air–water interface as an exponential function of time. The exponents characterizing the removal of hexadecanoic acid from the interface co-vary with the concentration of V. natriegens cells in the underlying water, with the largest exponent corresponding to the highest cell abundance. Radiochemical budgets show that evaporative fluxes from the system are linearly proportional to the quantity of hexadecanoic acid at the interface. Thus, bacterioplankton could influence the rate of evaporation and gas transfer in the ocean through the metabolism of otherwise insoluble surfactants.     

Proteomic changes in the brain of the western painted turtle (Chrysemys picta bellii) during exposure to anoxia

During anoxia, overall protein synthesis is almost undetectable in the brain of the western painted turtle. The aim of this investigation was to address the question of whether there are alterations to specific proteins by comparing the normoxic and anoxic brain proteomes. Reductions in creatine kinase, hexokinase, glyceraldehyde‐3‐phosphate dehydrogenase, and pyruvate kinase reflected the reduced production of adenosine triphosphate (ATP) during anoxia while the reduction in transitional endoplasmic reticulum ATPase reflected the conservation of ATP or possibly a decrease in intracellular Ca²⁺. In terms of neural protection programed cell death 6 interacting protein (PDCD6IP; a protein associated with apoptosis), dihydropyrimidinase‐like protein, t‐complex protein, and guanine nucleotide protein G_(o) subunit alpha (G_o alpha; proteins associated with neural degradation and impaired cognitive function) also declined. A decline in actin, gelsolin, and PDCD6IP, together with an increase in tubulin, also provided evidence for the induction of a neurological repair response. Although these proteomic alterations show some similarities with the crucian carp (another anoxia‐tolerant species), there are species‐specific responses, which supports the theory of no single strategy for anoxia tolerance. These findings also suggest the anoxic turtle brain could be an etiological model for investigating mammalian hypoxic damage and clinical neurological disorders.