The presenilin 1 (PS1) gene has been identified by positional cloning. More than 30 mutations were detected in this gene which cosegregate with Alzheimer's disease (AD). Understanding their role in disease pathogenesis requires a characterization of the PS1 protein. We have generated a set of antibodies against the three major hydrophilic domains of the deduced amino acid sequence. Analyzing cultured cells and brain samples, we identified the endogenous PS1 polypeptide as well as amino- and carboxy-terminal fragments. These metabolites were much more abundant than the full-length molecule, indicating substantial processing. Overexpression of human PS1 markedly increased the full-length polypeptide but hardly altered the amount of the metabolites. Instead, additional proteolytic fragments appeared suggesting a different metabolism of the excess PS1, which may impede studies in transfected cells. Our results indicate a tight regulation of the endogenous PS1 metabolites. PS1 and its fragments are shown to be integral membrane proteins of the endoplasmic reticulum. The mechanisms regulating the generation of the metabolites, their potential function, and role in AD remain to be studied.

Blotting, Western↗

PubMedDate not supplied

Delay in diastolic restitution of full myocardial contractility in guinea pig atrium.

In an isolated perfused left atrium of guinea pig, pressure amplitudes were recorded at 37 degrees C and a stimulation rate of 240/min with interposed variable resting pauses. After prolonged intervals the preparation develops maximum pressure, which does not depend on perfusion time or on any positive inotropic intervention. The latter is found to shorten the time needed for restitution of full contractility. Nifedipine (5 X 10(-7)M) exerts its negative inotropic effect mainly by a delay in restitution time; acetylcholine (2 X 10(-7)M), by a concomitant reduction of all pressure amplitudes over the whole range of stimulus intervals. The latter effect is similar to that of lowering [Ca2+]o.

Acetylcholine↗

PubMedDate not supplied

Quantitative studies of protein uptake in microperfused renal proximal tubules.

Proximal convoluted tubules were microperfused with an iodine 125 egg-white-lysozyme containing perfusion solution. The intraluminal lysozyme concentration decreased about 10% per mm tubular length over a wide range of intraluminal lysozyme concentrations tested indicating a constant fractional reabsorption over a wide concentration range. Lysozyme reabsorption at a high intraluminal lysozyme concentration of 10 mg/ml indicated that the tubular protein uptake by endocytosis is a saturable process. High intraluminal concentrations of basic amino acids inhibited the cellular uptake of lysozyme, while neutral amino acids had no effect.

Animals↗