Reduced antioxidant enzyme activity in brains of mice transgenic for human presenilin-1 with single or multiple mutations

Alzheimer's disease-related mutations in the presenilin-1 gene (PS1) are leading to an elevated production of neurotoxic beta-amyloid 1-42 and may additionally enhance oxidative stress. Here, we provide in vivo evidence indicating that brains of transgenic mice expressing different human Alzheimer-linked PS1 mutations exhibit a reduced activity of two antioxidant enzymes. For this purpose, mice transgenic for human PS1 and for single and multiple PS1 mutations were generated. Mice with multiple PS1 mutations showed a significantly decreased activity of the antioxidant enzymes Cu/Zn superoxide dismutase and glutathione reductase already at an age of 3-4 months. As expected, this effect was less pronounced for the mice with a single PS1 mutation. By contrast, animals bearing normal human PS1 showed significantly elevated enzyme activities relative to non-transgenic littermate controls

Studies on the role of parainfluenzavirus type 3 and adenovirus in respiratory disease of sheep

Investigations were undertaken to isolate viruses from sheep, and to assess their role in respiratory diseases by means of epidemiological observations and experimental studies of their pathogenesis.Viruses were isolated from 0*7 per cent, of samples taken at necropsies and from 16 per cent, of sheep in 3 of 4 flocks currently experiencing outbreaks of respiratory disease, but not from 7 flocks with few or no signs of clinical illness.An adenovirus (strain 7769) was isolated from rectal swabs, but not nasal swabs, from 3 of 15 lambs during an outbreak of pneumonia in a group of 4 to 10-week-old lambs. This adenovirus differed antigenically from other ovine, bovine and human adenoviruses, and the species of erythro¬ cytes that were agglutinated by strain 7769 differed from those agglutinated by porcine, canine, equine and murine adenoviruses. It was concluded that strain 7769 was a previously unreported type of adenovirus and was designated ovine adenovirus type 4 (0A4).Although antibodies to the adenovirus group specific antigen were detected in only 6 per cent, of 661 sheep sera, neutralizing antibodies to 4 serotypes of ovine adenovirus were more common. Neutralizing antibodies to ovine adeno¬ virus types 1-4 were more prevalent in animals over 12 months of age.Following exposure of specific pathogen-free (SPF) - 2 - lambs to an aerosol of 0A4 virus, replication of this virus occurred in the respiratory and alimentary tracts and liver, and neutralizing antibodies could be detected in the serum and nasal secretions as early as 8 days after inoculation. Infection was associated with a mild clinical illness, detectable by auscultation only, and accompanied by lesions in the lungs and liver. The lesions found in the lungs of infected lambs were pulmonary oedema and peribronchiolar accumulations of mononuclear cells and in the livers were focal necrosis, lymphangitis and occlusive cholangitis.The clinical disease and pneumonic lesions observed in SPF lambs infected with both ovine adenovirus type 4 and Pasteurella haemolytica were no more severe than those in lambs infected with P.haemolytica alone.Enzootic pneumonia was induced consistently in SPF lambs inoculated with parainfluenza virus type 3 (PI3) followed by P.haemolytica 4 or 7 days later. Seventyeight per cent, of lambs developed severe respiratory disease by this method, 54 per cent, died and 95 per cent, had macroscopic lung lesions. The illness and lesions were more marked in lambs inoculated with both PI3 virus and P.haemolytica than in lambs inoculated with either agent alone and were associated with rapid multiplication of P.haemolytica within the lung

Hemorheological abnormalities in human arterial hypertension

Blood rheology is impaired in hypertensive patients. The alteration involves blood and plasma viscosity, and the erythrocyte behaviour is often abnormal. The hemorheological pattern appears to be related to some pathophysiological mechanisms of hypertension and to organ damage, in particular left ventricular hypertrophy and myocardial ischemia. Abnormalities have been observed in erythrocyte membrane fluidity, explored by fluorescence spectroscopy and electron spin resonance. This may be relevant for red cell flow in microvessels and oxygen delivery to tissues. Although blood viscosity is not a direct target of antihypertensive therapy, the rheological properties of blood play a role in the pathophysiology of arterial hypertension and its vascular complications

Presenilin-1 mutations associated with familial Alzheimer’s disease do not disrupt protein transport from the endoplasmic reticulum to the Golgi apparatus

AbstractMutations in genes encoding presenilin-1 (PS1) and presenilin-2 (PS2) have been linked to familial forms of Alzheimer’s disease (AD). Cells expressing mutant presenilins produce elevated levels of Aβ42, the major amyloid peptide found in AD plaques. The mechanism whereby this occurs remains unknown, but the localization of presenilins to endoplasmic reticulum (ER) and Golgi compartments has suggested that they may function in intracellular trafficking pathways involved in processing β-amyloid precursor proteins (APP). To test this possibility, we coexpressed PS1(wt), PS1(M146L), or PS1(L286V) in HEK293 cells together with the LDL receptor, a classic glycoprotein marker that undergoes post-translational O-glycosylation in the Golgi compartment. Pulse-chase analysis of the receptor indicated that mutant presenilins had no effect on ER→Golgi transport. Similar results were obtained when the studies were carried out with cells expressing the Swedish variant of APP (SWAPP751) instead of the LDL receptor. Moreover, secretion of the soluble exodomain polypeptide fragments of SWAPP751 that arise from α-secretase and β-secretase cleavage was not markedly affected by the PS1 mutants. Despite the lack of discernible effect of the PS1 mutants on trafficking of proteins through the Golgi apparatus, they caused a substantial increase in the proportion of Aβ42 relative to total Aβ in the culture medium. The results suggest that mutant forms of PS1 cause elevated production of Aβ42 by a mechanism that is independent of a major disruption of exocytic trafficking of APP