Mutations in the gene encoding the amyloid protein precursor (APP) cause autosomal dominant Alzheimer's disease. Cleavage of APP by unidentified proteases, referred to as beta- and gamma-secretases, generates the amyloid beta-peptide, the main component of the amyloid plaques found in Alzheimer's disease patients. The disease-causing mutations flank the protease cleavage sites in APP and facilitate its cleavage. Here we identify a new membrane-bound aspartyl protease (Asp2) with beta-secretase activity. The Asp2 gene is expressed widely in brain and other tissues. Decreasing the expression of Asp2 in cells reduces amyloid beta-peptide production and blocks the accumulation of the carboxy-terminal APP fragment that is created by beta-secretase cleavage. Solubilized Asp2 protein cleaves a synthetic APP peptide substrate at the beta-secretase site, and the rate of cleavage is increased tenfold by a mutation associated with early-onset Alzheimer's disease in Sweden. Thus, Asp2 is a new protein target for drugs that are designed to block the production of amyloid beta-peptide peptide and the consequent formation of amyloid plaque in Alzheimer's disease.
Minoxidil, a potent vasodilator, stimulates the growth of terminal hair from vellus or miniaturized follicles in balding scalp. To study minoxidil's action on isolated follicles we developed and validated an organ culture system using mouse whisker follicles. Control follicles cultured without minoxidil showed macroscopic changes including kinking of the hair shafts and bending of the follicles. Necrosis was evident in the differentiating epithelial elements forming the cuticle, cortex, and inner root sheath. These abnormalities were eliminated or greatly reduced in minoxidil-treated follicles. The morphology of these follicles was consistent with the production of new hair during culture. Direct measurement demonstrated that minoxidil-treated follicles grew significantly longer than control follicles during the 3-d culture. Minoxidil increased the incorporation of radiolabeled cysteine and glycine in follicles compared with control treatment. Doses of minoxidil up to 1 mM caused increased cysteine incorporation, while higher doses were inhibitory. Experiments with labeled thymidine indicated that minoxidil induced proliferation of hair epithelial cells near the base of the follicle. Autoradiography also showed that cysteine accumulated in the keratogenous zone above the dermal papilla. These studies demonstrate that organ cultured follicles are suitable for determining minoxidil's mechanism of action and may be useful for studying other aspects of hair biology. The results also show that minoxidil's effect on hair follicles is direct. This suggests that minoxidil's action in vivo includes more than just increasing blood flow to hair follicles.
Male rhesus monkey fetuses have significantly more testosterone (T) in their circulation than females on days 35--50 of gestation (P less than 0.01; n = 6 males and 6 females). However, we found no sex differences for androstenedione (delta 4). T concentrations remained significantly higher in male fetuses than in females later in gestation, e.g. days 79--84, 100--133, and 140--160. Levels of delta 4 differed between the sexes only on days 79--84, and dihydrotestosterone concentrations were significantly higher in male fetuses than in females on days 100--133 and 140--163. The fact that delta 4 concentrations were not different between the sexes at the earliest period studied (days 35--50) indicates that systemic concentrations of this hormone in the fetus probably are not important for sexual differentiation, especially of the central nervous system. Quantification of three steroids (T, delta 4, and dihydrotestosterone) in umbilical arterial and venous plasma from five male and nine female fetuses (days 35--100) revealed significant arterial/venous differences only for T in males (arterial greater than venous). These data, which suggest that fetal testes secrete T during morphological differentiation, lend credence to the hypothesis that endogenous T partially regulates sexual differentiation.
Mutations in the human presenilin genes (PS1 or PS2) have been linked to autosomal dominant, early onset Alzheimer's disease (AD). Presenilins, probably as an essential part of gamma-secretase, modulate gamma-cleavage of the amyloid protein precursor (APP) to the amyloid b-peptide (Ab). Mutations in sel-12, a Caenorhabditis elegans presenilin homologue, cause a defect in egg laying that can be suppressed by loss of function mutations in a second gene, SEL-10. SEL-10 protein is a homologue of yeast Cdc4, a member of the SCF (Skp1-Cdc53/CUL1-F-box protein) E2-E3 ubiquitin ligase family. In this study, we show that human SEL-10 interacts with PS1 and enhances PS1 ubiquitination, thus altering cellular levels of unprocessed PS1 and its N-and C-terminal fragments. Co-transfection of sel-10 and APP cDNAs in HEK293 cells leads to an alteration in the metabolism of APP and to an increase in the production of amyloid b-peptide, the principal component of amyloid plaque in Alzheimer's disease.
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.