Showing papers on "Neurodegeneration published in 1990"

Spontaneous neurodegeneration in transgenic mice with mutant prion protein.

Abstract: Transgenic mice were created to assess genetic linkage between Gerstmann-Straussler-Scheinker syndrome and a leucine substitution at codon 102 of the human prion protein gene. Spontaneous neurologic disease with spongiform degeneration and gliosis similar to that in mouse scrapie developed at a mean age of 166 days in 35 mice expressing mouse prion protein with the leucine substitution. Thus, many of the clinical and pathological features of Gerstmann-Straussler-Scheinker syndrome are reproduced in transgenic mice containing a prion protein with a single amino acid substitution, illustrating that a neurodegenerative process similar to a human disease can be genetically modeled in animals.

The identification and suppression of inherited neurodegeneration in Caenorhabditis elegans.

Abstract: The dominant mutation deg-1(u38) results in a toxic gene product that leads to the late-onset degeneration of a small number of neurons in the nematode Caenorhabditis elegans. Both intragenic and extragenic mutations as well as changes in wild-type gene dosage can delay or block the time of onset of the neuronal deaths. The deg-1 gene has been cloned and a partial complementary DNA reveals that the gene encodes a novel protein that may act as a membrane receptor. Because the late-onset loss of specific sets of neurons, often as a result of dominant mutations, is characteristic of several human neurodegenerative diseases, the analysis of the deg-1 gene and its suppressors may provide a means of understanding the mechanisms underlying some of these human diseases.

Diffuse plaques do not accentuate synapse loss in Alzheimer's disease.

Abstract: Applying the relatively new technique of laser confocal imaging, vibratome sections which were double immunolabeled for amyloid beta protein and the presynaptic terminal marker synaptophysin were examined. It was found that while synaptic density was generally diminished in Alzheimer's disease (AD) cortical neuropil as compared to controls, the reduction was no greater within the diffuse plaques than outside them. Synapse loss was accentuated, however, within immature and mature plaques. These findings suggest that the pathogenetic process in AD might commence with synapse loss and neurodegeneration rather than with deposition of amyloid beta protein.

Distribution of calcium-activated protease calpain in the rat brain.

Abstract: Calpain is a calcium-activated neutral protease that degrades a number of cytoskeletal proteins. It may participate in the maintenance of the cytoskeleton and in the rapid turnover of structural proteins associated with synaptic plasticity. Calpain may also be involved in the neurodegeneration that accompanies aging and age-related diseases. To aid in the interpretation of disease-related alterations in staining patterns, the present study examined calpain's normal distribution in the mammalian brain and spinal cord. A monoclonal antibody was employed with the avidin-biotin-peroxidase immunocytochemical technique on samples of rat tissue. Glia (astrocytes, microglia) and virtually all neurons were immunopositive, although neuronal processes exhibited varying staining patterns. The axonal staining pattern depended upon either the origin or destination of the process: those axons remaining within the brain (e.g., corpus callosum) were only lightly immunoreactive, whereas spinal cord and peripheral axons (trigeminal nerve) were more darkly labeled. The architecture of the dendritic tree determined the dendritic staining pattern: neurons with prominent apical and basal dendritic trees (e.g., pyramidal cells) were immunolabeled along their entire extent; labeling of multipolar cells (e.g., hilar cells of dentate gyrus) was limited to the proximal dendrites. The ubiquitous distribution of calpain argues against a primary role for the enzyme in the regional pattern of neuronal death seen in Alzheimer's disease. An alteration in the concentration, localization, or inhibition of the enzyme could, however, lead to the abnormal accumulations of cytoskeletal elements seen with the disease.

Cholinergic Neurons of the Nucleus basalis Express Elevated Levels of Nerve Growth Factor Receptor mRNA in Senile Dementia of the Alzheimer Type

Abstract: Magnocellular cholinergic neurons in the nucleus basalis of Meynert (nbM) undergo a profound and selective degeneration in patients with senile dementia of the Alzheimer type (SDAT). We show by in sit

Neuronal cytoskeletal lesions induced in the CNS by intraventricular and intravenous aluminium maltol in rabbits.

Abstract: The antigenicity of neuronal cytoskeletal lesions was studied immunohistochemically in adult New Zealand white rabbits after intraventricular (subacute) and intravenous (chronic) administration of a water-soluble aluminium compound, aluminium (Al) maltol. After short-term intraventricular administration, rabbits developed widespread neurofibrillary degeneration (NFD) involving pyramidal neurons of the isocortex and allocortex, projection neurons of the diencephalon, and nerve cells of the brain stem and spinal cord. There was a predilection for motor neuron involvement and for the infratentorial portions of the neuraxis. Perikarya and proximal neurites were especially affected. Bundles of 10 nm filaments were frequently present. Three of the animals treated intravenously for 12 weeks or longer displayed NFD in the oculomotor complex and in the pyramidal neurons of the occipital isocortex. Following either mode of administration, the affected neurons exhibited immunostaining with a panel of monoclonal antibodies (MAbs) against phosphorylated (SMI-31), non-phosphorylated/phosphatase-sensitive (SMI-32), and dephosphorylation-independent (SMI-33) epitopes of high and middle molecular weight neurofilament (NF) protein subunits. They were non-reactive with MAbs to microtubule-associated protein 2 and the class III neuron-associated beta-tubulin isotype. Our findings indicate that intraventricular Al maltol produces similar, but more widespread degeneration of projection-type neurons than the less water-soluble Al compounds as reported by others. The NFD lesions are compared with those of senile dementia of the Alzheimer type (SDAT) and motor neuron disease.

Ubiquitin conjugate immunoreactivity in the brains of scrapie infected mice

Abstract: Sections of brain from normal mice or clinically-ill mice infected with either the 87V or the ME7 strains of sheep scrapie were immunostained to show the localization of ubiquitin-protein conjugates or a specific marker of disease, the scrapie-associated fibril protein (PrP) In both scrapie models immunoreactive ubiquitin-protein conjugates were seen in thread-like structures found throughout the neuropil, in inclusion bodies within vacuolated neurones, and in areas surrounding anti-PrP positive amyloid plaques The PrP protein was visualized in diffuse deposits in highly vacuolated parts of the scrapie-affected brain, and focally in amyloid plaques, microglia and neuronal processes The ubiquitin-protein conjugate staining of scrapie amyloid plaques is very similar to that seen in the plaques of Alzheimer's disease The ubiquitinated intraneuronal inclusion bodies seen in scrapie resemble the granulovacuolar lesions also seen in Alzheimer's disease, but appear much larger and possibly correspond to material in giant autophagic vacuoles We suggest that these inclusions may be the result of ubiquitinated abnormal proteins being directed to the lysosomal system, and that scrapie and Alzheimer's disease share at least some common processes of neurodegeneration

Excitatory amino acids, growth factors, and calcium: a teeter-totter model for neural plasticity and degeneration.

Abstract: This paper presents and examines the hypothesis that excitatory amino acids (EAAs) and growth factors (GFs) exert opposing actions on neuronal cytoarchitecture by influencing cellular Ca2+ homeostasis. This hypothesis is supported by experiments with cultured hippocampal pyramidal neurons in which EAAs induced dendritic regression and cell death, whereas fibroblast GF (FGF) promoted neurite outgrowth and cell survival. FGF protected against glutamate-induced neuronal degeneration by raising the threshold for the actions of this EAA. Pharmacological studies, and direct monitoring of intracellular Ca2+ levels, demonstrated that a sustained rise in intracellular Ca2+ levels was largely responsible for the degenerative actions of glutamate. FGF attenuated the Ca2+ response to glutamate. Experiments with glutamate, Ca2+ ionophore A23187, and Na(+)-deficient culture medium provided evidence that FGF can enhance Na(+)-dependent Ca2+ extrusion. These data suggest a model in which cell survival and neurite outgrowth in hippocampal neurons is regulated by the opposing actions of EAAs and GFs acting through the Ca2+ second messenger system. In this "teeter-totter" model the relative levels of input from EAAs and GFs determine whether a neuron lives or dies, and whether its outgrowth is in a progressive or regressive state. Interactions of EAAs and GFs may play important roles in: developmental events such as neurite outgrowth, synaptogenesis, and natural cell death; maintenance and plasticity of neural circuitry in the mature nervous system; and maladaptive neurodegeneration that occurs in aging and disorders such as Alzheimer's disease.

Tau protein and neurodegeneration.

Abstract: Many of the human neurodegenerative conditions involve a reorganization of the neuronal cytoskeleton. The way in which the cytoskeleton is reorganized may provide a clue to the nature of the insult causing the neurodegeneration. The most common of these conditions is Alzheimer's disease, in which microtubules are lost from neurites that fill up with filamentous structures. One component of the filamentous structures is the microtubule-associated protein (MAP), tau. The tau protein is the product of a single gene expressed predominantly in neurons. The tau gene undergoes complex alternative splicing that is regulated both by development, and by the particular neuronal cell population in which it is expressed. Tau protein can be further modified, following its translation by phosphorylation at several sites. Much of the recent interest in the transition of tau to an abnormal state within a tangle-bearing neuron has focused on phosphorylation. A group of proteins that migrate slightly more slowly than tau, designated PHF-tau, are found in regions of the Alzheimer brain rich in dystrophic neurites, are hyperphosphorylated, fail to bind to microtubules, have distinct solubility properties, and can be derived from fractions of paired helical filaments (PHF).

α 1 á-Antichymotrypsin

Abstract: Normal brain aging, Alzheimer’s disease, and Down’s syndrome are all characterized by similar neuropathological lesions. Such neuropathology is much more severe and occurs at much earlier ages in Alzheimer’s disease and Down’s syndrome than in normal aging and suggests that these diseases should be studied as model systems of a more widespread problem. In addition, the fact that Alzheimer’s disease arises repeatedly in certain families in which it appears to be passed down from generation to generation as an autosomal-dominant trait indicates that mutation in a single gene can lead to the disease (Heston et al., 1981; for reviews, Matsuyama et al., 1985; Jarvik and Matsuyama, 1986). The same neurodegeneration, loss of memory, and neuropathological lesions characterize both these familial and the more common sporadic cases of Alzheimer’s disease (Terry 1978a,b; Heston et al., 1981; McKahnnet al., 1984). Therefore, the study of an aberrant protein in inherited Alzheimer’s disease might lead to an understanding of the biochemical mechanism for the generation of the disease in certain families, and by extension, perhaps all other cases as well. Furthermore, an understanding of the physiological basis of the disorder should be directly relevant to understanding the process of normal aging.

The Role of Proteases and Their Inhibitors in the Amyloid Deposition of Alzheimer's Disease and Normal Brain Aging

Abstract: Nonnal brain aging, Alzheimer's disease, and Down's syndrome are all characterized by similar neuropathological lesions. Such neuropathology is much more severe and occurs at much earlier ages in Alzheimer's disease and Down's syndrome than in nonnal aging and suggests that these diseases should be studied as model systems of a more widespread problem. In addition, the fact that Alzheimer's disease arises repeatedly in certain families in which it appears to be passed down from generation to generation as an autosomal-dominant trait indicates that mutation in a single gene can lead to the disease (Heston et al., 1981; for reviews, Matsuyama et al., 1985; Jarvik and Matsuyama, 1986). The same neurodegeneration, loss of memory, and neuropathological lesions characterize both these familial and the more common sporadic cases of Alzheimer's disease (Terry 1978a,b; Heston et al., 1981; McKahnn et al., 1984). Therefore, the study of an aberrant protein in inherited Alzheimer's disease might lead to an understanding of the biochemical mechanism for the generation of the disease in certain families, and by extension, perhaps all other cases as well. Furthermore, an understanding of the physiological basis of the disorder should be directly relevant to understanding the process of nonnal aging. The approach we have taken to studying the biochemical basis of Alzheimer's disease and nonna! aging is to isolate the genes that code for key proteins involved in the neurodegenerative process. It may then be possible to deduce the functions of the proteins encoded by these genes from their derived amino acid sequence. The fact that inherited cases of Alzheimer's indicate that a single protein that is abnonnal in structure or amount is alone sufficient to cause disease makes isolating the gene for such a protein of particular interest.

Gene Activity and Neurodegeneration in the Extrapyramidal System: A Progress Report on Molecular and Morphological Correlates

Abstract: Functional neuronal plasticity and synaptic remodelling appear to be consistent feature of aging brain (Coleman et al., 1986). However, even in the absence of overt neuropathology, heterogeneous atrophic changes may occur in the brain with advancing age, suggesting differential mechanisms on specific brain regions, even in the same anatomical structure. For example hippocampal dentate granule neurons apparently remain intact and show hypertrophy of dendritic processes and increased perikaryal size in the aged brain (Coleman and Flood, 1987). Nonetheless many others e.g., pyramidal neurons of the hippocampus (Ringborg 1966) and cerebral cortex (Peters et al., 1987) show reduced perikaryal RNA content and decreased size of their perikarya, nuclei, or nucleoli. In addition, the nucleolar shrinkage is less in human locus ceruleus (LC) than substantia nigra (s.nigra) neurons (Mann and Yates, 1979), further confirming the cellular selectivity of changes. These studies support the general concept that age-related neuronal atrophic changes is not an universal or inevitable characteristic of the senescence, but may be brain region, cell type, and species specific.