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Biomedical subjects

Margaret Fahnestock

Publications and source records attributed to Margaret Fahnestock.

6 recordsLinked to original sources
PubMed2003

Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer's disease.

Brain-derived neurotrophic factor (BDNF) promotes the function and survival of the major neuronal types affected in Alzheimer disease, such as hippocampal, cortical and basal forebrain cholinergic neurons. We and others have demonstrated a reduction in BDNF mRNA expression in Alzheimer's disease hippocampus and cortex, which may help to explain the selective vulnerability of these neurons. Several studies have also shown decreased BDNF protein in Alzheimer's disease. BDNF protein is synthesized as a precursor, proBDNF, which is cleaved to the mature 14-kDa form. We demonstrate here that BDNF exists as a mixture of proBDNF and mature BDNF in all regions tested of human brain. Using Western blotting, we observe a 40% reduction in proBDNF levels in Alzheimer's disease parietal cortex compared to controls. Thus, decreased BDNF protein measured by ELISA and immunohistochemistry likely represents a mixture of the two BDNF forms, and previously reported decreases in BDNF protein may be due, at least in part, to a significant reduction in proBDNF levels. Although the biological activity of proBDNF is unknown, reduced proBDNF may have functional consequences for the selective neuronal degeneration in Alzheimer's disease brain.

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PubMed2002

Differential expression of nerve growth factor transcripts in glia and neurons and their regulation by transforming growth factor-beta1.

Nerve growth factor (NGF) influences neuronal development, function, and response to injury. Using reverse transcriptase polymerase chain reaction, we find that mouse and rat cortex and spinal cord, and both neurons and glia in culture, express NGF mRNA. In the mouse, NGF is regulated by at least two promoters that govern synthesis of four different transcripts, A through D, that are all expressed in the mouse tissues and cells examined. In contrast, rat NGF expression varies with tissue and with cell type: transcript C is expressed strongly in brain but weakly in spinal cord, and transcript D is undetectable in rat central nervous system (CNS). In addition to species- and tissue-specific expression, NGF transcripts also exhibit cell type-specific expression: transcripts B, C and D are expressed in rat astrocytes but poorly or not at all in rat neurons, identifying glia as an important source of NGF in rat. NGF increases sharply after injury. TGF-beta1, which also increases immediately after injury, induces NGF mRNA and protein in rat and mouse glia but not in neurons. Furthermore, transcripts A, B and D, but not C, are upregulated by TGF-beta1 in mouse glia, whereas in rat glia, the major responsive transcript is C. Thus, there may be multiple TGF-beta1-responsive elements in the NGF promoters located upstream of exons 1 and 3 that may differ between mouse and rat. Moreover, NGF transcripts are differentially expressed in a species-, cell type-, and inducer-specific manner. These results have implications for the use of mice versus rats as models for the study of NGF regulation following CNS injury.

Alternative Splicing↗
PubMed2002

The cholinergic system modulates kindling and kindling-induced mossy fiber sprouting.

In a previous study, our laboratory demonstrated that the intraventricular infusion of nerve growth factor (NGF) accelerated kindling rates and enhanced mossy fiber sprouting in the absence of noticeable kindling-associated neuronal loss. The purpose of the present study was to investigate whether these NGF effects were mediated via the cholinergic system. This study evaluated the effects of the cholinergic agonist pilocarpine and the cholinergic antagonist scopolamine on kindling rates and kindling-induced mossy fiber sprouting in adult rats. The results showed that pilocarpine accelerated kindling rates and enhanced kindling-induced mossy fiber sprouting in the CA3 region of the hippocampus, whereas scopolamine retarded kindling rates and blocked kindling-induced mossy fiber sprouting in the CA3 and IML regions. These findings suggest that the cholinergic system may contribute to the long-term structural and functional alterations that are characteristic of the kindled state. Moreover, these data provide support for the hypothesis that NGF infusions may mediate kindling and kindling-induced mossy fiber sprouting via regulation of the cholinergic system.

Animals↗
PubMed2002

Glial cell line-derived neurotrophic factor modulates kindling and activation-induced sprouting in hippocampus of adult rats.

Kindling, a phenomenon in which repeated electrical stimulation of certain forebrain structures leads to an increase in the evoked epileptogenic response, is widely used to investigate the mechanisms of epilepsy. Kindling also results in sprouting of the dentate gyrus mossy fiber pathway and triggers astrocyte hypertrophy and increased volume of the hilus of the dentate gyrus. Our previous studies showed that infusion of the neurotrophin nerve growth factor accelerated the behavioral progression of amygdala kindling and affected kindling-induced structural changes in the brain, whereas intrahilar infusion of another neurotrophin, brain-derived neurotrophic factor, delayed amygdala kindling-induced seizure development and reduced the growth in afterdischarge duration, but had little effect on kindling-induced structural changes. In this paper, we report the effects of infusion of glial cell line-derived neurotrophic factor, a neurotrophic factor of the TGF-beta superfamily having similar central nervous system neuronal targets as brain-derived neurotrophic factor. We show that continuous intraventricular infusion of glial cell line-derived neurotrophic factor inhibits the behavioral progression of perforant path kindling-induced seizures without affecting afterdischarge duration. In addition, we demonstrate that intraventricular administration of glial cell line-derived neurotrophic factor prevents kindling-induced increases in hilar area and blocks mossy fiber sprouting in the CA3 region of the hippocampus. Glial cell line-derived neurotrophic factor did not have a statistically significant effect on the mossy fiber density in the inner molecular layer. Our results raise the possibility that glial cell line-derived neurotrophic factor plays a role in kindling and activation-induced neural growth via mechanisms distinct from those of the neurotrophins.

Age Factors↗
PubMed2002

A new brain-derived neurotrophic factor transcript and decrease in brain-derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer's disease parietal cortex.

Brain-derived neurotrophic factor (BDNF) supports hippocampal, cortical and basal forebrain cholinergic neurons, which lose function in Alzheimer's disease. In Alzheimer's tissues such as hippocampus and parietal cortex, brain- derived neurotrophic factor mRNA is decreased three- to four-fold compared with controls. However, the molecular mechanism of the down-regulation of BDNF in Alzheimer's disease is unknown. The human brain-derived neurotrophic factor gene has multiple promoters governing six non-coding upstream exons that are spliced to one downstream coding exon, leading to six different transcripts. Here we report an alternate human splice variant within exon 4I for a total of seven transcripts. Previous brain-derived neurotrophic factor mRNA measurements in Alzheimer's disease tissue were done using the downstream coding exon present in all transcripts. Using RT-PCR primers specific for each upstream exon, we observe a significant decrease in three human brain-derived neurotrophic factor mRNA transcripts in Alzheimer's disease samples compared with controls. Transcripts 1 and 3 each exhibit a two-fold decrease, and transcript 2 shows a five-fold decrease. There are no significant differences between control and Alzheimer's disease samples for the other transcripts, including the new splice variant. In rat, both transcripts 1 and 3 are regulated through the transcription factor cAMP response element binding protein, whose phosphorylation is decreased in the Alzheimer's disease brain. This could lead to specific down-regulation of the brain-derived neurotrophic factor transcripts shown here.

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