Michail A. Esterman

Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides

We have previously shown that apolipoprotein E (Apoe) promotes the formation of amyloid in brain and that astrocyte-specific expression of APOE markedly affects the deposition of amyloid-β peptides (Aβ) in a mouse model of Alzheimer disease. Given the capacity of astrocytes to degrade Aβ, we investigated the potential role of Apoe in this astrocyte-mediated degradation. In contrast to cultured adult wild-type mouse astrocytes, adult Apoe−/− astrocytes do not degrade Aβ present in Aβ plaque–bearing brain sections in vitro. Coincubation with antibodies to either Apoe or Aβ, or with RAP, an antagonist of the low-density lipoprotein receptor family, effectively blocks Aβ degradation by astrocytes. Phase-contrast and confocal microscopy show that Apoe−/− astrocytes do not respond to or internalize Aβ deposits to the same extent as do wild-type astrocytes. Thus, Apoe seems to be important in the degradation and clearance of deposited Aβ species by astrocytes, a process that may be impaired in Alzheimer disease.

Fenoprofen: Inhibitor of prostaglandin synthesis

Abstract Fenoprofen, an anti-inflammatory agent, is a potent inhibitor of prostaglandin synthesis at physiological substrate concentration. I 50 s of 1 μM to 100 μM were obtained when the concentration of arachidonate was increased from 1 μM to 82 μM. In contrast, a small change in I 50 was observed with indomethacin. Kinetic studies indicated that inhibition by fenoprofen was competitive while that of indomethacin was non-competitive.

Statistical aspects of quantitative image analysis of β-amyloid in the APPV717F transgenic mouse model of Alzheimer's disease

Cerebral beta-amyloidosis is a central part of the neuropathology of Alzheimers disease (AD). Quantitation of beta-amyloid plaques in the human AD brain, and in animal models of AD, is an important study endpoint in AD research. Methodologic approaches to the measurement of beta-amyloid in the brain vary between investigators, and these differences affect outcome measures. Here, one quantitative approach to the measurement of beta-amyloid plaques in brain sections was analyzed for sources of variability due to sampling. Brain tissue was from homozygous APP(V717F) transgenic male mice. Sampling variables were at the mouse and microscopic slide and field levels. Results indicated that phenotypic variability in the mouse sample population was the largest contributor to the standard error of the analyses. Within each mouse, variability between slides or between fields within slides had smaller effects on the error of the analyses. Therefore, when designing studies of adequate power, in this and in other similar models of cerebral beta-amyloidosis, sufficient numbers of mice per group must be included in order for change in mean plaque burden attributable to an experimental variable to outweigh phenotypic variability.

Tibenelast, 5,6-diethoxybenzo (B) thiophebe-2-carboxylic acid, sodium salt (LY 186655), is an orally active anti-asthma compound in the guinea pig

Anaphylactic shock was induced in actively sensitized guinea pigs by free inhalation of a high dose of ovalbumin (10 mg/ml) aerosol. Tibenelast (LY186655), 5,6-diethoxybenzo(b)-thiophene-2-carboxylic acid, sodium salt, proved to be a potent orally active compound against anaphylactic shock induced by high dose antigen aerosol. When a lower aerosol challenge (0.05 mg/ml) was employed, bronchoconstriction was observed with a concomitant increase in lung resistance (RL) and a fall in dynamic compliance (Cdyn). Tibenelast at 25 mg/kg p.o. prevented these changes. Tibenelast was 10 times more potent than aminophylline by i.v. administration; normalization of pulmonary function was achieved at 1 mg/kg i.v. Tibenelast was synergistic with epinephrine. Combination of no-effect doses of epinephrine (0.025 mg/kg s.c.) and tibenelast (0.1 mg/kg i.v.) normalized pulmonary function. The oral dose response curve of tibenelast was enhanced with the co-administration of epinephrine. These data suggest that tibenelast may act at a site different from that of epinephrine, although the mechanism of action of tibenelast is unclear at present. Tibenelast may be of significant value in the treatment of asthma and other respiratory diseases.

Culture of L1210 cells stored at −190 °C

Abstract Cultured L1210 lymphocytic leukemia cells that were frozen and stored in liquid nitrogen up to 1 year were recultured directly without an intermediate passage in mice. There was no significant change in the population doubling time of 16 hr, and the cells retained their ability to induce leukemia in DBA/2 mice.