Showing papers on "Neurodegeneration published in 1993"
TL;DR: Two broad mechanisms--oxidative stress and excessive activation of glutamate receptors--are converging and represent sequential as well as interacting processes that provide a final common pathway for cell vulnerability in the brain.
Abstract: There is an increasing amount of experimental evidence that oxidative stress is a causal, or at least an ancillary, factor in the neuropathology of several adult neurodegenerative disorders, as well as in stroke, trauma, and seizures. At the same time, excessive or persistent activation of glutamate-gated ion channels may cause neuronal degeneration in these same conditions. Glutamate and related acidic amino acids are thought to be the major excitatory neurotransmitters in brain and may be utilized by 40 percent of the synapses. Thus, two broad mechanisms--oxidative stress and excessive activation of glutamate receptors--are converging and represent sequential as well as interacting processes that provide a final common pathway for cell vulnerability in the brain. The broad distribution in brain of the processes regulating oxidative stress and mediating glutamatergic neurotransmission may explain the wide range of disorders in which both have been implicated. Yet differential expression of components of the processes in particular neuronal systems may account for selective neurodegeneration in certain disorders.
3,844 citations
TL;DR: Aggregation properties of an overlapping series of synthetic beta-amyloid peptides were investigated and compared with beta AP neurotoxic properties in vitro, finding that few beta APs assembled into aggregates immediately after solubilization, but that over time peptides containing the highly hydrophobic beta 29–35 region formed stable aggregations.
Abstract: The progressive neurodegeneration of Alzheimer9s disease has been hypothesized to be mediated, at least in part, by beta-amyloid protein. A relationship between the aggregation state of beta-amyloid protein and its ability to promote degeneration in vitro has been previously suggested. To evaluate this hypothesis and to define a structure- activity relationship for beta-amyloid, aggregation properties of an overlapping series of synthetic beta-amyloid peptides (beta APs) were investigated and compared with beta AP neurotoxic properties in vitro. Using light microscopy, electrophoresis, and ultracentrifugation assays, we found that few beta APs assembled into aggregates immediately after solubilization, but that over time peptides containing the highly hydrophobic beta 29–35 region formed stable aggregations. In short-term neuronal cultures, toxicity was associated specifically with those beta APs that also exhibited significant aggregation. Further, upon the partial reversal of beta 1–42 aggregation, a concomitant loss of toxicity was observed. A synthetic peptide derived from a different amyloidogenic protein, islet amyloid polypeptide, exhibited aggregation but not toxicity, suggesting that beta AP-induced neurotoxicity in vitro is not a nonspecific reaction to aggregated protein. The correlation between beta AP aggregation and neurotoxicity was also observed in long-term neuronal cultures but not in astrocyte cultures. These data are consistent with the hypothesis that beta-amyloid protein contributes to neurodegeneration in Alzheimer9s disease.
1,460 citations
TL;DR: It is reported that synthetic A beta Ps trigger the degeneration of cultured neurons through activation of an apoptotic pathway, suggesting that apoptosis may play a role in the neuronal loss associated with Alzheimer disease.
Abstract: The molecular mechanism responsible for the neurodegeneration in Alzheimer disease is not known; however, accumulating evidence suggests that beta-amyloid peptide (A beta P) contributes to this degeneration. We now report that synthetic A beta Ps trigger the degeneration of cultured neurons through activation of an apoptotic pathway. Neurons treated with A beta Ps exhibit morphological and biochemical characteristics of apoptosis, including membrane blebbing, compaction of nuclear chromatin, and internucleosomal DNA fragmentation. Aurintricarboxylic acid, an inhibitor of nucleases, prevents DNA fragmentation and delays cell death. Our in vitro results suggest that apoptosis may play a role in the neuronal loss associated with Alzheimer disease.
1,080 citations
TL;DR: Point mutations in the cytosolic Cu/Zn superoxide dismutase (SOD-1) gene have been detected in association with familial amyotrophic lateral sclerosis, consistent with the hypothesis that free radicals contribute to the pathogenesis of FALS and possibly to the Pathogenesis of other neurodegenerative disorders such as Parkinson's disease.
751 citations
TL;DR: Results from cortical tissue demonstrate that SOD1 activity is reduced and complex I activity is increased in FALS‐1 patients and that oxidative damage to proteins is increase in SALS patients.
Abstract: The cause of neuronal death in amyotrophic lateral sclerosis (ALS) is unknown. Recently, it was found that some patients with autosomal-dominant familial ALS (FALS) have point mutations in the gene that encodes Cu/Zn superoxide dismutase (SOD1). In this study of postmortem brain tissue, we examined SOD activity and quantified protein carbonyl groups, a marker of oxidative damage, in samples of frontal cortex (Brodmann area 6) from 10 control patients, three FALS patients with known SOD1 mutations (FALS-1), one autosomal-dominant FALS patient with no identifiable SOD1 mutations (FALS-0), and 11 sporadic ALS (SALS) patients. Also, we determined the activities of components of the electron transport chain (complexes I, II-III, and IV) in these samples. The cytosolic SOD activity, which is primarily SOD1 activity, was reduced by 38.8% (p < 0.05) in the FALS-1 patients and not significantly altered in the SALS patients or the FALS-0 patient relative to the control patients. The mitochondrial SOD activity, which is primarily SOD2 activity, was not significantly altered in the FALS-1, FALS-0, or SALS patients. The protein carbonyl content was elevated by 84.8% (p < 0.01) in the SALS patients relative to the control patients. Finally, the complex I activity was increased by 55.3% (p < 0.001) in the FALS-1 patients relative to the control patients. These results from cortical tissue demonstrate that SOD1 activity is reduced and complex I activity is increased in FALS-1 patients and that oxidative damage to proteins is increased in SALS patients.
619 citations
TL;DR: Lactate concentrations were increased in the occipital cortex of symptomatic HD patients when compared with normal controls, and the lactate level correlated with duration of illness, consistent with a possible defect in energy metabolism in HD.
Abstract: The Huntington9s disease (HD) gene mutation has recently been found; however, the biochemical defect that leads to neurodegeneration is still unknown. A progressive impairment of neuronal energy metabolism is a possible etiologic factor. We tested this possibility using localized proton nuclear magnetic resonance (NMR) spectroscopy in 18 patients at high risk for, or suffering from, HD as compared with normal controls. Lactate concentrations were increased in the occipital cortex of symptomatic HD patients when compared with normal controls, and the lactate level correlated with duration of illness. In addition, several patients showed highly elevated lactate levels in the basal ganglia. Basal ganglia levels of N-acetylaspartate were lowered and choline dramatically elevated, relative to creatine, reflecting neuronal loss and gliosis in this brain region. These findings are consistent with a possible defect in energy metabolism in HD, which could contribute to the pathogenesis of the disease. The presence of elevated lactate in HD brains may provide a simple marker that can be followed over time noninvasively and repeatedly to aid in devising and monitoring possible therapies for HD patients.
445 citations
TL;DR: Findings show an age‐associated progressive impairment of mitochondrial complex I and complex IV activities in cerebral cortices of primates.
Abstract: It has been hypothesized that some of the functional impairments associated with aging are the result of increasing oxidative damage to mitochondrial DNA that produces defects in oxidative phosphorylation. To test this hypothesis, we examined the enzymes that catalyze oxidative phosphorylation in crude mitochondrial preparations from frontoparietal cortex of 20 rhesus monkeys (5-34 years old). Samples were assayed for complex I, complex II-III, complex IV, complex V, and citrate synthase activities. When enzyme activities were corrected for citrate synthase activities (to account for variable degrees of mitochondrial enrichment), linear regression analysis demonstrated a significant negative correlation of the activities of complex I (p < 0.002) and complex IV (p < 0.03) with age but no significant change in complex II-III or complex V activities. Relative to animals 6.9 +/- 0.9 years old (n = 7), the citrate synthase-corrected activity of complex I was reduced by 17% in animals 22.5 +/- 0.9 years old (n = 6) (p < 0.05) and by 22% in animals 30.7 +/- 0.9 years old (n = 7) (p < 0.01). Similar age-related reductions in the activities of complexes I and IV were obtained when enzyme activities were corrected for complex II-III activity. These findings show an age-associated progressive impairment of mitochondrial complex I and complex IV activities in cerebral cortices of primates.
276 citations
207 citations
TL;DR: These responses provide models for studying the increases of TGF‐β1 protein observed in βA/amyloid‐containing extracellular plaques of Alzheimer's disease and Down's syndrome and in brain cells of AIDS victims, and in relation to the potent effects of T GF‐ β1 on wound healing and inflammatory responses in peripheral tissues.
Abstract: TGF-beta 1 mRNA and protein were recently found to increase in animal brains after experimental lesions that cause local deafferentation or neuron death. Elevations of TGF-beta 1 mRNA after lesions are prominent in microglia but are also observed in neurons and astrocytes. Moreover, TGF-beta 1 mRNA autoinduces its own mRNA in the brain. These responses provide models for studying the increases of TGF-beta 1 protein observed in beta A/amyloid-containing extracellular plaques of Alzheimer's disease (AD) and Down's syndrome (DS) and in brain cells of AIDS victims. Involvement of TGF-beta 1 in these human brain disorders is discussed in relation to the potent effects of TGF-beta 1 on wound healing and inflammatory responses in peripheral tissues. We hypothesize that TGF-beta 1 and possibly other TGF-beta peptides have organizing roles in responses to neurodegeneration and brain injury that are similar to those observed in non-neural tissues. Work from many laboratories has shown that activities of TGF-beta peptides on brain cells include chemotaxis, modification of extracellular matrix, and regulation of cytoskeletal gene expression and of neurotrophins. Similar activities of the TGF-beta's are well established in other tissues.
192 citations
TL;DR: Pharmacological modulation of the expression and/or actions of cytokines in the brain may be of considerable therapeutic benefit in the treatment of acute neurodegeneration.
174 citations
Book•
01 Jan 1993
TL;DR: Partial table of contents: DIAGNOSIS and BIOMarkers A Rational Clinical Approach to Patients with Dementia, and Pharmacotherapy of Alzheimer's Disease.
Abstract: Partial table of contents: DIAGNOSIS AND BIOMARKERS A Rational Clinical Approach to Patients with Dementia (A. Wallin & K. Blennow) Tau and Ubiquitin as Markers for Alzheimer's Disease (I. Grundke-Iqbal & K. Iqbal) An Abnormality of Plasma A4 Amyloid Protein Precursor in Alzheimer's Disease (S. Whyte, et al.) EPIDEMIOLOGY AND RISK FACTORS Descriptive Epidemiology and Risk Factors for Alzheimer's Disease (L. Amaducci, et al.) STRUCTURAL PATHOLOGY, PATTERNS OF CELL LOSS AND THE BLOOD-BRAIN BARRIER Involvement of the Visual Thalamus in Alzheimer's Disease (G. Leuba & K. Saini) MECHANISMS OF CELL DEATH: GENETIC FACTORS Inheritance of Multiple Loci in Familial Alzheimer's Disease (J. Haines, et al.) TRANSMISSIBLE DEMENTIAS Neurodegeneration and Prion Diseases (S. Prusiner) THERAPEUTICS Pharmacotherapy of Alzheimer's Disease: New Drugs and Novel Strategies (E. Giacobini) Index.
TL;DR: Upon acute activation, microglia, the immuneffector cells of the brain parenchyma, express the amyloid precursor protein (APP) that is otherwise prominent in pathological structures related to Alzheimer's disease.
Abstract: Upon acute activation, microglia, the immuneffector cells of the brain parenchyma, express the amyloid precursor protein (APP) that is otherwise prominent in pathological structures related to Alzheimer's disease. In this disease complex amyloidbearing neuritic plaques contain βA4-amyloid protein, the APP, and numerous inflammatory proteins. The accompanying activation of microglia has mostly been viewed as a secondary reaction to amyloid deposits.
Activation of microglia was performed in a graded fashion. Transection of peripheral nerves such as the facial or sciatic nerve causes a microglial reaction within hours in the nucleus of origin or in projection areas of the CNS. A predominantly glial up-regulation of APP mRNA and protein could be detected as early as 6 h post lesion not only at the site of affected neuronal cell bodies but also in corresponding projection areas. Its time course suggests rapid transneuronal signalling to glial cells in the projection area. Light and electron microscopy demonstrate that microglia, which are cells of mononuclear phagocyte lineage and comprise up to 20% of all glial cells, are the dominant source for non-neuronal APP expression. Ultrastructurally, brain perivascular cells within the basal lamina constitutively express APP and thus are a possible source of vascular amyloid.
Additionally, microglia express leukocyte-derived (L)-APP mRNA and protein that have recently been described in mononuclear cells of the immune system. Increased L-APP expression may serve as a potential marker for glial/microglial activation. Such immune-mediated amyloidogenesis initiated by microglia might have implications for the treatment of neurodegenerative diseases. © 1993 Wiley-Liss, Inc.
TL;DR: The data indicate that a variety of alterations in [Ca2+]i regulation may contribute to the neuronal damage in stroke and AD, and suggest possible means of preventing neuronalDamage in these disorders.
Abstract: Several cellular signaling systems have been implicated in the neuronal death that occurs both in development ("natural" cell death) or in pathological conditions such as stroke and Alzheimer's disease (AD). Here we consider the possibility that neuronal degeneration in an array of disorders including stroke and AD arises from one or more alterations in calcium-regulating systems that result in a loss of cellular calcium homeostasis. A long-standing hypothesis of neuronal injury, the excitatory amino acid (EAA) hypothesis, is revisited in light of new supportive data concerning the roles of EAAs in stroke and the neurofibrillary degeneration in AD. Two quite new concepts concerning mechanisms of neuronal injury and death are presented, namely: 1) growth factors normally "stabilize" intracellular free calcium levels ([Ca2+]i) and protect neurons against ischemic/excitotoxic injury, and 2) aberrant processing of beta-amyloid precursor protein (APP) can cause neurodegeneration by impairing a neuroprotective function of secreted forms of APP (APPs) which normally regulate [Ca2+]i. Altered APP processing also results in the accumulation of beta-amyloid peptide which contributes to neuronal damage by destabilizing calcium homeostasis; in AD beta-amyloid peptide may render neurons vulnerable to excitotoxic conditions that accrue with increasing age (e.g., altered glucose metabolism, ischemia). Growth factors may normally protect neurons against the potentially damaging effects of calcium influx resulting from energy deprivation and overexcitation. For example, bFGF, NGF and IGFs can protect neurons from several brain regions against excitotoxic/ischemic insults. Growth factors apparently stabilize [Ca2+]i by several means including: a reduction in calcium influx; enhanced calcium extrusion or buffering; and maintenance or improvement of mitochondrial function. For example, bFGF can suppress the expression of a N-methyl-D-aspartate (NMDA) receptor protein that mediates excitotoxic damage in hippocampal neurons. Growth factors may also prevent the loss of neuronal calcium homeostasis and the increased vulnerability to neuronal injury caused by beta-amyloid peptide. Since elevated [Ca2+]i can elicit cytoskeletal alterations similar to those seen in AD neurofibrillary tangles, we propose that neuronal damage in AD results from a loss of calcium homeostasis. The data indicate that a variety of alterations in [Ca2+]i regulation may contribute to the neuronal damage in stroke and AD, and suggest possible means of preventing neuronal damage in these disorders.
TL;DR: This “trophic‐like” action of selegiline might account for the reported slowing of the progression of PD and AD and suggests that seLegiline therapy may be of value with acute nervous system damage, particularly damage caused by trauma.
Abstract: Selegiline [(-)-deprenyl] has been reported to slow the progression of disabling deficits in Parkinson's disease (PD) and cognitive decline in Alzheimer disease (AD). The apparent slowing has been proposed to be based on either symptomatic improvement due to increased dopaminergic neurotransmission or alternately on protection of neurons from damage caused by toxic oxidative radicals. Both mechanisms are hypothesized to result from the inhibition of monoamine oxidase type B (MAO-B) activity. Our experiments in two animal models have shown that selegiline has a second, previously unsuspected action. That is, selegiline can rescue neurons after they have sustained lethal damage and the rescue is independent of MAO-B inhibition. It was previously shown that the coadministration of selegiline with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could protect dopaminergic substantia nigra neurons (dSNns) from damage by blocking conversion of MPTP to its active radical N-methyl-4-phenylpyridinium (MPP+) by inhibiting MAO-B. In the first model, we treated C57BL mice with MPTP but delayed selegiline treatment for 72 h after the MPTP treatment to allow for complete conversion of MPTP to MPP+ and for maximal dSNn damage by MPP+. The delayed selegiline treatment rescued approximately 69% of the dSNns that had not died by the time the treatment began but were found to die with saline treatment. Selegiline doses that were too small to cause inhibition of MAO-B substrate oxidation rescued the MPTP-damaged dSNns. The second model was based on previous work showing that immature (14-day-old) rat facial motoneurons die after axotomy because of a loss of trophic support from the muscle they innervate. Selegiline treatment increased the number of motoneurons surviving axotomy from 24 to 52%, showing that selegiline can rescue neurons by partially compensating for the loss of target-derived trophic support. This "trophic-like" action of selegiline might account for the reported slowing of the progression of PD and AD and suggests that selegiline therapy may be of value with acute nervous system damage, particularly damage caused by trauma.
TL;DR: Changes in the lysosomal system are a sensitive morphologic indicator of certain types of metabolic distress; however, whether they reflect a salutary response of a compromised neuron or a mechanism to promote cell death and removal of debris from the brain remains to be established for most conditions.
Abstract: The lysosomal system has often been considered a prominent morphologic marker of distressed or dying neurons. Lysosomes or their constituent hydrolases have been viewed in different neuropathologic states as either initiators and direct agents of cell death, agents of cellular repair and recompensation, effectors of end-stage cellular dissolution, or autolytic scavengers of cellular debris. Limited data and limitations of methodology often do not allow these potential roles to be discriminated. In all forms of neurodegeneration, it may be presumed that lysosomes ultimately rupture and release various hydrolases that promote cell autolysis during the final stages of cellular disintegration. Beyond this perhaps universal contribution to cell death, the degree to which the lysosomal system may be involved in neurodegenerative states varies considerably. In many conditions, morphologic evidence for activation of the lysosomal system is minimal or undetectable. In other cases, lysosomal activation is evident only when other morphologic signs of cell injury are also present. This level of participation may be viewed as either an attempt by the neuron to compensate for or repair the injury or a late-stage event leading to cell dissolution. The early involvement of the lysosomal system in neurodegeneration occurs most commonly in the form of intraneuronal accumulations of abnormal storage profiles or residual bodies (tertiary lysosomes). Very often the lysosomal involvement can be traced to a primary defect or dysfunction of lysosomal components or to accelerated or abnormal membrane breakdown that leads to the buildup of modified digestion-resistant substrates within lysosomes. Because they are often striking, changes in the lysosomal system are a sensitive morphologic indicator of certain types of metabolic distress; however, whether they reflect a salutary response of a compromised neuron or a mechanism to promote cell death and removal of debris from the brain remains to be established for most conditions. Factors that may influence the lysosomal response during lethal neuronal injury include species differences, stage of neuronal development, duration of injury and pace of cell death. The lysosomal system may be more closely coupled to certain forms of neuronal cell death in lower vertebrate or invertebrate systems than in mammalian systems.
TL;DR: It is reported that a neuronal population exhibiting GABA-immunoreactivity is resistant to beta-amyloid-induced toxicity in vitro, a finding consistent with observations in the Alzheimer brain.
TL;DR: It is concluded that biologically delivered NGF protects neurons against excitotoxicity and mitochondrial blockade—both energy‐depleting processes—implying that appropriate neurotrophic support in the adult brain could protect against neurodegenerative diseases caused in part by energy depletion.
Abstract: Consistent with the notion that a defect in cellular energy metabolism is a cause of human neurodegenerative disease, systemic treatment with the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NPA) can model the striatal neurodegeneration seen in Huntington's disease. Previously, we have found that nerve growth factor (NGF), delivered biologically by the implantation of a genetically altered fibroblast cell-line, can protect locally against striatal degeneration induced by infusions of high doses of glutamate receptor agonists. We now report that implantation of NGF-secreting fibroblasts reduces the size of adjacent striatal 3-NPA lesions by an average of 64%. We conclude that biologically delivered NGF protects neurons against excitotoxicity and mitochondrial blockade—both energy-depleting processes—implying that appropriate neurotrophic support in the adult brain could protect against neurodegenerative diseases caused in part by energy depletion. © 1993 Wiley-Liss, Inc.
TL;DR: It is shown that a specific neurotrophic factor, nerve growth factor (NGF), acts to reverse Ts 16-induced atrophy of BFCNs and stimulates hypertrophy of these cells, suggesting that NGF may be useful in reversing cholinergic neurodegeneration in DS and AD.
Abstract: Atrophy and dysfunction of certain neurons, including cholinergic neurons in the basal forebrain, are key features of the neuropathology of Alzheimer's disease (AD). Since all individuals with Down syndrome (DS) develop AD neuropathology by the 4th decade, we reasoned that a genetic model of DS, the trisomy 16 (Ts 16) mouse, may provide an animal model to study the neurodegeneration in AD. Ts 16 mice fail to survive birth; to evaluate neurons for long periods in vivo required transplantation of fetal tissue. We previously demonstrated that Ts 16 basal forebrain cholinergic neurons (BFCNs) undergo age-related atrophy similar to DS and AD, and now show that a specific neurotrophic factor, nerve growth factor (NGF), acts to reverse Ts 16-induced atrophy of BFCNs and stimulates hypertrophy of these cells. As NGF levels were not decreased in the host, abnormalities intrinsic to Ts 16 BFCNs presumably caused the atrophy. Our results suggest that NGF may be useful in reversing cholinergic neurodegeneration in DS and AD.
TL;DR: It is concluded that dialytic delivery of 3.3 mumol quinolinic acid produces an area of neuronal destruction that resembles the selective neuronal loss seen in Huntington's disease.
TL;DR: The ability of BDNF to confer protection on cultured dopaminergic neurons against the neurotoxic effects of 6‐hydroxyDOPA (TOPA or 2,3,5,‐trihydroxyphenylalanine), a metabolite of the dopamine pathway suggested to participate in the pathology of Parkinson's disease is examined.
Abstract: Brain-derived neurotrophic factor (BDNF) supports the survival of sensory neurons as well as retinal ganglion cells, basal forebrain cholinergic neurons, and mesencephalic dopaminergic neurons in vitro. Here we examined the ability of BDNF to confer protection on cultured dopaminergic neurons against the neurotoxic effects of 6-hydroxyDOPA (TOPA or 2,3,5,-trihydroxyphenylalanine), a metabolite of the dopamine pathway suggested to participate in the pathology of Parkinson's disease. Cells prepared from embryonic day 14–15 rat mesencephalon were maintained with 10–50 ng/ml BDNF for 7 days prior to addition of TOPA (10–30 μM) for 24 hr. In BDNF-treated cultures, the extensive loss ( >90%) of tyrosine hydroxylase immunopositive cells was virtually ( 90%) of the overall cell population was limited to only a 25–30% recovery. Furthermore, the monosialoganglioside GM1 (1–10 μM), although inactive alone, acted synergistically with subthreshold amounts of BDNF to rescue tyrosine hydroxylase-positive cells against TOPA neurotoxicity. These results add impetus to exploring the therapeutic potential of gangliosides and BDNF in Parkinson's disease. © 1993 Wiley-Liss, Inc.
TL;DR: These experiments indicate that horizontal neurons are heterogeneous with respect to susceptibility to transformation and that T antigen expression in a subset of horizontal neurons can be a direct cause of neuronal cell death.
TL;DR: Characterization of the murine glutamate receptor family includes mapping of Glur-1 to the same region as neurological mutants spasmodic, shaker-2, tipsy, and vibrator on chromosome 11; GlUR-2 near spastic on chromosome 3; glur-6 near waltzer and Jackson circler on chromosome 10; andglur-7 near clasper on chromosome 4.
Abstract: Receptors for the major excitatory neurotransmitter glutamate may play key roles in neurodegeneration. The mouse Glur-5 gene maps to chromosome 16 between App and Sod-1. The homologous human GLUR5 gene maps to the corresponding region of human chromosome 21, which contains the locus for familial amyotrophic lateral sclerosis. This location, and other features, render GLUR5 a possible candidate gene for familial amyotrophic lateral sclerosis. In addition, dosage imbalance of GLUR5 may have a role in the trisomy 21 (Down syndrome). Further characterization of the murine glutamate receptor family includes mapping of Glur-1 to the same region as neurological mutants spasmodic, shaker-2, tipsy, and vibrator on chromosome 11; Glur-2 near spastic on chromosome 3; Glur-6 near waltzer and Jackson circler on chromosome 10; and Glur-7 near clasper on chromosome 4.
TL;DR: The results demonstrate a relationship between c-fos and HSP72 gene expression and suggest that prolonged co-expression of these genes plays a role in kainic acid-induced neuronal death.
Abstract: The relationship between heat shock protein 72 (HSP72) and c-fos gene expression following systemic administration of kainic acid was investigated by combining immunocytochemistry for HSP72 with in situ hybridization for c-fos. Increased HSP72 expression was detected in adult rat hippocampus 4 h after seizure-onset. Transient co-expression of c-fos and HSP72 occurred in neurons that are resistant to kainic acid, whereas prolonged co-expression was observed in vulnerable neurons. The spatial distribution and developmental time course of kainic acid-induced HSP72 expression were similar to those of kainic acid-induced neurodegeneration. The results demonstrate a relationship between c-fos and HSP72 gene expression and suggest that prolonged co-expression of these genes plays a role in kainic acid-induced neuronal death.
TL;DR: There is increasing evidence that the neurotoxic effects of excitatory amino acids and their analogues are part of the pathogenesis of neuronal degeneration in acute and chronic neurological disease and metabolic diseases in which excitatories alone or in combination with energy deficiency could play a pathogenetic role.
Abstract: There is increasing evidence that the neurotoxic effects of excitatory amino acids and their analogues are part of the pathogenesis of neuronal degeneration in acute and chronic neurological disease. Recent studies indicate that activation of excitatory amino acid receptors is also induced in the mechanism of neuronal damage induced by impairment of cellular energy metabolism. This article briefly summarizes the evidence for the presence of such a mechanism and discusses metabolic diseases in which excitatory amino acids alone or in combination with energy deficiency could play a pathogenetic role. In these and other metabolic diseases, antagonists to excitatory amino acid receptors may offer a therapeutic opportunity; however, there are potential limits that may prevent chronic use.
TL;DR: It is shown that transferrin, beta 2-microglobulin and heat shock 72 kD protein all increase in astrocytes in the course of infection and is speculated in the discussion on the possible functions of these and other proteins in neurodegenerative processes and why these functions so frequently reside in theAstrocyte.
TL;DR: The results indicate that both the overactivation and the abnormal degradation of PKC can lead to neuron degeneration, and that the neurotrophic competence of bFGF may reside in its ability to regulate and normalize the PKC phosphorylating system.
Abstract: Recent evidence suggests that protein kinase C (PKC) is involved in the pathophysiology of neurodegenerative diseases. We examined the effect of basic fibroblast growth factor (bFGF) on the survival of cultured rat hippocampal neurons exposed to conditions in which PKC is likely to play a role. bFGF reduced neuron damage caused by the PKC-activating phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), glutamate and ischaemia-like culture conditions. bFGF was able to counteract the excessive activation of PKC caused by these treatments. Moreover, bFGF prevented the loss of PKC occurring after prolonged exposure to TPA or ischaemia-like conditions. These results indicate that both the overactivation and the abnormal degradation of PKC can lead to neuron degeneration, and that the neurotrophic competence of bFGF may reside in its ability to regulate and normalize the PKC phosphorylating system.
TL;DR: It is shown that following heat shock, mouse‐derived C1300 N2A neuroblastoma cells contain increased levels of mRNA coding for the inducible form of heat shock protein 70 and for ubiquitin, suggesting that there is production of cytoprotective heat shock proteins in response to iron‐mediated cell damage, probably involving free radical generation, in neural cells.
Abstract: We have shown that following heat shock (42.5 degree C for 30 min), mouse-derived C1300 N2A neuroblastoma cells contain increased levels of mRNA coding for the inducible form of heat shock protein 70 and for ubiquitin. Incubation of C1300 cells with iron also induces an elevation in content of mRNAs coding for the same two proteins that can be blocked by alpha-tocopherol and desferrioxamine. Iron was shown to increase mitochondrial and lysosomal activities in differentiated C1300 N2A cultures, as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and neutral red cytotoxicity assays. These responses were not initially associated with any loss of viability, as assessed by the lactate dehydrogenase release assay. These results suggest that there is production of cytoprotective heat shock proteins in response to iron-mediated cell damage, probably involving free radical generation, in neural cells. The apparent stress response of vulnerable neurones in human neurodegenerative diseases, particularly Parkinson's disease, may be induced by iron-mediated free radical production in degenerating neurones, making investigation of the mechanism of free radical-induced responses in neuronal cells of special interest.
TL;DR: The theory and evidence in support of different mechanisms and possible strategies that might provide neuroprotection and interfere with the natural progression of Parkinson's disease are reviewed.
Abstract: The desire to introduce neuroprotective therapy for Parkinson's disease has begun to focus attention on pathogenetic mechanisms responsible for cell death. Considerable theory and some evidence have now accumulated to suggest that factors related to oxidative stress, mitochondrial bioenergetic defects, excitatory neurotoxicity, calcium cytotoxicity, and trophic factor deficiencies acting either singularly or in combination may contribute to the development of cell death in Parkinson's disease. A better understanding of the specific pathogenetic mechanism involved in cell degeneration might provide a scientific basis for testing a putative neuroprotective therapy. This chapter reviews the theory and evidence in support of these different mechanisms and possible strategies that might provide neuroprotection and interfere with the natural progression of Parkinson's disease.
TL;DR: Experimental studies indicate that NGF administration is able to counteract degenerative changes of cholinergic neurons and to stimulate presynaptic function of survivingCholinergic axons, which translates into functional changes at the postsynaptic level and associated behavioral functions.
Abstract: Publisher Summary This chapter discusses the pharmacology of nerve growth factor (NGF) in the brain. Neurotrophic factors regulate survival and growth of neurons, suggesting that these molecules may become useful in the treatment of neurodegeneration. NGF is the best-characterized neurotrophic factor and serves as paradigmatic example for other proteins. In the brain, NGF selectively acts on forebrain cholinergic neurons, which are involved in cognitive functions and degenerate in Alzheimer's disease. Detailed information is available on the pharmacologic effects of NGF in the brain of animals with experimental lesions of cholinergic systems. These studies indicate that NGF administration is able to counteract degenerative changes of cholinergic neurons and to stimulate presynaptic function of surviving cholinergic axons. These changes translate into functional changes at the postsynaptic level and associated behavioral functions.
TL;DR: In aged rats, basal forebrain cholinergic neurons show a substantial decline in their capacity to take up and retrogradely transport 125 I-labelled NGF from their target region, and neurons not transporting labelled NGF appear severely atrophic.