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J Neurosci Res 1997 Apr 15;48(2):168-180
Keane RW, Srinivasan A, Foster LM, Testa MP, Ord T, Nonner D, Wang HG, Reed JC, Bredesen DE, Kayalar C
Program on Aging, Burnham Institute, La Jolla, California, USA.
Members of the interleukin-1 beta-converting enzyme (ICE)/CED-3 protease family have been implicated in apoptosis in both vertebrates and invertebrates. Using primary culture methods, we report that neurons and astrocytes require the activity of the ICE/CED-3 family of proteases to undergo apoptosis induced by staurosporine, ceramide, and serum-free media. We show that specific inhibitors of ICE/CED-3 proteases can inhibit apoptosis and that cytosolic fractions from apoptosing neurons, but not healthy cells, induced apoptosis in a cell-free system. Cell extracts from neurons induced to undergo apoptosis contained ICE/ CED-3 protease activity. To determine which member of the ICE/CED-3 family was activated in neurons and astrocytes during apoptosis, we developed a novel affinity-labeling technique that labeled the active site cysteine and identified a 17-kDa subunit of the activated protease. The affinity-labeled 17-kDa protease subunit shares antigenic and molecular mass identity with the processed form of CPP32 on immunoblots, suggesting that CPP32 may be the principal effector in the apoptotic pathway in neurons and astrocytes. In time-course experiments, the activation of CPP32 preceded the detection of PARP cleavage and DNA laddering, suggesting that processing of CPP32 is a very early event in apoptosis of neurons and astrocytes and may be involved in the proteolytic action on specific cellular targets. The affinity-labeling technique developed and used in this report with neural cells allows for the sensitive detection, purification, and identification of ICE/CED-3 proteases that may be activated in other cells types under a variety of conditions, including certain diseased states.
Brain Res Mol Brain Res 1997 Jun;46(1-2):39-53
Igwe OJ, Filla MB
Division of Pharmacology, School of Pharmacy, University of Missouri at Kansas City, 64108, USA.
To determine the effects of the aging process on the regulation of phosphoinositide signal transduction pathway, inositol 1,4,5-trisphosphate and inositol 1,4,5-trisphosphate receptor-associated parameters were examined in the striatum of brains removed from young (3 months), adult (12 months) and senescent (25 months) male Fischer 344 rats. Inositol 1,4,5-trisphosphate content was significantly increased (P < or = 0.01) at 25 months of age compared to 3 and 12 months. No age-related differences in phosphatidylinositol 4,5-bisphosphate hydrolysis were found in striatal slices after stimulation with trans-(1S,3R)-1-aminocyclopentane-1,3-dicarboxylate, a metabotropic glutamatergic receptor agonist. Phosphatidylinositol 4,5-bisphosphate hydrolysis following stimulation with (R,S)-alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid, a glutamatergic/quisqualate agonist, showed a significantly increased accumulation of net [3H]inositol 1,4,5-trisphosphate in senescent striatum whereas the muscarinic cholinergic agonist carbachol induced highest response in the young striatum. In each case, agonist-stimulated response was significantly reduced in the presence of the receptor-associated antagonist. The density of inositol 1,4,5-trisphosphate receptor in the particulate membranes derived from 12- and 25-month-old rats was decreased (P < 0.01) compared to that from young rats. Binding affinity of inositol 1,4,5-trisphosphate receptor for [3H]inositol 1,4,5-trisphosphate was increased (P = 0.05) only at 25 months of age when compared with 3 months of age. Incubation of partially purified inositol 1,4,5-trisphosphate receptor with striatal cytosol in the presence of Ca2+ showed an age-dependent susceptibility to proteolytic degradation of this receptor that was completely inhibited by calpain I inhibitor peptide. Paradoxically, the quantity of inositol 1,4,5-trisphosphate receptor mRNA-encoding transcripts was increased (P < or = 0.01) at 25 months of age, suggesting an age-dependent change in either transcriptional rate, stability or processing of inositol 1,4,5-trisphosphate receptor mRNAs in the striatum. The activity of inositol 1,4,5-trisphosphate3-kinase decreased (P < or = 0.01) with age whereas the activity of soluble inositol 1,4,5-trisphosphate 5-phosphatase was highest at 3 months but significantly decreased at 12 months of age. However, the activity of inositol 1,4,5-trisphosphate 5-phosphatase remained unchanged between 12 and 25 months of age, suggesting possible developmental modulation of the activity of the enzyme. Taken together with the established 'cross-talk' between signal transduction systems, the present data suggest that molecular/cellular changes in striatal inositol 1,4,5-trisphosphate/Ca2+ signal transduction pathway along with neuronal cell loss may contribute to aging-related decrease in striatal functioning.
FASEB J 1997 Apr;11(5):322-330
Gilchrest BA, Bohr VA
Department of Dermatology, Boston University School of Medicine, Massachusetts 02118, USA.
The second triennial FASEB Summer Research Conference on "Clonal Senescence and Differentiation" (August 17-22, 1996) focused on the interrelationships between aging processes and DNA damage and repair. The attendees represented a cross section of senior and junior investigators working in fields ranging from classic cellular gerontology to yeast and nematode models of aging to basic mechanisms of DNA damage and repair. The meeting opened with a keynote address by Dr. Bruce Ames that emphasized the documented relationships between oxidative damage, cancer, and aging. This was followed by eight platform sessions, one poster discussion, one featured presentation, and an after-dinner address. The following sections highlight the key points discussed.
Cell Mol Biol (Noisy-le-grand) 1997 Jun;43(4):529-541
Fabris N, Mocchegiani E, Provinciali M
Haematological Institute, S. Matteo Policlinic, University of Pavia, Italy.
Thymic regrowth and reactivation of thymic endocrine activity may be achieved even in old animals by different endocrinological or nutritional manipulations. In particular: a) intrathymic transplant of pineal gland or treatment with melatonin; b) implantation of a growth hormone secreting tumor cell line or treatment with exogenous growth hormone; c) castration or treatment with exogenous LH-RH; d) treatment with exogenous thyroxine or triiodothyronine, and e) nutritional interventions such as arginine or zinc supplementation. These data strongly support the idea that thymic involution is a phenomenon secondary to age-related alterations in neuroendocrine-thymus interactions and that it is the disruption of such interactions in old age which is responsible for most of age-associated dysfunctions. With regard to the mechanisms involved in hormone-induced thymic reconstitution, it is, at present, difficult to draw any definitive conclusion. The effect of GH, thyroid hormones and LH-RH may be due to the presence on thymic epithelial cells, supposed to produce thymic peptides, of the specific hormone receptors. Melatonin or pineal derived factors may as well act through specific receptors but experimental demonstration is still lacking. The role of zinc, whose turnover is usually reduced in old age, is of quite wide-range: from the reactivation of zinc-dependent enzymes, required for both cell proliferation and apoptosis, to the reactivation of thymulin, a zinc-dependent thymic hormone. The role of zinc may be even more crucial. According to recent preliminary data obtained both in animal and in man, it appears that the above reported endocrinological manipulations, capable of restoring thymic activity in old age, may act also by normalizing the altered zinc pool.
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