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S A Frautschy

Publications and source records attributed to S A Frautschy.

35 records · Page 2Linked to original sources
PubMed1992

Phagocytosis and deposition of vascular beta-amyloid in rat brains injected with Alzheimer beta-amyloid.

The presence of extracellular deposits of beta-amyloid protein in the brain is a hallmark of Alzheimer's disease (AD). In an effort to determine the effect of amyloid in an animal model, the authors injected amyloid cores isolated from AD brains into the cortex and hippocampus of rats. Lipofuscin, a major contaminant of the plaque core preparation, was injected on the contralateral side and used as a control to induce an analogous phagocytic cell response. Rats were sacrificed 2 days, 7 days, and 1 month after injection and amyloid located by four histochemical techniques. Amyloid and lipofuscin move from the site of injection into otherwise undamaged neuropil, persist for at least 1 month and are both associated with increases in glial fibrillary acidic protein and microglia (OX-42) staining. By 1 week, many of the amyloid cores are ingested by phagocytes. Some of the beta-amyloid-containing phagocytes migrate to the vessels and to the ventricles, and by 1 month, a significant amount of the amyloid is directly associated with the vessels. This suggests that phagocytic cells can internalize exogenous amyloid and attempt to clear it from the central nervous system (CNS). Therefore, the observed distribution of amyloid is not necessarily the initial site of deposition.

Amyloid beta-Peptides↗
PubMed1992

A time course for the focal elevation of synthesis of basic fibroblast growth factor and one of its high-affinity receptors (flg) following a localized cortical brain injury.

Traumatic injury to the CNS initiates transient and unsuccessful regeneration of damaged neural pathways, accompanied by reactive gliosis, angiogenesis, and deposition of a dense fibrous glial/meningeal scar at the wound site. Basic fibroblast growth factor (basic FGF) is a CNS protein with potent effects on neurons, glia, fibroblasts, and vascular endothelial cells. Hybridization and immunocytochemical methods were used to examine temporal and spatial changes in distribution and levels of basic FGF protein and mRNA and also of its receptor mRNA (flg), following a defined wound to the cerebral cortex of adult rat brains. In the injured brain, a rapid, transient increase in basic FGF mRNA and protein is readily detectable within 7 d of surgery and thereafter declines in the tissues bordering the lesion. The increased expression is localized to multiple cell types including macrophages, neurons, astrocytes, and vascular endothelial cells. The changes in immunoreactive basic FGF parallel changes in the bioactivity of extracted heparin-binding proteins, which include basic FGF. Focal increases in flg mRNA appear 7 d after injury and subside by 14 d. The changes in local basic FGF synthesis, concentration, localization, and bioactivity suggest that this growth factor may contribute to the cascade of cellular events that occur in CNS wound repair.

Animals↗
PubMed1991

Effects of injected Alzheimer beta-amyloid cores in rat brain.

Although amyloid deposits have long been known to accumulate in Alzheimer disease (AD) brain, their origin and significance remain speculative. Because of the lack of an in vivo model where amyloid deposits can be induced, the relationship of the extracellular beta-amyloid deposits to other AD pathology has never been directly investigated. Therefore, we injected SDS-isolated amyloid cores into rat cortex and hippocampus. Similarly isolated lipofuscin fractions from control human brains were injected on the contralateral side. Rats were perfused and brains were examined immunohistochemically at 2 days, 7 days, and 1 month after injection. Alz-50, a monoclonal antibody against abnormally phosphorylated tau proteins, stained neurons along the cortical needle track at 2 but not 7 days after injection of either amyloid or lipofuscin. At 1 month, however, ubiquitin, Alz-50 antigen, and silver-positive structures were observed only in response to amyloid. In 7 of 10 animals, there was considerable neuronal loss in the hippocampal layers. In each instance, these effects were in the immediate vicinity of beta-protein immunoreactive material. Marked neuronal loss was never observed at any time after lipofuscin injection. These results indicate a neuronal response to amyloid. When preparations of mature plaque amyloid isolated from the AD brain are injected into the rat brain, they exert neurotoxic effects and induce antigens found in the AD brain.

Alzheimer Disease↗
PubMed1991

Localization of basic fibroblast growth factor and its mRNA after CNS injury.

Basic fibroblast growth factor (FGF) mRNA is increased 4 h after cortical brain injury. In situ hybridization reveals that the increased mRNA persists for at least 2 weeks and that, in areas adjacent and ipsilateral to the lesion, the expression of basic FGF mRNA is also modified. As an example, at three days distal from the lesion, mRNA can be detected in ependymal cells of the lateral ventricle and in selected cells of the hippocampus and cortex. Endothelial cells also synthesize basic FGF mRNA. The increase in basic FGF mRNA is paralleled by similar changes in the localization of the basic FGF protein. Both the intensity and number of cells which stain for basic FGF are increased when they are compared to staining in either the contralateral side or to comparable areas of unlesioned brains. The pattern of mRNA expression is similar from 4 hours to 14 days. Early in the response (4 h to 3 days) on the border of the lesion, the presence of basic FGF is most obvious within the MAC-1-immunopositive population (macrophages and/or microglia). From 7 days to 2 weeks, there has been extensive hypertrophy of the reactive astrocytes which stain intensely for anti-basic FGF(1-24). We conclude that there is increased basic FGF as a function of injury to the CNS. In view of the observation that it is an early and persistent response, the possibility that it plays multiple functions in the regenerative capacity of the CNS is discussed.

Animals↗
PubMed1991

Expression of basic fibroblast growth factor and its receptor in the rat subfornical organ.

Basic fibroblast growth factor (FGF), its mRNA and the mRNA that encodes for its receptor have all been localized in the rat subfornical organ (SFO). Basic FGF is widely distributed throughout the SFO; it is present in neurons, in the vascular basement membrane of lateral blood vessels (but not those within the SFO) and in ependymal cells surrounding the SFO. Results of in situ hybridization show that the expression of basic FGF mRNA is detected throughout the organ. Similarly, the expression of flg, the gene for the putative basic FGF receptor, can also be detected in the SFO. The results all support the possibility that this growth factor may modulate the known physiological functions of the SFO.

Animals↗
PubMed1990

Facilitatory role of neuropeptide Y on the onset of puberty: effect of immunoneutralization of neuropeptide Y on the release of luteinizing hormone and luteinizing-hormone-releasing hormone.

To examine the role of neuropeptide Y (NPY) in the first luteinizing hormone (LH) surge of puberty, the effect of passive immunoneutralization of NPY with antiserum against NPY (anti-NPY) injected centrally (third ventricle) or peripherally (jugular vein) was studied in pubertal female rats on the day of first proestrus. Both peripheral and central anti-NPY administration reduced the magnitude of the LH surge during the afternoon of first proestrus; however, the central route of administration appeared to be most effective. Centrally administered anti-NPY also reduced the magnitude of proestrous LH-releasing hormone (LHRH) release into pituitary portal blood in these rats. These results suggest that endogenous NPY plays a facilitatory role in the generation of the LHRH surge necessary for preovulatory gonadotropin release and puberty.

Animals↗
PubMed1989

Chronic inhibition of hypothalamic-pituitary-ovarian axis and body weight gain by brain-directed delivery of estradiol-17 beta in female rats.

The effect of preferential delivery of estradiol (E2) into the brain on both the hypothalamic-pituitary-ovarian axis and weight gain was studied in female rats. When E2 was coupled to a lipoidal dihydropyridine-pyridinium carrier, the resulting carrier E2 complex (CE), upon a single intravenous administration to cycling female rats, caused a dose-dependent inhibition of ovulation which lasted 3 times longer than with uncoupled E2. The dose of CE that delayed ovulation for 4 days was one twentieth the amount of E2 needed to produce the same effect. Studies in ovariectomized (OVEX) rats indicated that the prolonged ovulation-blocking action of CE appeared to be related to a sustained storage and release of E2 in the brain, which in turn suppressed the release of hypothalamic luteinizing hormone-releasing hormone (LHRH) and pituitary luteinizing hormone (LH). Upon single intravenous administration in pubertal female rats, CE caused a dose-dependent reduction of body weight gain for a minimum period of 28 days. The inhibitory action of CE on body weight gain was more potent and longer lasting than that of E2 in pubertal rats. When administered in OVEX rats, CE produced a loss of body weight that lasted significantly longer than that produced by uncoupled E2 in these rats. These results suggest that the biological action of E2 can be potentiated by this novel chemical delivery system.

Animals↗
PubMed1989

Effect of dexamethasone on gonadotrophin secretion in the gonadectomized sow and boar.

Saline solution or dexamethasone (DXM, 35 micrograms/kg bodyweight) was injected intramuscularly twice daily for four days into five ovariectomized sows and five castrated boars. Blood samples from an indwelling jugular vein catheter were taken at 15 min intervals for 12 h prior to DXM injection and on the fourth day of treatment in order to compare the effect on variables describing the pulsatile secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH). Dexamethasone treatment caused a decrease (p less than 0.05) in the number of pulsatile episodes of LH secretion in both gonadectomized boars and sows resulting in a significant decrease in mean concentrations. Follicle stimulating hormone secretion parameters appeared to be unaffected by DXM injection in both groups of animals. It is concluded that previously described differences in LH suppression in boars and sows given glucocorticoids may be attributed to the influence of gonadal hormones.

Animals↗
PubMed1988

Anovulation and plasma hormone concentrations after administration of dexamethasone during the middle of the luteal phase in sows undergoing estrous cycles.

The effect of glucocorticoids on early follicular growth in sows undergoing normal estrous cycles was evaluated by administration of dexamethasone during the middle of the luteal phase. Plasma specimens were obtained for measurement of luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, and estradiol-17 beta concentrations. Fifteen sows were used. Control sows (n = 5) were given physiologic saline solution twice daily from day 9 to day 14 of the estrous cycle. Sows of the second group (n = 5) were given dexamethasone (30 micrograms/kg of body weight, IM) similarly, and those of the third group (n = 5) were given dexamethasone plus gonadotropin-releasing hormone (GnRH; 50 micrograms at 6-hour intervals, IV). Plasma specimens, obtained twice daily from day 8 through day 26, indicated that progesterone production and luteal regression were not inhibited by any of the 3 treatment regimens. Although preovulatory plasma estradiol concentration increased in control sows, such was not observed in the sows treated with dexamethasone or dexamethasone plus GnRH (P less than 0.01). Ovulation, with formation of corpora lutea, occurred in gilts given saline solution. Dexamethasone administration resulted in persistence of 19 to 41 follicles/ovary (2 to 4 mm in diameter), and dexamethasone-plus-GnRH treatment resulted in 6 to 18 follicles/ovary (5 to 6 mm in diameter). Plasma was obtained at 15-minute intervals for 12 hours to compare the effect of treatment on hormone concentrations on day 12 of the estrous cycle with the values on day 8.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Solvent effects on beta protein toxicity in vivo.

Human beta (1-40) and rat beta (1-42) were dissolved in three different solvents and stereotaxically injected into rat hippocampus with the contralateral side injected with control reverse sequence peptide or vehicle alone. Results at 1 week showed gross toxicity of the 35% acetonitrile solvent which was markedly enhanced by 3 nmol of beta protein but not by reverse sequence peptide. Beta peptide in water also appeared more toxic than reverse sequence, but the results were less clear cut. In contrast, 3 nmol of beta peptide in a cyclodextrin/PBS solution produced no marked short-term toxic effects. Peripheral injection of substance P failed to prevent toxicity. We conclude that solvent effects play a major role in acute beta protein neurotoxicity.

Amyloid beta-Peptides↗
PubMedDate not supplied

Lack of long-term effects after beta-amyloid protein injections in rat brain.

Rat beta(1-42) peptide (beta/A4) or phosphate buffered saline (PBS) was bilaterally injected into the hippocampus (HIP) or the lateral ventricle (ICV) of 3-month-old Fischer-344 rats. Fifteen months later, the animal's ability to learn a spatial memory task was tested using the Morris water maze. Acquisition of the task was impaired by the bilateral injection of either peptide or PBS into the hippocampus. Hippocampal-injected animals showed an increased average latency to find the platform by approximately 6 s (p < 0.05). However, injection of rat beta-peptide into the hippocampus or lateral ventricles failed to induce behavioral impairment when compared to vehicle injected controls. Retention of this task was not significantly impaired in any group. The spatial acuity test, a trial without the platform, revealed that both groups of animals that received hippocampal injections were impaired, spending 23% less time in the target quadrant compared to ICV-injected animals (p < 0.005). Hippocampal ChAT activity was decreased in beta/A4-injected animals but not significantly (p < 0.06). beta/A4-immunoreactivity was detected at the bottom of the needle track and the adjacent parenchyma of beta/A4 hippocampal-injected animals after 16 months. However, long-term in vivo deposition of beta/A4 in both regions did not result in an upregulation of hippocampal amyloid precursor protein (APP) expression and there was no qualitative neuronal loss in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMedDate not supplied

Rodent models of Alzheimer's disease: rat A beta infusion approaches to amyloid deposits.

The development of rodent models for Alzheimer's disease is a critical step for both understanding the disease and developing therapeutic drugs. Transgenic and knockout mouse models will elucidate some important aspects of the etiology of the disease and the development of pharmaceutical treatments. Here, we will focus on the advantages of nontransgenic models. In nontransgenic rat models, intraventricular infusion of A beta 1-40 (alone) generally results in diffuse deposition of A beta with very few focal plaque-like amyloid deposits after a 30-day intraventricular infusion. However, we have recently found that large numbers of scattered A beta immunoreactive plaque-like deposits can be produced in retired female Sprague-Dawley rat breeders using intraventricular infusion of A beta combined with neuropil injection of transforming growth factor beta 1(TGF beta). A beta that was not associated with the large deposits was often immunolocalized with neurons and cell processes. Immunogold electron microscopy demonstrated the presence of A beta in endosome/lysosomes of neuronal processes and glia and basal lamina. In some cases this labeling was clearly in lysosomes of degenerating neurites. This model allows one to introduce A beta and other plaque-associated factors without overexpression of potentially confounding APP domains. We conclude that A beta infusion models will be a useful complement to transgenic approaches to Alzheimer's pathology.

Alzheimer Disease↗
PubMedDate not supplied

Estrogen (E2) and glucocorticoid (Gc) effects on microglia and A beta clearance in vitro and in vivo.

The accumulation of fibrillar aggregates of beta Amyloid (A beta) in Alzheimer's Disease (AD) brain is associated with chronic brain inflammation. Although activated microglia (mu glia) can potentially clear toxic amyloid, chronic activation may lead to excessive production of neurotoxins. Recent epidemiological and clinical data have raised questions about the use of anti-inflammatory steroids (glucocorticoids, Gcs) and estrogens for treatment or prevention of AD. Since very little is known about steroid effects on mu glial interactions with amyloid, we investigated the effects of the synthetic Gc dexamethasone (DXM) and 17-beta estradiol (E2) in vitro in a murine mu glial-like N9 cell line on toxin production and intracellular A beta accumulation. To determine whether the steroid alterations of A beta uptake in vitro had relevance in vivo, we examined the effects of these steroids on A beta accumulation and mu glial responses to A beta infused into rat brain. Our in vitro data demonstrate for the first time that Gc dose-dependently enhanced mu glial A beta accumulation and support previous work showing that E2 enhances A beta uptake. Despite both steroids enhancing uptake, degradation was impeded, particularly with Gcs. Distinct differences between the two steroids were observed in their effect on toxin production and cell viability. Gc dose-dependently increased toxicity and potentiated A beta induction of nitric oxide, while E2 promoted cell viability and inhibited A beta induction of nitric oxide. The steroid enhancement of mu glial uptake and impedence of degradation observed in vitro were consistent with observations from in vivo studies. In the brains of A beta-infused rats, the mu glial staining in entorhinal cortex layer 3, not associated with A beta deposits was increased in response to A beta infusion and this effect was blocked by feeding rats prednisolone. In contrast, E2 enhanced mu glial staining in A beta-infused rats. A beta-immunoreactive (ir) deposits were quantitatively smaller, appeared denser, and were associated with robust mu glial responses. Despite the fact that steroid produced a smaller more focal deposit, total extracted A beta in cortical homogenate was elevated. Together, the in vivo and in vitro data support a role for steroids in plaque compaction. Our data are also consistent with the hypothesis that although E2 is less potent than Gc in impeding A beta degradation, long term exposure to both steroids could reduce A beta clearance and clinical utility. These data showing Gc potentiation of A beta-induced mu glial toxins may help explain the lack of epidemiological correlation for AD. The failure of both steroids to accelerate A beta degradation may explain their lack of efficacy for treatment of AD.

Amyloid beta-Peptides↗
PubMedDate not supplied

Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice.

We previously showed the non-steroidal anti-inflammatory drug (NSAID) ibuprofen suppresses inflammation and amyloid in the APPsw (Tg2576) Tg2576 transgenic mouse. The mechanism for these effects and the impact on behavior are unknown. We now show ibuprofen's effects were not mediated by alterations in amyloid precursor protein (APP) expression or oxidative damage (carbonyls). Six months ibuprofen treatment in Tg+ females caused a decrease in open field behavior (p < 0.05), restoring values similar to Tg- mice. Reduced caspase activation per plaque provided further evidence for a neuroprotective action of ibuprofen. The impact of a shorter 3 month duration ibuprofen trial, beginning at a later age (from 14 to 17 months), was also investigated. Repeated measures ANOVA of Abeta levels (soluble and insoluble) demonstrated a significant ibuprofen treatment effect (p < 0.05). Post-hoc analysis showed that ibuprofen-dependent reductions of both soluble Abeta and Abeta42 were most marked in entorhinal cortex (p < 0.05). Although interleukin-1beta and insoluble Abeta were more effectively reduced with longer treatment, the magnitude of the effect on soluble Abeta was not dependent on treatment duration.

Aging↗
PubMedDate not supplied

Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology.

Both oxidative damage and inflammation have been implicated in age-related neurodegenerative diseases including Alzheimer's Disease (AD). The yellow curry spice, curcumin, has both antioxidant and anti-inflammatory activities which confer significant protection against neurotoxic and genotoxic agents. We used 22 month Sprague-Dawley (SD) rats to compare the effects of the conventional NSAID, ibuprofen, and curcumin for their ability to protect against amyloid beta-protein (Abeta)-induced damage. Lipoprotein carrier-mediated, intracerebroventricular infusion of Abeta peptides induced oxidative damage, synaptophysin loss, a microglial response and widespread Abeta deposits. Dietary curcumin (2000 ppm), but not ibuprofen, suppressed oxidative damage (isoprostane levels) and synaptophysin loss. Both ibuprofen and curcumin reduced microgliosis in cortical layers, but curcumin increased microglial labeling within and adjacent to Abeta-ir deposits. In a second group of middle-aged female SD rats, 500 ppm dietary curcumin prevented Abeta-infusion induced spatial memory deficits in the Morris Water Maze and post-synaptic density (PSD)-95 loss and reduced Abeta deposits. Because of its low side-effect profile and long history of safe use, curcumin may find clinical application for AD prevention.

Amyloid beta-Peptides↗