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Showing papers on "Neurodegeneration published in 1992"


Journal ArticleDOI
TL;DR: It is concluded that the phospholipid abnormalities described here are not an epiphenomenon of neurodegeneration and that they may be specific for the pathomechanism of Alzheimer disease.
Abstract: To determine whether neurodegeneration in Alzheimer disease brain is associated with degradation of structural cell membrane molecules, we measured tissue levels of the major membrane phospholipids and their metabolites in three cortical areas from postmortem brains of Alzheimer disease patients and matched controls. Among phospholipids, there was a significant (P less than 0.05) decrease in phosphatidylcholine and phosphatidylethanolamine. There were significant (P less than 0.05) decreases in the initial phospholipid precursors choline and ethanolamine and increases in the phospholipid deacylation product glycerophosphocholine. The ratios of glycerophosphocholine to choline and glycerophosphoethanolamine to ethanolamine were significantly increased in all examined Alzheimer disease brain regions. The activity of the glycerophosphocholine-degrading enzyme glycerophosphocholine choline-phosphodiesterase was normal in Alzheimer disease brain. There was a near stoichiometric relationship between the decrease in phospholipids and the increase of phospholipid catabolites. These data are consistent with increased membrane phospholipid degradation in Alzheimer disease brain. Similar phospholipid abnormalities were not detected in brains of patients with Huntington disease, Parkinson disease, or Down syndrome. We conclude that the phospholipid abnormalities described here are not an epiphenomenon of neurodegeneration and that they may be specific for the pathomechanism of Alzheimer disease.

524 citations


Journal ArticleDOI
TL;DR: The data suggest that cellular systems for calcium homeostasis are integral to both the adaptive and aberrant neuroarchitectural changes that occur throughout the lifespan of the nervous system.

260 citations


Journal ArticleDOI
TL;DR: The presence of CaBP28K may protect neurons from calcium-mediated neurotoxicity, and Immunocytochemical characterization of the substantia nigra of the MPTP-treated mice revealed that there was significant dopaminergic cell loss in this brain area after MPTP treatment.

196 citations


Journal ArticleDOI
TL;DR: The emerging neurobiology of SGP-2 encompasses the subjects of cell death, synaptic remodelling, neuroendocrinology and neurodegenerative diseases, and is consistent with sequence data that predict binding of dinucleotides, heparin and lipids.

176 citations


Journal ArticleDOI
TL;DR: This pathological accumulation of APP is consistent with alterations of APP recently described in other models of neurodegeneration and implies a role for this protein in the response to CNS injury.

174 citations


Journal ArticleDOI
TL;DR: It is hypothesized that excess glucocorticoid activation and neuronal calcium dysregulation may be two phases of a single process that increases the susceptibility of neurons to neurodegeneration during aging and Alzheimer's disease.
Abstract: This paper reviews evidence that brain aging and Alzheimer's disease (AD) are somehow closely related and that the hippocampus (CA1) is highly vulnerable to cell loss under both conditions. In addition, two current lines of evidence on the mechanisms of hippocampal cell loss with aging are considered, including studies of neuronal calcium dysregulation and studies of cumulative glucocorticoid (GC) neurotoxicity. Moreover, recent electrophysiological studies have shown that excess glucocorticoid activation of hippocampal neurons increases the influx of calcium through voltage-activated calcium channels. Second messenger systems may mediate the steroid modulation of calcium channels. Therefore, it is hypothesized that excess glucocorticoid activation and neuronal calcium dysregulation may be two phases of a single process that increases the susceptibility of neurons to neurodegeneration during aging and Alzheimer's disease.

126 citations


Journal ArticleDOI
TL;DR: It is conceivable therefore that regardless of whether oxidative stress or mitochondrial damage represents the initial insult, these toxic mechanisms may both contribute to neuronal degeneration via changes in glutathione levels.
Abstract: Several links exist between the two mechanisms of neuronal degeneration (i.e., oxygen radical production and mitochondrial damage) proposed to have a role in Parkinson's disease. Indeed, mitochondria are critical targets for the toxic injury induced by oxygen radicals, and experimental evidence suggests that mitochondrial damage may cause an increased generation of oxygen radicals. A potentially important link between these two mechanisms of neurodegeneration is glutathione. Because of the scavenging activity of glutathione against accumulation of oxygen radicals, its decrease in the brains of parkinsonian patients has been interpreted as a sign of oxidative stress; however, this change may also result from or lead to mitochondrial damage. It is conceivable therefore that regardless of whether oxidative stress or mitochondrial damage represents the initial insult, these toxic mechanisms may both contribute to neuronal degeneration via changes in glutathione levels.

115 citations


Journal ArticleDOI
TL;DR: It is reported that simple beta-carbolines derived from tryptophan or related open chain indoles, when specifically methyl-substituted on both available nitrogens, display mitochondrial inhibitory potencies and neurotoxic effects in vitro (PC12 cultures) and in vivo (striatal microdialysis) which approach or even surpass MPP+.

104 citations


Journal ArticleDOI
TL;DR: It is demonstrated that intraventricular injection of 130 ng deferoxamine to rats prior to 250 μg of 6‐OHDA partially prevented the decrease in striatal dopamine content caused by 6‐ OHDA, and this protection was sufficient to produce normal dopamine‐related behavioral responses.
Abstract: Recent studies in Parkinson's disease suggest that the degeneration of the nigrostriatal melanin-containing dopaminergic neurons results from toxic effects of free radicals, which are generated during dopamine metabolism in the substantia nigra (SN). This has been linked to the selective accumulation of iron, a known catalyst of radical formation, in the zona compacta of the SN. We have shown that interaction of iron with melanin may result in a high affinity binding of iron to melanin (KD = 13.0 +/- 0.15 nM). Indeed, x-ray analysis of melanized dopamine neurons of parkinsonian SN has shown an interaction of iron with melanin that is absent in control brains. In the presence of excess Fe3+, melanin potentiates iron-induced lipid peroxidation. Since iron chelators prevent lipid peroxidation, we have ascertained the ability of the iron chelator deferoxamine to prevent the lesion of the nigrostriatal dopamine neuron induced by 6-hydroxy dopamine (6-OHDA). Our results demonstrated that intraventricular injection of 130 ng deferoxamine to rats prior to 250 micrograms of 6-OHDA partially prevented the decrease in striatal dopamine content caused by 6-OHDA (56% reduction vs 90%, respectively). This protection was sufficient to produce normal dopamine-related behavioral responses. These results suggest that iron and iron chelators play a crucial role in the process of dopaminergic neurodegeneration and neuroprotection. The latter is further supported by our recent findings that intranigral injection of iron (50 micrograms) resulted in a substantial selective decrease of striatal dopamine (95%) and impaired dopamine-related responses.

93 citations


Journal ArticleDOI
TL;DR: The results suggest that the carboxyl-terminal fragment of beta APP may cause specific neuropathology and neurodegeneration in vivo.
Abstract: PC12 cells transfected with retroviral recombinants expressing the carboxyl-terminal 104 amino acids of the Alzheimer amyloid protein precursor (beta APP-C104) or PC12 cells transfected with the retroviral vector (DO) alone were transplanted into the brains of newborn mice. At 20 days after grafting, transplants could be detected in all of the mouse brains examined. At 4 months after transplantation, experimental animals exhibited significant cortical atrophy. Some also revealed immunoreactivity with Alz-50, an antibody that detects an Alzheimer disease-related protein, in the somatodendritic domain of neurons in the cortex surrounding the transplants. In addition, disorganization of the neuropil in the CA2/3 region of the hippocampus ipsilateral to the transplant was revealed by staining with an antibody to the carboxyl-terminal end of the amyloid protein precursor. A decrease in cell body immunoreactivity for this portion of the amyloid protein precursor was also detected with this antibody. Together, these results suggest that the carboxyl-terminal fragment of beta APP may cause specific neuropathology and neurodegeneration in vivo.

88 citations


Journal ArticleDOI
TL;DR: It is suggested that aggregation of the peptide and physical displacement of tissue may be responsible for both the neuronal and tissue loss, although this hypothesis is not consistent with other published findings.

Journal ArticleDOI
TL;DR: A genetic pathway for programmed cell death which includes genes that perform such functions as the determination of which cells die, the execution of cell death, the engulfment of cell corpses, and the digestion of DNA from dead cells is defined.
Abstract: In C. elegans, cell death can be readily studied at the cellular, genetic, and molecular levels. Two types of death have been characterized in this nematode: (1) programmed cell death, which occurs as a normal component in development; and (2) pathological cell death which occurs aberrantly as a consequence of mutation. Analysis of mutations that disrupt programmed cell death in various ways has defined a genetic pathway for programmed cell death which includes genes that perform such functions as the determination of which cells die, the execution of cell death, the engulfment of cell corpses, and the digestion of DNA from dead cells. Molecular analysis is providing insightinto the nature of the molecules that function in these aspects of programmed cell death. Characterization of some genes that mutate to induce abnormal cell death has defined a novel gene family called degenerins that encode putative membrane proteins. Dominant alleles of at least two degenerin genes, mec-4 and deg-1, can cause cellular swelling and late onset neurodegeneration of specific groups of cells. © 1992 John Wiley & Sons, Inc.

Journal ArticleDOI
TL;DR: It is suggested that an interaction between growth factors and excitotoxins can dramatically modify patterns of selective neuronal death in Huntington's disease.

Journal ArticleDOI
TL;DR: It is shown that beta APP-C104 synthesized in vitro binds specifically and with high affinity to the surface of NGF-treated PC12 cells and is dependent at least in part on the presence of a tyrosine residue that is a potential site of phosphorylation at the carboxy terminus of the fragment.
Abstract: One of the hallmarks of Alzheimer's disease neurodegeneration is the accumulation of deposits of amyloid in neuritic plaques and in the cerebral vasculature. Recent studies have implicated carboxy-terminal fragments of the Alzheimer amyloid precursor protein (beta APP) in the processes of amyloidogenesis and neurodegeneration. In particular, the carboxy-terminal 104 amino acids of beta APP (beta APP-C104) have been shown to cause amyloid-like fibrils when expressed in non-neuronal cells and to cause the degeneration of neuronal cells. These data suggest that it may play a role in the development of the progressive neuropathology of Alzheimer's disease. We hypothesized that beta APP-C104 may cause the degeneration of neurons by interacting with a cell surface receptor. In the present report, we show that beta APP-C104 synthesized in vitro binds specifically and with high affinity to the surface of NGF-treated PC12 cells. Both the cell surface binding and the neurotoxicity of beta APP-C104 are pH dependent and are not inhibited by tachykinins. Mutational analysis suggests that both the binding and the neurotoxicity are dependent at least in part on the presence of a tyrosine residue that is a potential site of phosphorylation at the carboxy terminus of the fragment.

Journal ArticleDOI
Mayer Rj1, Michael Landon1, L. Laszlo1, Julia Lowe1, G. Lennox1 
TL;DR: It is now appropriate to consider therapeutic manipulation of the lysosomal system as an approach to treatment for the treatment of neurodegeneration.

Journal ArticleDOI
TL;DR: Mouse trisomy 16 provides a model of spontaneous, genetically determined neurodegeneration that may be used to understand better the molecular pathogenesis of neuronal dysfunction in Alzheimer disease and Down syndrome.
Abstract: Vulnerability of specific brain regions and neuronal populations is a characteristic feature of Alzheimer disease and Down syndrome. Cholinergic neurons of the basal forebrain degenerate in both disorders. The basis for neuronal degeneration is unknown. Mouse trisomy 16 (Ts 16) is an animal model of Down syndrome. We sought an experimental system in which the survival and development of Ts 16 basal forebrain cholinergic neurons could be examined beyond the fetal period. As Ts 16 mice do not survive birth, we transplanted fetal Ts 16 and control basal forebrain into the hippocampus of young adult mice. Transplanted neurons survived and grew neurites in all grafts. Over time, we observed selective atrophy of cholinergic neurons in Ts 16 grafts. Denervation of the hippocampus produced a significant increase in the size of Ts 16 cholinergic neurons. This suggests that hippocampal-derived neurotrophic factors acted to prevent degeneration. beta/A4-amyloid-containing plaques were not seen. Ts 16 provides a model of spontaneous, genetically determined neurodegeneration that may be used to understand better the molecular pathogenesis of neuronal dysfunction in Alzheimer disease and Down syndrome.

Journal ArticleDOI
TL;DR: DNA repair appears important to maintain the functional integrity of the nervous system and an accumulation of DNA damages in neurons as a result of impaired DNA repair mechanisms may lead to neuronal degenerations.

Book ChapterDOI
TL;DR: Alzheimer's disease may represent an example of a disorder in which the body's response contributes significantly and perhaps essentially to the final pathology, whereas the initial insult is, by itself, of relatively minor consequence.
Abstract: Publisher Summary The chapter discusses how astrocytes are involved in the neurodegeneration of Alzheimer's disease. Specifically, it appears that the astrocytes participate in “acute phase response” in the Alzheimer brain, similar to the acute phase response that is mounted in the periphery in response to various types of inflammation. Indeed, much of the neuronal damage that occurs in Alzheimer's disease arises as much from this brain acute phase response as from the initial insult. The particular astrocytic contribution includes the overproduction of the acute phase protein α 1 -antichymotrypsin (ACT), which then becomes an intimate component of the Alzheimer amyloid deposits themselves. The interactive contribution of astrocytes and neurons to Alzheimer's disease reflects a parallel intimate balance between proteases and protease inhibitors involved in the production of amyloid. It appears that Alzheimer pathology and neuronal degeneration result from both β-A4 production, probably of neuronal origin, coupled with an acute phase astrocytic response to the initial P-A4 deposits. Together, these lead to the development of mature Alzheimer amyloid. Thus, Alzheimer's disease may represent an example of a disorder in which the body's response contributes significantly and perhaps essentially to the final pathology, whereas the initial insult is, by itself, of relatively minor consequence.

Journal ArticleDOI
TL;DR: There was a high correlation between glial cell count and3H-L-deprenyl binding with a relation indicating enhanced MAO-B protein in glial cells within areas of neurodegeneration.
Abstract: The present investigation has applied quantitative autoradiography and histochemistry to study the regional distribution of MAO-B and its relation to the number of cells in respective regions. L-deprenyl binds irreversibly and quantitatively to the B-form of monoamine oxidase, MAO, and is an ideal3H-ligand to measure the MAO-B enzyme protein in tissues by means of in vitro autoradiography. The investigation is performed on spinal sections from five controls and five cases with amyotrophic lateral sclerosis (ALS) on cervical, thoracic and lumbar level. The highest density of3H-L-deprenyl binding was found around the central canal (lamina X). MAO-B was markedly increased (up to 2.5 times of values in controls) specifically in regions of neurodegeneration e.g. motor neuron laminae and corticospinal tracts. There was a high correlation between glial cell count and3H-L-deprenyl binding with a relation indicating enhanced MAO-B protein in glial cells within areas of neurodegeneration. In contrast the increased microglial cell number in ALS did not show any correlation with3H-L-deprenyl binding.

Journal ArticleDOI
TL;DR: In the review, some examples that may provide new avenues for treatment or altering the course of infections are focused on, i.e., antibodies to fusogenic virus membrane proteins, drugs that interfere with lipid metabolism, calcium channel blockers, immunoregulatory molecules, and, and inhibitors of excitotoxic amino acids.
Abstract: Viruses have the capacity to induce alterations and degenerations of neurons by different direct and indirect mechanisms. In the review, we have focused on some examples that may provide new avenues for treatment or altering the course of infections, i.e., antibodies to fusogenic virus membrane proteins, drugs that interfere with lipid metabolism, calcium channel blockers, immunoregulatory molecules, and, and inhibitors of excitotoxic amino acids. Owing to their selectivity in attack on regions of nervous tissue, governed by viral factors and by routes of invasion, viral receptors or metabolic machineries of infected cells, certain viral infections show similarities in distribution of their resulting lesions in the nervous system to that of the common human neurodegenerative diseases (namely, motor neurons disease, Parkinson’s disease, and Alzheimer’s disease). However, it should be emphasized that no infectious agent has as yet provided a complete animal model for any of these diseases, nor has any infectious agent been linked to them from observations on clinical or postomortem materials.

Journal ArticleDOI
TL;DR: The present data suggest that high levels of PCP can disrupt the normal development of neural circuitry in the human fetus, which would be expected to result in profound functional impairments.

Journal ArticleDOI
Robert Siman1
TL;DR: The overviews of calpain I and of excitotoxicity will be followed by a critical discussion of the evidence that an excitOToxic mechanism may play a part in the neurodegeneration associated with AD.
Abstract: Proteases are now recognized to participate not only in the “housekeeping” function of protein turnover, but also in a number of dynamic cellular processes as well. Among the latter, there is an increasing body of evidence implicating a variety of proteases and their inhibitors in mediating structural change in the nervous system. For the most part, proteolytic mechanisms have been implicated in nervous system developmental processes, such as axon outgrowth, neuronal adhesive and migratory phenomena, and other manifestations of the terminal differentiation of nerve cells. These studies are summarized in TABLE 1. It is an intuitively attractive possibility that irreversible degradative enzymes such as proteases, in addition to mediating neuroplastic developmental structural change, may also participate in irreversible degenerative processes in neurons. However, only very recently have cell culture and animal systems relevant to Alzheimer’s disease (AD) been established, and our understanding of the involvement of biochemical processes such as proteolysis in producing the neuropathologies of AD is just beginning to emerge. Instead, there has been considerable interest for a number of years in a proteolytic mechanism which may mediate a type of neurodegeneration referred to as “excitotoxicity.”1-3 Specifically, activation of calpain I, an intraneuronal calciumdependent cysteine protease, has been suggested to be an obligatory step in the excitotoxic process. Calpain I has been the subject of recent review,'^^ as has its involvement in excitotoxicity,6.’ and so these topics will only be briefly outlined in the present paper. The overviews of calpain I and of excitotoxicity will be followed by a critical discussion of the evidence that an excitotoxic mechanism may play a part in the neurodegeneration associated with AD. The discussion will highlight areas in which further advances are required in order to more definitively evaluate mechanisms which may underlie AD neurodegeneration.

Journal Article
TL;DR: The results suggest that an abnormal production or accumulation of TOPA or its oxidation product(s) might be involved in excitotoxicity directed to areas of the brain with dopaminergic innervation, and in other brain areas in Parkinson's disease patients on long-term dopa therapy.
Abstract: The neurotoxic properties of 2,4,5-trihydroxyphenylalanine (TOPA; the 6-hydroxylated derivative of dopa) was investigated in cultures of central neurons. Application of solutions of TOPA to cerebellar granule cells resulted in a concentration- and time-dependent neuronal death, with prolonged (24 hr) exposure producing a clear left-handed shift in the dose-response relationship from the one observed with a 60-min exposure (LD50: 4 and 29 microM, respectively). This toxicity was largely blocked by the non-N-methyl-D-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Solutions of TOPA were also toxic to mesencephalic neurons after acute or chronic exposure, displaying the same leftward shift in LD50. This latter preparation contained a minor population of dopaminergic, tyrosine hydroxylase immunopositive cells which were likewise sensitive to the excitotoxic effects of TOPA. Neurotoxic activity of TOPA appeared to depend upon its oxidation in solution, as judged using chemical analysis and reducing agents. The monosialoganglioside GM1 was effective in protecting against neurodegeneration induced by brief or prolonged exposure to solutions of TOPA. These results suggest that an abnormal production or accumulation of TOPA or its oxidation product(s) might be involved in excitotoxicity directed to areas of the brain with dopaminergic innervation, and in other brain areas in Parkinson's disease patients on long-term dopa therapy. The selective action of gangliosides in disrupting the pathological consequences of glutamate receptor activation proposes their use as chemoprophylactic agents for preventing or arresting the neuronal losses accompanying such situations.

Journal ArticleDOI
TL;DR: The crucial question is: What causes neuronal stress and, ultimately, neuronal death?
Abstract: Conventional definitions of neurodegeneration imply that it is a process of idiopathic progressive neuronal death, generally occurring in a selective distribution that often involves hnctionally related pathways. Such a definitibn would encompass the orchestrated death of neurons that takes place in fetal development, and the regionally heterogeneous attrition that occurs in the aging nervous system. However, fetal development and aging are normal occurrences, and the term neurodegeneration implies abnormality. Thus neurodegeneration implicitly denotes disease, and there can be no doubt that the three major examples of this are dementia of Alzheimer's type (DAT), idiopathic parkinsonism (IP), and amyotrophic lateral sclerosis (ALS). A shared pathologic feature of these disorders is the accumulation of cytoskeletal products, which seems to represent a nonspecific marker of cell stress, rather than providing a clue to a specific pathogenesis. For example, the Lewy body has been reported in such a wide range of disturbances that it is difficult to argue that its presence sheds any light on etiology. The crucial question is: What causes neuronal stress and, ultimately, neuronal death?

Journal ArticleDOI
TL;DR: It is concluded that the most likely determinant of the specific patterns of nigral cell loss and striatal dopamine deficit might be the peculiar topomorphological arrangement of the melanin-containing neurones in the human substantia nigra.

Journal Article
TL;DR: An in vivo model of focal brain ischemia using the photosensitive dye, Rose bengal, is employed to determine the neuroprotective actions of MK-801, a noncompetitive blocker of GLU at the NMDA-sensitive receptor and of the semisynthetic gangliosides LIGA 4 and LigA 20 which in vitro have been demonstrated to block PKC translocation.
Abstract: In culture the protracted and abusive stimulation of glutamate (GLU) receptors results in neuronal death through a mechanism involving the persistent translocation of PKC and the destabilization of (Ca2+)i homeostasis [(Ca2+)i HD]. In contrast, intermittent GLU receptor use elicits a coordinated expression of immediate early genes (IEG) acting as nuclear third messenger. Brain ischemia also is known to result in the paroxysmal abusive stimulation of glutamate receptors. The glutamate receptive elements in turn degenerate largely as a function of their inability to control homeostatic Ca2+ due to the irreversible translocation of PKC. In the present study we employed an in vivo model of focal brain ischemia using the photosensitive dye, Rose bengal. With this model we sought to determine the neuroprotective actions of MK-801, a noncompetitive blocker of GLU at the NMDA-sensitive receptor and of the semisynthetic gangliosides LIGA 4 and LIGA 20 which in vitro have been demonstrated to block PKC translocation. Moreover, we sought to establish whether the persistent stimulation of ionotropic glutamate receptors would led to a change in ionotropic glutamate expression in the focal and perifocal area. Importantly, the perifocal area (i. e., the region surrounding the area of primary insult) is a region in which profound cellular reorganization occurs including neuronal death and glial proliferation and is a key region to target various neuroprotective drugs aimed at ameliorating the neurodegeneration following stroke. Receptor abuse dependent antagonists (RADA) drugs such as gangliosides selectively curtail the amplification steps that specifically differentiate signal transduction following physiological receptor use from that following pathological receptor abuse.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal Article
TL;DR: In this review, following a brief description of the ability of the nervous system to counteract the degenerative process, the main neurotoxic-based animal models for neurodegeneration are examined and might give interesting clues for understanding the pathogenetic mechanism(s) of Neurodegenerative process.
Abstract: In the last few years, an increasing amount of studies have been dedicated to the etiopathogenesis of age-related neurodegenerative disorders, such as Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease The discovery of synthetic, as well as natural molecules, able to reproduce in the animals biochemical and morphological alterations of neurodegenerative disorders, has provided a major impetus to the "environmental" hypothesis of neurodegeneration In this review, following a brief description of the ability of the nervous system to counteract the degenerative process, the main neurotoxic-based animal models for neurodegeneration are examined These might give us interesting clues for understanding the pathogenetic mechanism(s) of neurodegenerative process

Book ChapterDOI
TL;DR: Analysis of the role that changes in calbindin D 28K gene expression may play in the etiology and pathogenesis of neurodegeneration in the brain, such as Huntington's, Parkinson's, and Alzheimer's diseases revealed that in each disease entity, the brain area that is particularly affected and used as a hallmark for the neuropathological changes exhibits a significant reduction in cal bindin D 27K geneexpression.
Abstract: Publisher Summary This chapter focuses on calbindin D 28K gene expression in aging and neurodegenerative diseases. The study described in the chapter has permitted an analysis of the role that changes in calbindin D 28K gene expression may play in the etiology and pathogenesis of neurodegeneration in the brain, such as Huntington's, Parkinson's, and Alzheimer's diseases. A method of molecular cloning of calbindin D 28K described in the chapter resulted in the isolation of a cloned calbindin D 28K cDNA via direct immunological screening of a mouse cerebellar λgt11 bacterial expression library. The calbindin D 28K cDNA could then be radiolabeled directly and utilized as a probe for detection of calbindin D 28K mRNA (slot-blot and Northern blot analyses) or converted to radiolabeled cRNA transcripts to detect calbindin D 28K mRNA at the cellular level by in situ hybridization. Slot-blot and Northern blot hybridization analyses revealed that in each disease entity, the brain area that is particularly affected and used as a hallmark for the neuropathological changes exhibits a significant reduction in calbindin D 28K gene expression.

Journal Article
TL;DR: In vitro studies and neuropathological examinations indicate that alpha 2-macroglobulin in neurons may be induced by cytokines and the protease inhibitor activity of this protein may prevent normal cleavage of APP, thereby resulting in increased alternative cleavage and deposition of beta A4.
Abstract: Alzheimer's dementia is a severe form of dementia characterised by three neuropathological changes: amyloid plaques, neurofibrillary tangles and neurodegeneration. Several laboratories are involved in studies of the molecular mechanisms underlying development of Alzheimer's disease. As a result of recent research, the main component of amyloid plaques, the beta A4-peptide, is focused upon in hypotheses of the pathogenesis of the disease. The beta A4-peptide is produced by cleavage of the larger amyloid precursor protein (APP). During normal processing of APP, production of beta A4 is hindered and the peptide is therefore presumably a result of alternative cleavage mechanisms. Several factors may increase alternative processing of APP. One possibility is that conformational changes in APP, e.g. induced by mutations in the APP gene, may facilitate alternative cleavage of APP and thereby production of beta A4. This seems to be the case in certain families with familial Alzheimer's disease. Another possibility for increased beta A4 production is excessive expression of APP. This seems to be the case in persons with trisomy 21 who all have neuropathological signs of Alzheimer's disease after the age of 40 years. The gene for APP is localised to the human chromosome 21 and these persons have 1.5 times the normal expression of APP. Furthermore, excessive APP-expression may be induced by an acute phase response in the brain. In vitro studies and neuropathological examinations indicate that alpha 2-macroglobulin in neurons may be induced by cytokines. The protease inhibitor activity of this protein may prevent normal cleavage of APP, thereby resulting in increased alternative cleavage and deposition of beta A4.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal ArticleDOI
TL;DR: Whether trisomy 16 brain tissue develops AD neurodegeneration and neuropathology is investigated and antibodies against ubiquitin, 200 kDa subunit of neurofilament and tau, which stain neurofibrillary tangles, and antidepressants are found in thioflavin Sor silver-stained sections.
Abstract: Down’s syndrome (DS, trisomy 21) results from an extra copy of human chromosome 21. Included in the phenotype of this syndrome is the development of neurofibrillary tangles and neuritic plaques that are characteristic of Alzheimer’s disease (AD) (Wisniewski KE et al., Ann Neurol 1985; 17: 278-282). The hippocampus is an early and critical site of this pathology. Animal models would greatly aid the elucidation of processes underlying the neuropathology of DS and AD. Murine trisomy 16 is a proposed genetic model for DS owing to the homology between mouse chromosome 16 and human chromosome 21 (Epstein CJ, Trends Genet 1985; 1: 129-134). To determine whether the trisomy 16 mouse could be a useful model for AD, we investigated whether trisomy 16 brain tissue develops AD neurodegeneration and neuropathology. Because age is an important factor in the development of AD neurodegeneration and trisomy 16 mice do not survive past birth, neural tissue was maintained by transplantation so that the neurons might live long enough to express the AD phenotype. Trisomy 16 mice were produced by mating males doubly heterozygous for the Robertsonian translocations Rb(11.16)2H/Rb(16.17)32 Lub to C57B1/6 females. Hippocampal anlagen from embryonic day 15-17 fetal mice, trisomic for chromosome 16 or euploid litter-mates, was dissected free, cut into two or three pieces and taken up into a 10 /zl Hamilton syringe. A craniotomy was performed in host 6-8 week old female C57B1/6 mice and the tissue was injected stereotaxically into striatum or lateral ventricle. In some cases, hippocampal tissue was dissociated with trypsin prior to grafting (Fine A, Neurosci Lett 1991; 122: 4-8). Following up to fourteen months of survival in vivo, brains were fixed by perfusion with 4% paraformaldehyde, sectioned and the grafts were examined by standard histochemical techniques and by immunocytochemistry for senile plaques and neurofibrillary tangles of AD patients. Nissl-stained grafts appeared healthy with no areas of necrosis or degeneration. The grafts contained neuronal aggregates similar to the pyramidalor the granule-cell layers of the normal adult hippocampus. No obvious morphological difference was detected between trisomic and control transplants. No evidence of neuropathology was found in thioflavin Sor silver-stained sections. The monoclonal antibody Alz-50 (provided by Dr. P. Davies, Albert Einstein College of Medicine, and Dr. H. Ghanbari, Abbott Lab.), which recognizes the paired helical filaments characteristic of AD, did not stain trisomic or euploid grafts. However, frontal cortex from an AD patient, stained in parallel with the mouse sections, reacted strongly, thus indicating that the lack of staining in the mouse sections was not a failure of the immunohistochemical procedure. An antibody to/3-amyloid peptide (R1280, provided by Dr. I. Lieberberg, Athena Neurosciences) revealed no/3-amyloid accumulation in these grafts, whereas concurrent staining of AD frontal cortex demonstrated numerous plaques. We examined four trisomic en bloc grafts after one year of survival, and two grafts each after four, six and fourteen months using Alz-50 and R1280 antibodies; none showed AD-type immunoreactivity. Four dissociated cell trisomic grafts, after 18 months in vivo, did not stain with Alz-50. Further, antibodies against ubiquitin, 200 kDa subunit of neurofilament and tau, which stain neurofibrillary tangles, and antibodies