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Biomedical subjects

G M Martin

Publications and source records attributed to G M Martin.

252 records · Page 14Linked to original sources
PubMedDate not supplied

Neurodegenerative mechanisms in Alzheimer disease. A role for oxidative damage in amyloid beta protein precursor-mediated cell death.

We have established a stably transformed human neuroblastoma cell line (MC65) that conditionally expresses a C-terminal derivative of the amyloid beta protein precursor (beta PP) termed S beta C (a fusion protein composed of the amino-17 and carboxyl-99 residues of beta PP). Conditional expression of S beta C (mediated by the withdrawal of tetracycline from the culture medium) induces pronounced nuclear DNA fragmentation and cytotoxicity in this cell line. These effects are enhanced by hyperoxygen and suppressed by hypooxygen and antioxidants. This cell line is relatively insensitive to the extracellular application of amyloid beta 25-35, and coculture experiments suggest that this cytotoxicity is mediated by an intracellular process. These findings suggest that the overexpression of the C-terminal domain of beta PP can disrupt normal cellular processes in these cells in such a way as to induce a directed (deoxyribonuclease-mediated) mechanism of cell death. This process appears to be modulated and/or mediated by a reactive oxygen specie(s) (ROS). Consistent with a role for ROS in the process of S beta C-mediated toxicity, we have found that the MC65 cell line is hypersensitive to oxidative stress and that it is this sensitivity that appears (at least in part) to underlie its susceptibility to S beta C.

Acetylcysteine↗
PubMedDate not supplied

Cell fusion corrects the 4-nitroquinoline 1-oxide sensitivity of Werner syndrome fibroblast cell lines.

We have shown that Werner syndrome (WRN) fibroblast cell lines are unusually sensitive to the DNA-damaging agent 4-nitroquinoline 1-oxide (4NQO), though not to gamma radiation or to hydrogen peroxide. The fusion of 4NQO-sensitive WRN and 4NQO-resistant control fibroblast cell lines generated proliferating WRN x control cell hybrids that expressed WRN protein and were 4NQO-resistant. These results establish the recessive nature of 4NQO sensitivity in WRN cell lines and provide a cellular assay for WRN protein function.

4-Nitroquinoline-1-oxide↗
PubMedDate not supplied

Evidence for etiologic heterogeneity in Alzheimer's disease.

We briefly describe the evidence for etiologic heterogeneity in Alzheimer's disease. Several different genetic and environmental factors may act separately or in combination to produce the AD phenotype. This potential heterogeneity presents special challenges to those attempting to identify specific genetic influences in the pathogenesis of AD.

Alzheimer Disease↗
PubMedDate not supplied

Trypsin inhibitor activities of fibroblasts increase with age of donor and are unaltered in familial Alzheimer's disease.

Increasing evidence suggests that proteases and their inhibitors play an important role in the etiology of beta-amyloidogenesis and Alzheimer's disease (AD). It is not clear, however, which proteases and protease inhibitors are responsible for the amyloidogenic proteolysis. Candidates include alpha-1-antichymotrypsin, inter-alpha-trypsin inhibitor, and forms of beta-amyloid precursor protein (beta PP) bearing Kunitz protease inhibitor domains. As one approach to this question, we have determined the trypsin inhibitor activity of fibroblast-like cells from 10 familial AD subjects and 20 controls. The activity was quantitated by measuring remaining trypsin activity of reaction mixtures containing trypsin and cell lysates using a fluorogenic substrate and two physiologically distinct populations of fibroblasts: proliferating cells (grown in the presence of 16% serum) and quiescent cells (maintained in 0.1% serum). The remaining trypsin activities of crude protein extracts from proliferating and quiescent AD cultures were not significantly different from those of controls. Perhaps of more general interest to the biology of aging, however, was our finding that protease inhibitor activity increased with the age of the donor (p = 0.005).

Adult↗
PubMedDate not supplied

Genetic modulation of the senescent phenotype of Homo sapiens.

The biology of aging is reviewed from the perspective of a medical geneticist. This was the perspective of the late Sam Goldstein, and this article is, therefore, dedicated to his memory. Aging can be defined as the set of phenotypes that escape the force of natural selection. These phenotypes can be modulated by mutation or polymorphism at numerous genetic loci. Given the remarkable genetic and environmental heterogeneity that characterizes our species, it is understandable that there should be considerable variation in patterns of aging. A genetic approach involving the mapping and positional cloning of major loci could provide basic understanding of the mechanisms underlying such variability. Prototypic examples being investigated by the author and his colleagues are the Werner syndrome and dementias of the Alzheimer type. The biochemical genetic analysis of these and other disorders could lead to a new style of medicine based upon preventive approaches tailored to the needs of individuals. Such interventions should ideally involve pediatricians.

Aging↗