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C E Finch

Publications and source records attributed to C E Finch.

At least 37 records · Page 2Linked to original sources
PubMed1999

The mosaic of brain glial hyperactivity during normal ageing and its attenuation by food restriction.

Food restriction of adult rodents increases lifespan, with commensurate attenuation of age-related pathological lesions in many organs, as well as attenuation of normal ageing changes that are distinct from gross lesions. Previous work showed that chronic food restriction attenuated age-associated astrocyte and microglial hyperactivity in the hippocampal hilus, as measured by expression of glial fibrillary acidic protein and major histocompatibility complex II antigen (OX6). Here, we examined other markers of astrocyte and microglial activation in gray and white matter regions of ad libitum-fed (Brown Norway x Fischer 344) F1 male rats aged three and 24 months and chronic food-restricted rats aged 24 months. In situ hybridization and immunohistochemical techniques evaluated glial expression of glial fibrillary acidic protein, apolipoprotein E, apolipoprotein J (clusterin), heme oxygenase-1, complement 3 receptor (OX42), OX6 and transforming growth factor-beta1. All markers were elevated in the corpus callosum during ageing and were attenuated by food restriction, but other regions showed marked dissociation of the extent and direction of changes. Astrocytic activation, as measured with glial fibrillary acidic protein expression (coding and intron-containing RNA, immunoreactivity), increased with age in the corpus callosum, basal ganglia and hippocampus. Generally, food restriction attenuated the age-related increase in glial fibrillary acidic protein messenger RNA and immunoreactivity. Food restriction also reduced the age-related increase in apolipoprotein J and E messenger RNA and heme oxygenase-1 immunoreactivity in the basal ganglia and corpus callosum. However, astrocytes in the hilus of the hippocampus showed an age-related decrease in apolipoprotein J and E messenger RNA, which was further intensified by food restriction. The age-associated microglial activation measured by OX6 and OX42 immunoreactivity was reduced by food restriction in most subregions. The localized subsets of glial age changes and effects of food restriction comprise a mosaic of ageing consistent with the regional heterogeneity of ageing changes reported by others. In particular, age has a differential effect on astrocytic and microglial hyperactivity in gray versus white matter areas. The evident mosaic of glial ageing and responses to food restriction suggests that multiple mechanisms are at work during ageing.

Aging↗
PubMed1999

Glial fibrillary acidic protein transcription responses to transforming growth factor-beta1 and interleukin-1beta are mediated by a nuclear factor-1-like site in the near-upstream promoter.

Elevated expression of glial fibrillary acidic protein (GFAP) is associated with astrocyte activation during responses to injury in the CNS. Because transforming growth factor-beta1 (TGF-beta1) and interleukin-1beta (IL-1beta) are released during neural responses to injury and because these cytokines also modulate GFAP mRNA levels, it is of interest to define their role in GFAP transcription. The increases of GFAP mRNA in response to TGF-beta1 and decreases in response to IL-1beta were shown to be transcriptionally mediated in rat astrocytes transfected with a luciferase-reporter construct containing 1.9 kb of 5'-upstream rat genomic DNA. Constructs containing sequential deletions of the rat GFAP 5'-upstream promoter identified a short region proximal to the transcription start (-106 to -53 bp) that provides full responses to TGF-beta1 and IL-1beta. This region contains an unusual sequence motif with overlapping nuclear factor-1 (NF-1)- and nuclear factor-kappaB (NF-kappaB)-like binding sites and homology to known TGF-beta response elements. Mutagenesis (3-bp exchanges) in -70 to -68 bp blocked the induction of GFAP by TGF-beta1 and the repression by IL-1beta. Gel shift experiments showed that the DNA segment -85 to -63 bp was bound by a factor(s) in nuclear extracts from astrocytes. The concentrations of these DNA binding factors were increased by treatment of astrocytes with TGF-beta1 and decreased by IL-1beta. Binding of these nuclear factors was blocked by mutation of -70 to -68 bp. Despite homology to NF-1 or NF-kappaB binding sites in the GFAP promoter at segment -79 to -67 bp, anti-NF-kappaB or anti-NF-1 antibodies did not further retard the gel shift of the nuclear factors/DNA complex. Moreover, astrocytic nuclear proteins do not compete for the specific binding to NF-1 consensus sequence. Thus, nuclear factors from astrocytes that bind to the -85- to -63-bp promoter segment might be only distantly related to NF-1 or NF-kappaB. These findings are pertinent to the use of GFAP promoter constructs in transgenic animals, because cisacting elements in the GFAP promoter are sensitive to cytokines that may be elaborated in response to expression of transgene products.

Animals↗
PubMed1998

Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.

Abeta1-42 is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer's pathogenesis. Neurotoxicity of amyloid beta protein (Abeta) has been attributed to its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins comprise small diffusible Abeta oligomers (referred to as ADDLs, for Abeta-derived diffusible ligands), which were found to kill mature neurons in organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surface-derived tryptic peptides blocked binding and afforded neuroprotection. Germ-line knockout of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer's disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by ADDLs occurred well in advance of cellular degeneration. Without lag, and despite retention of evoked action potentials, ADDLs inhibited hippocampal long-term potentiation, indicating an immediate impact on signal transduction. We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Abeta-derived diffusible ligands acting upon particular neural signal transduction pathways.

Alzheimer Disease↗
PubMed1998

Increased synaptic sprouting in response to estrogen via an apolipoprotein E-dependent mechanism: implications for Alzheimer's disease.

Estrogen replacement therapy appears to delay the onset of Alzheimer's disease (AD), but the mechanisms for this action are incompletely known. We show how the enhancement of synaptic sprouting by estradiol (E2) in response to an entorhinal cortex (EC) lesion model of AD may operate via an apolipoprotein E (apoE)-dependent mechanism. In wild-type (WT) mice, ovariectomy decreased commissural/associational sprouting to the inner molecular layer of the dentate gyrus, with synaptophysin (SYN) as a marker. E2 replacement returned SYN in the inner layer to levels of EC-lesioned, ovary-bearing controls and increased the area of compensatory synaptogenesis in the outer molecular layer. In EC-lesioned apoE-knock-out (KO) mice, however, E2 did not enhance sprouting. We also examined apoJ (clusterin) mRNA, which is implicated in AD by its presence in senile plaques, its transport of Abeta across the blood-brain barrier, and its induction by neurodegenerative lesioning. ApoJ mRNA levels were increased by E2 replacement in EC-lesioned WT mice but not in apoE-KO mice. These data suggest a mechanism for the protective effects of estrogens on AD and provide a link between two important risk factors in the etiology of AD, the apoE epsilon4 genotype and an estrogen-deficient state. This is also the first evidence that SYN, a presynaptic protein involved in neurotransmitter release, is regulated by E2 in the adult brain, and that apoE is necessary for the induction of apoJ mRNA by E2 in brain injury.

Alzheimer Disease↗
PubMed1998

Environmental influences that may precede fertilization: a first examination of the prezygotic hypothesis from maternal age influences on twins.

The prezygotic hypothesis considers the possibility that development is subject to environmental influences on the oocyte prior to conception. Such influences may occur in the maternal grandmother's uterus where oogenesis is completed or in the mother before fertilization. According to this hypothesis, the separate eggs from which DZ twins are derived may be sensitive to microenvironmental variations within an ovary. As a first approach, we examined same-sex MZ and DZ twins for maternal age effects on differences between pairs in cognitive and behavioral traits. While no differences between MZ and DZ pairs were found that would indicate a major effect of the prezygotic environment, suggestions are made for further experimental studies of this unexplored question in human development.

Achievement↗
PubMed1998

Bidirectional transcription regulation of glial fibrillary acidic protein by estradiol in vivo and in vitro.

Glial fibrillary acidic protein (GFAP) expression shows cyclic variation in the rat hypothalamus and hippocampus during the normal estrous cycle. To elucidate the role of transcription in the regulation of GFAP, we examined levels of GFAP intron 1 by in situ hybridization in the hypothalamus and hippocampus of normal, cycling rats. On the afternoon of proestrus, when plasma estradiol levels are highest, GFAP transcription and messenger RNA were both increased in the arcuate nucleus of the hypothalamus and decreased in the outer molecular layer of the dentate gyrus. In the hilus of the hippocampus, neither GFAP transcription nor messenger RNA changed during the estrous cycle. In vitro, astrocytes showed bidirectional responses, such that estradiol treatment increased GFAP transcription in monotypic astrocytic cultures but decreased GFAP transcription in astrocytes cocultured with neurons. The functionality of an estrogen response element in the 5'-upstream region of the GFAP promoter was established by site-directed mutagenesis and binding of human recombinant estrogen receptor in gel shift assays. We conclude that estrogen may act directly upon astrocytes by estrogen receptor binding, and that the direction of the transcriptional response is influenced by astrocyte-neuron interactions.

Animals↗
PubMed1997

NSAIDS inhibit the IL-1 beta-induced IL-6 release from human post-mortem astrocytes: the involvement of prostaglandin E2.

Epidemiological studies have shown that steroidal as well as non-steroidal anti-inflammatory drugs lower the risk of developing Alzheimer's Disease (AD). A suppressive effect of these anti-inflammatory drugs on local inflammatory events in AD brains has been suggested, however the mechanisms responsible are still unknown. In this study we investigated at cellular level the influence of two anti-inflammatory drugs-dexamethasone and indomethacin--and an experimental specific cyclooxygenase-2 inhibitor, BF389, on the production of the pro-inflammatory cytokine IL-6 and the inflammatory mediator PGE2 by human astrocytes. Two human post-mortem astrocyte cultures (A157 and A295) and astroglioma cell lines (U251 and U373 MG) were found to secrete considerable amounts of IL-6 upon stimulation with IL-1beta. The glucocorticoid dexamethasone inhibited the IL-1beta-activated release of IL-6 from the postmortem astrocyte cultures A157 and A295 and from the astroglioma cell lines. The non-specific cyclooxygenase inhibitor indomethacin and BF389 only suppressed the IL-6 release by post-mortem astrocyte culture A157. This post-mortem astrocyte culture was found to produce large amounts of PGE2 upon stimulation with IL-1beta, whereas in the supernatants of the postmortem astrocyte culture A295 and the astroglioma cell lines, low PGE2 concentrations were detected. Addition of exogenous PGE2 prevented the inhibitory effect of indomethacin and BF389 on the IL-1beta-activated IL-6 release from A157 astrocytes and largely potentiated the IL-1-induced release of IL-6 from all astrocytes/astroglioma cells tested. Dexamethasone also inhibited the PGE2 release from the astrocytes and astroglioma cells, however the inhibitory effect of dexamethasone on the IL-1beta-activated IL-6 release could not be prevented by the addition of PGE2. The observed reduction of IL-6 and/or PGE2 from astrocytes may be involved in the mechanism underlying the beneficial effects of these drugs in AD.

Anti-Inflammatory Agents↗
PubMed1997

Genetics of aging.

The role of genetics in determining life-span is complex and paradoxical. Although the heritability of life-span is relatively minor, some genetic variants significantly modify senescence of mammals and invertebrates, with both positive and negative impacts on age-related disorders and life-spans. In certain examples, the gene variants alter metabolic pathways, which could thereby mediate interactions with nutritional and other environmental factors that influence life-span. Given the relatively minor effect and variable penetrance of genetic risk factors that appear to affect survival and health at advanced ages, life-style and other environmental influences may profoundly modify outcomes of aging.

Aging↗
PubMed1997

Scavenger receptor mRNAs in rat brain microglia are induced by kainic acid lesioning and by cytokines.

The expression and localization of two distinct mRNAs from the macrophage scavenger receptor gene family were studied in rat brain cells in vivo and in vitro. In general, brains of control male rats showed low level signals by in situ hybridization for the macrophage scavenger receptor (MSR) and murine adherent macrophage (MAMA) receptor. In contrast, the reticular thalamic nucleus had a subpopulation of intensely labeled cells. Kainic acid (KA) treatment induced MSR and MAMA mRNA levels on different schedules in brain regions that are susceptible to KA, including hippocampal areas CA1 and CA3. The combination of immunocytochemistry and in situ hybridization localized the MSR and MAMA mRNA to microglia of KA-treated rats. Northern blot hybridization detected both MSR and MAMA mRNAs in primary cultures of mixed glia that contained microglia. Both MSR and MAMA mRNA were induced by treatment of primary mixed glia with lipopolysaccharide and interferon-gamma, but not TGF beta 1. MSR, but not MAMA, mRNA levels were increased after treatment with interleukin-1 alpha. These results demonstrate the differential regulation of scavenger receptor mRNAs in microglia that is consistent with distinct roles for scavenger receptors in responses to neurodegeneration.

Animals↗
PubMed1997

Aging, metabolism, and Alzheimer disease: review and hypotheses.

Relationships are considered among aging, metabolism, and Alzheimer disease (AD). In particular, after 60 years, human populations show progressive age-related trends for increased blood glucose that are concurrent with the accelerating incidence of AD. The accumulation of glycated products in the AD brain, such as is also found in peripheral tissues during diabetes, suggests interactions of AD with age-related changes in metabolism. A review of 13 recent studies on AD and diabetes shows no consensus, although most studies indicate an apparent exclusion of AD and diabetes. We argue that longitudinal studies are needed to evaluate the possibility that an initial age-related hyperglycemic state is reversed by the cachexia and weight loss common to later stages of AD. A review of literature on chronic food restriction in rodents shows the slowing of some aspects of aging in the nervous system and generally supports interactions of peripheral metabolism with brain aging. Finally, we discuss aspects of intermediary metabolism that could ensue from oxidative damage to enzymes by glycation or oxidative stress which include excess production of ammonia from the inhibition of glutamine synthetase and the production of glyceraldehyde-3-phosphate, a glycating agent that could contribute to damage in addition to the hyperglycemic trends during aging.

Aging↗
PubMed1997

Astrocytes and microglia respond to estrogen with increased apoE mRNA in vivo and in vitro.

This study examined the regulation of apolipoprotein E (apoE) by 17beta-estradiol (E2) in brain glia, using rats with regular ovulatory cycles as an in vivo model and cultured astrocytes and mixed glia as in vitro models. Two brain regions were examined which had demonstrated transient synaptic remodeling during the estrous cycle. In the hippocampal CA1 region and the hypothalamic arcuate nucleus, apoE mRNA was elevated at proestrus when plasma E2 was high and synaptic density was increasing. Both astrocytes and microglia contributed to this increase in apoE mRNA. In vitro, E2 treatment had no effect on apoE mRNA levels in monotypic cultures of either astrocytes or microglia. In contrast, mixed glial cultures responded to E2 with increased apoE mRNA and protein, suggesting that heterotypic cellular interactions are important in the brain response to estrogens. In situ hybridization in combination with cell-specific markers showed that E2 increased apoE mRNA levels in both astrocytes and microglia. These results, which are the first evidence of apoE mRNA localization to microglia in vivo and the control of apoE expression in brain cells by estrogens, are discussed in terms of the possible protective role of E2 in Alzheimer's disease and prior findings that emphasize the expression of apoE mRNA in astrocytes within the brain.

Animals↗
PubMed1997

Relevance of 'adaptive' mutations arising in non-dividing cells of microorganisms to age-related changes in mutant phenotypes of neurons.

Brattleboro rats do not produce vasopressin (VP) because of a germ-line single-base deletion (di) that causes a frame shift downstream from the VP sequences and a loss of a stop codon. The resulting frame-shifted peptide precursor does not enter the secretory pathway in hypothalamic neurons, thereby blocking the neurosecretion of VP and other peptides. Yet, from birth onwards, a subpopulation of neurons in di/di rats slowly accumulates revertant cells with a hemizygous wild-type phenotype. Because the rate of reversion during aging is slowed by vasopressin infusion, it is of interest to consider these phenomena in relation to recent observations on 'adaptive' mutations in single cell bacteria and yeast that enable reversion of mutations that blocked cell division under conditions of nutrient deficits. In considering mechanisms that could produce revertant phenotypes in non-dividing cells of both pro- and eukaryotes, we note the pertinence of transcription-coupled repair and SOS 'error-prone' repair.

Adaptation, Physiological↗
PubMed1997

Increased transcription of the astrocyte gene GFAP during middle-age is attenuated by food restriction: implications for the role of oxidative stress.

Glial fibrillary acidic protein (GFAP), an intermediate filament of astrocytes, shows increased expression during aging. Because we found that chronic food restriction retards the increase of GFAP mRNA in aging rats and because food restriction decreases the load of oxidized proteins and lipids in association with increased life span, we investigated the regulation of GFAP during oxidative stress and aging. First, we showed that food restriction decreased the transcription of GFAP in aging rats. This result generalizes effects of food restriction on age changes of transcription; whether transcription decreases during aging as in hepatic genes, or increases during aging as in astrocytic GFAP, food restriction attenuates the age change. Moreover, food restriction decreased microglial activation during aging, which suggested the hypothesis that GFAP expression is sensitive to oxidative stress. Because GFAP transcription in cultured glia is increased by oxidative stress in response to hydrogen peroxide and cysteamine whether or not microglia were present, we conclude that responses of GFAP to oxidative stress in astrocytes do not depend on microglial activation. The results implicate oxidative stress in the increased expression of GFAP during aging, but also in responses to brain injury.

Aging↗
PubMed1997

Kainic acid and decorticating lesions stimulate the synthesis of C1q protein in adult rat brain.

The first component of the classic complement cascade, C1q, was increased in whole rat brain after lesioning by intraperitoneally injected kainic acid (KA) (20-fold, 3 days after KA) and in the striatum ipsilateral to unilateral decortication (fivefold, 10 days after decortication). C1q was measured after purification by chromatography and electrophoresis. De novo biosynthesis of C1q 3 days after KA was increased >10-fold, as measured by the incorporation of [35S]methionine into C1q after incubation of brain slices from KA-treated rats for 2 h. In parallel with these responses, KA induced fivefold increase of C1q bioactivity, as evaluated with C1q-dependent hemolysis. The contribution of C1q from entrapped cerebrovascular blood was evaluated by the effects of perfusion and was minor relative to the increases of C1q in response to KA lesioning. These findings support the hypothesis that the C1q protein detected by immunocytochemistry in senile plaques of Alzheimer brains and in the hippocampus after deafferenting lesions is synthesized by resident brain cells.

Animals↗
PubMed1997

Can estrogens prevent neurodegeneration?

Estrogen replacement therapy appears to have significant beneficial effects on cognition and mood in the elderly. In recent studies, its use has been associated with short term symptomatic cognitive improvement and with a decreased risk of (or a delay in) developing Alzheimer's disease (AD). Clinical reports are supported by substantial basic scientific evidence of the neuroprotective effects of estrogens. Their specific effects on dementia and cognitive impairment remain to be delineated. Ongoing randomised trials in AD will only provide information on the symptomatic effects of estrogen. Although basic research will progress, there is currently sufficient knowledge to promote active clinical research on the possible disease-modifying or neuroprotective effects of estrogens in the elderly.

Affect↗
PubMed1996

Transcription supports age-related increases of GFAP gene expression in the male rat brain.

During aging, rodent and human brains show progressive increases in the levels of glial fibrillary acidic protein (GFAP) mRNA and protein. The role of transcription was investigated by in situ hybridization, using an intron-containing cRNA probe as a measure of primary GFAP transcripts. We found parallel age-related increases in GFAP intron RNA in the hippocampus, internal capsule, and corpus callosum of 3 versus 24 month old male F344 rats. We conclude that increased transcription supports the age-related increase of GFAP mRNA and protein. GFAP is a unique example of a gene that shows increased expression during aging in contrast to the decreased transcription of certain genes reported in non-neural tissues.

Aging↗
PubMed1996

Perforant path transection induces complement C9 deposition in hippocampus.

The presence of complement system proteins in amyloid plaques and the up-regulation of several complement mRNAs in neurons and glial cells in affected brain regions during Alzheimer disease (AD) provided a basis for further examination of complement protein expression in a rodent lesion model of AD. Perforant path transection in rats was used as a model for the degeneration of entorhinal cortex (EC) layer II neurons and the consequent deafferentation of the hippocampus that occurs during AD. Immunostaining for C9, a key terminal component of the complement cascade membrane attack complex (MAC), showed extracellular C9 deposition in parenchyma around the EC wound and in hippocampus as early as 1 day, and disappeared by 14 days postlesion. Apoptosis of EC layer II neurons was seen and was presumably due to severing of their axonal projections to the hippocampus by the transection lesion. However, apoptotic EC layer II neurons were not immunostained by anti-rat C9 antibody, suggesting complement was not involved in inducing apoptosis. In the deafferented hippocampus, extracellular C9 immunostaining was localized to the dentate gyrus middle molecular layer, a region of synaptic loss, dendritic degeneration, and early synaptogenesis. In addition, intracellular C9 immunostaining was seen only in select hippocampal interneurons. Dentate gyrus granule neurons and pyramidal neurons were not C9 immunostained. Clusterin (SGP-2), a soluble inhibitor of the MAC that is up-regulated in AD, was also detected in the wound area (extracellular), the dentate gyrus middle molecular layer (extracellular), and intracellularly in scattered hippocampal interneurons. The data support the hypothesis that the complement system generally participates in responses to brain injury, as well as in AD.

Afferent Pathways↗