BACKGROUND AND PURPOSE
γ‐Secretase modulators represent a promising therapeutic approach for Alzheimer's disease (AD) because they selectively decrease amyloid β 42 (Aβ42), a particularly neurotoxic Aβ species that accumulates in plaques in the brains of patients with AD. In the present study, we describe the in vitro and in vivo pharmacological properties of a potent novel γ‐secretase modulator, 2‐(S)‐(3,5‐bis(4‐(trifluoromethyl)phenyl)phenyl)‐4‐methylpentanoic acid (JNJ‐40418677).
EXPERIMENTAL APPROACH
The potency and selectivity of JNJ‐40418677 for Aβ reduction was investigated in human neuroblastoma cells, rat primary neurones and after treatment with single oral doses in non‐transgenic mouse brains. To evaluate the effect of JNJ‐40418677 on plaque formation, Tg2576 mice were treated from 6 until 13 months of age via the diet.
KEY RESULTS
JNJ‐40418677 selectively reduced Aβ42 secretion in human neuroblastoma cells and rat primary neurones, but it did not inhibit Notch processing or formation of other amyloid precursor protein cleavage products. Oral treatment of non‐transgenic mice with JNJ‐40418677 resulted in an excellent brain penetration of the compound and a dose‐ and time‐dependent decrease of brain Aβ42 levels. Chronic treatment of Tg2576 mice with JNJ‐40418677 reduced brain Aβ levels, the area occupied by plaques and plaque number in a dose‐dependent manner compared with transgenic vehicle‐treated mice.
CONCLUSIONS AND IMPLICATIONS
JNJ‐40418677 selectively decreased Aβ42 production, showed an excellent brain penetration after oral administration in mice and lowered brain Aβ burden in Tg2576 mice after chronic treatment. JNJ‐40418677 therefore warrants further investigation as a potentially effective disease‐modifying therapy for AD.
One-day-old specific-pathogen-free White Leghorn chicks were inoculated orally with Salmonella enteritidis phage type 4 to study adhesion and invasion of the ceca by immunohistochemistry. Positive staining bacilli were associated with the epithelial surface and were present in the lumen of the cecal crypts. They were observed in the interstitial tissue and in the cytoplasm of macrophage-like cells in the lamina propria. A granulomatous nodule containing positive staining bacilli was present in the submucosa of the cecum of one bird at 14 d after inoculation.
An indirect enzyme-linked immunosorbent assay (ELISA) based on the lipopolysaccharide (LPS) of Salmonella enteritidis phage type 4, was developed for the detection of antibodies to salmonella. Sera and yolks from chickens infected experimentally with S enteritidis showed strong positive reactions. Cross-reactions occurred with sera from chickens inoculated with S typhimurium or S gallinarum. Cross-reactions were weak with sera from chickens infected with five strains of other Enterobacteriaceae. The ELISA was tested with sera and yolks from commercial poultry flocks which were bacteriologically negative for salmonella or infected with salmonella serotypes belonging to serogroup D or to other serogroups. The serological reactions were strong in most flocks infected with S enteritidis and were weaker in flocks infected with S typhimurium. In some flocks infected with these serotypes no antibodies were detected. The correct setting of the cut-off value of the optical density in the ELISA makes it possible to discriminate between chickens which are infected with S enteritidis and chickens which are not infected with S enteritidis.
SUMMARYCases of Enterococcus hirae septicaemia are described in 10 different species of psittacine birds. In most of the cases other disease causes were not detected, and cytological examination confirmed the aetiological role of the bacteria isolated. Despite these findings, attempts to reproduce the disease in young budgerigars failed. The bacterium was isolated frequently from the faeces of healthy psittacine birds belonging to a wide range of species, and appeared to be member of the normal intestinal flora of these birds. The bacteriological diagnosis of E. hirae, and especially its differentiation from Enterococcus durons, is discussed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.