Showing papers on "Neurodegeneration published in 1989"

Fibroblast growth factor and glutamate: opposing roles in the generation and degeneration of hippocampal neuroarchitecture

Abstract: Neuritic regression and cell death (neurodegeneration) are common features of both normal nervous system development and neurodegenerative disorders. Growth factors and excitatory amino acid neurotransmitters have been suggested independently to play roles in neurodegenerative processes. The present study investigated the combined effects of fibroblast growth factor (FGF) and glutamate on the development and degeneration of cultured hippocampal neurons. Consistent with previous data, we found that FGF, but not NGF, promoted neuronal survival and dendritic outgrowth. In contrast, a low level of glutamate (50 microM) caused a reduction in dendritic outgrowth, and high levels (100 microM-1 mM) reduced neuronal survival in a dose-dependent manner. When cultures were maintained in the presence of FGF, there was a striking reduction in neuronal death normally caused by 100-500 microM glutamate. FGF raised the threshold for glutamate neurotoxicity. FGF also antagonized the outgrowth-inhibiting actions of glutamate. Measurements of intracellular calcium levels with fura-2 demonstrated a direct relationship between glutamate-induced rises in intracellular calcium and neurodegeneration. FGF reduced the glutamate-induced increases in intracellular calcium levels. However, when cultures were pretreated with the RNA synthesis inhibitor actinomycin D or with the protein synthesis inhibitor cycloheximide, FGF did not prevent glutamate-induced increases in intracellular calcium or neurodegeneration. Taken together, these results suggest that (1) interactions between growth factors and neurotransmitters may be important in brain development; (2) imbalances in these systems may lead to neurodegeneration; and (3) cellular calcium-regulating systems may be a common focus of growth factor and neurotransmitter actions.

Intrinsic factors in the selective vulnerability of hippocampal pyramidal neurons.

Abstract: Selective degeneration of pyramidal neurons in regions CA1 and CA3 of the hippocampus is a common structural correlate of several neurodegenerative conditions including Alzheimer's disease, epilepsy and stroke. Several lines of evidence suggest that glutamate, an excitatory neurotransmitter intimately involved in learning and memory processes, may also be involved in hippocampal neurodegeneration. High levels of glutamate are toxic to select groups of pyramidal neurons both in vivo and in vitro and subtoxic levels of glutamate can cause the regression of pyramidal neuron dendrites. In order to determine the basis for this selective vulnerability we employed two rat hippocampal culture paradigms. The first paradigm consisted of neurons isolated from different hippocampal regions (CA1, CA2, CA3, dentate gyrus). Selective vulnerability in the isolated neurons mirrored the selective cell loss that occurs in situ. Dentate granule cells and CA2 pyramidal-like neurons were relatively resistant to glutamate-induced neurodegeneration, while CA1 and CA3 pyramidal neurons were significantly more vulnerable. The second paradigm consisted of sister pyramidal neurons arising from a common progenitor cell. Sister neurons were found to be either both sensitive or both resistant to the degenerative effects of glutamate indicating that mitotic history was an important determinant of selective vulnerability. Experiments which examined the cellular mechanisms underlying selective vulnerability revealed that glutamate caused a large and sustained rise in intracellular calcium levels only in vulnerable neurons. Pharmacological experiments with glutamate receptor antagonists, the inhibitory transmitter GABA, and calcium blockers indicated that vulnerable, but not resistant, neurons expressed glutamate receptors which mediated large rises in intracellular calcium and subsequent degeneration. These results indicate that intrinsic differences in the expression of glutamate receptors linked to calcium influx may account for selective neuronal vulnerability. Treatments which block glutamate receptors, suppress electrical activity, or block calcium channels directly may prove useful in preventing the degeneration of the hippocampal circuitry whose integrity is critical for learning and memory processes.

Roles for mitotic history in the generation and degeneration of hippocampal neuroarchitecture.

Abstract: The mechanisms regulating the highly ordered neuroarchitecture of the mammalian brain are largely unknown. The present study took advantage of hippocampal pyramidal-like neurons that arose from a common progenitor cell in cell culture (sister neurons) to ascertain the contribution of intrinsic factors to both the generation and degeneration of neuroarchitecture. Sister neurons were similar in overall cell form and dendritic numbers and lengths. Control non-sister neurons that grew in contact did not generate similar morphologies, indicating that the similarity of sister cells did not result from influences of the local microenvironment or cell interactions. These results suggest that intrinsic factors related to mitotic history play a role in the generation of neuroarchitecture. Since particular groups of hippocampal neurons are sensitive to glutamate neurotoxicity in situ and are vulnerable in neurodegenerative disorders, it was of interest to test glutamate sensitivity in the neuronal population and in mitotic sister neurons. A subpopulation of pyramidal neurons was sensitive to glutamate neurotoxicity. A striking finding was that sister neurons were invariably either both sensitive or both resistant to glutamate, while non-sister neurons often showed different responses to glutamate. Pharmacological studies indicated that glutamate neurotoxicity was mediated by kainate/quisqualate type receptors by a mechanism involving calcium influx through membrane channels. Fura-2 measurements of intracellular calcium revealed that sister neurons had similar rest levels of calcium and, strikingly, glutamate caused a dramatic increase in intracellular calcium levels only in neurons which subsequently degenerated. Apparently, intrinsic differences in sensitivity to glutamate lie at a point prior to calcium entry, probably at the level of glutamate receptors. Taken together, these results indicate that the mitotic history of a neuron can determine its presence and potential for connectivity as well as its susceptibility to neurodegeneration.

Increase in kynurenic acid in Huntington's disease motor cortex.

Abstract: Huntington's disease is a neurological disorder characterised by a progressive chorea and dementia. Recent evidence has suggested that dysfunction involving endogenous excitatory amino acids may be important in the pathogenesis of this disease. Following the recent demonstration that kynurenic acid is present in the brain, we examined the levels in various areas of brain from patients who died with Huntington's disease and from age/sex-matched controls. Blocks (100-500 mg) of cortex (Brodmann's areas 4 and 10) and caudate nucleus and globus pallidus (lateral and medial parts) were obtained from the Cambridge Brain Bank. The tissue was then processed for the extraction and analysis of kynurenic acid. Whereas no differences in the content of kynurenic acid were observed in the caudate nucleus, lateral or medial globus pallidus, or prefrontal cortex (area 10) between controls' brains and those from patients who died with Huntington's disease, there was a 94% (p less than 0.01; n = 5) increase in the kynurenic acid content in the motor cortex (area 4) from Huntington's disease brains, relative to those of controls. Some time ago we suggested that a subtle change in the relative concentrations of quinolinic and kynurenic acids might be important in the pathogenesis of neurodegeneration. It is possible that the observation of raised kynurenic acid levels supports this supposition. Further work is now in progress to determine whether the change in kynurenic acid is a primary effect or a compensatory response to an increase in excitatory activity.

Endoplasmic reticulum abnormality in Alzheimer's disease: selective alteration in platelet NADH-cytochrome c reductase activity.

Abstract: Previous evidence suggests that the increase in platelet membrane fluidity associated with a subgroup of patients with Alzheimer's disease results from the accumulation of internal membrane. The specific activities of enzyme markers for selective cell membrane compartments were compared in platelets from subgroups of demented patients with normal or increased fluidity as well as from normal control subjects. A statistically significant change in enzyme activity was observed only for antimycin A-insensitive NADH-cytochrome reductase, a selective marker for smooth endoplasmic reticulum (SER) in platelets. This reduction was limited to the subgroup of demented patients who had increased platelet membrane fluidity, and therefore is not a nonspecific concomitant of neurodegeneration, medication exposure, or chronic illness in general. Since the platelet membrane alteration associated with Alzheimer's disease results from the inheritance of a single major locus, these results suggest that a defect in SER function may exist in brain cells as well as peripheral cells that express this genotype.

Calcium-Induced Neuronal Degeneration: A Normal Growth Cone Regulating Signal Gone Awry (?)

Abstract: The neuronal growth cone is involved in neurite elongation, directional pathfinding, and target recognition. These activities are essential for proper assembly of functional circuits within the developing nervous system, for regeneration of functional circuitry following damage, and also, perhaps, for remodeling of the nervous system in response to environmental stimuli. Our studies of both molluscan and mammalian neurons in culture have shown that neurite outgrowth can only proceed when intracellular calcium levels lie within a specific outgrowth-permissive range. Cessation of outgrowth can be induced by a variety of signals normally used for communication within the adult nervous system, including neurotransmitters, and action potentials; all of these signals elevate levels of intracellular calcium above the outgrowth-permissive range. For example, glutamate, whether added to the medium or released from co-cultured entorhinal explants, can selectively inhibit dendritic outgrowth. Conversely, inhibitory neurotransmitters can block the outgrowth-inhibitory effects of glutamate and actually promote expansion of dendritic arbors. Dendritic outgrowth is therefore regulated by a balance between excitatory and inhibitory neurotransmitter activity. Extreme excitatory imbalance in neurotransmitter input to pyramidal neurons causes cell death. Each of these changes in neuroarchitecture is mediated by changes in levels of intracellular calcium. We therefore put forward the hypothesis that key mechanisms which normally control the development and plasticity of neural circuitry, are also involved in neurodegeneration. Local, moderate elevations in calcium result in dendritic pruning. Higher, global elevations in calcium result in cell death. This cell death may serve an important function during normal development; aging may result in the same mechanism being employed pathologically. When intracellular calcium levels are not regulated within normal limits, as may occur in aging, neurodegeneration may occur.

Altered Protein Kinase and Amyloid ß-Protein Precursor in Alzheimer’s Disease: Which Comes First?

Abstract: AD is a neurodegenerative disease characterized by the formation of neuronal inclusions, termed NFT, and extracellular amyloid deposits surrounded by dystrophic neuntes, collectively referred to as NP. NP are specific to AD, whereas NFT are found in many other neurodegenerative diseases. The purpose of this report is to present a hypothesis regarding the biochemical basis for these pathologic features of AD — neurodegeneration and NFT and NP formation.