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  • 1
    ISSN: 1432-0533
    Keywords: Key words Neuronal storage disease ; Cholesterol ; metabolism ; Tau ; Paired helical filaments ; Lysosomal disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Niemann-Pick disease type C (NPC) is an autosomal recessive disease, belonging to a clinically heterogeneous group of lipid storage diseases, distinguished by a unique error in cellular trafficking of exogenous cholesterol, associated with lysosomal accumulation of unesterified cholesterol. Unlike Niemann-Pick disease types A and B, there is no primary genetic defect in sphingomyelinase in NPC. During the routine neuropathological study of NPC patients, we found neurofibrillary tangles (NFT) in a series of cases with a slowly progressive chronic course. These were not associated with β-amyloid deposits. The NFT were most frequent in the orbital gyrus, cingulate gyrus and entorhinal region of the cerebral cortex, but were also frequently found in the basal ganglia, thalamus and hypothalamus. In one of the most severely affected case, the NFT were even found in the neurons in the inferior olivary nucleus and in the spinal cord. The NFT were immunostained with Alz 50, and consisted of paired helical filaments. The distribution of the neurons bearing the NFT was generally similar to that of the swollen storage neurons, and storage neurons often contained NFT in their perikarya and/or in the meganeurites. However, neurons with NFT could be noted without swollen perikarya. The coexistence of neuronal storage and NFT in NPC without amyloid deposits suggests that perturbed cholesterol metabolism and/or lysosomal membrane trafficking may play a role in the formation of NFT, and that amyloid deposits are not necessarily the prerequisite for NFT formation. The results of our study also suggest that NFT formation may be a rather nonspecific cellular reaction of neurons to certain slowly progressive metabolic perturbations of an as yet undefined nature.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0533
    Keywords: Neuronal storage disease ; Cholesterol metabolism ; Tau ; Paired helical filaments ; Lysosomal disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Niemann-Pick disease type C (NPC) is an autosomal recessive disease, belonging to a clinically heterogeneous group of lipid storage diseases, distinguished by a unique error in cellular trafficking of exogenous cholesterol, associated with lysosomal accumulation of unesterified cholesterol. Unlike Niemann-Pick disease types A and B, there is no primary genetic defect in sphingomyelinase in NPC. During the routine neuropathological study of NPC patients, we found neurofibrillary tangles (NFT) in a series of cases with a slowly progressive chronic course. These were not associated with β-amyloid deposits. The NFT were most frequent in the orbital gyrus, cingulate gyrus and entorhinal region of the cerebral cortex, but were also frequently found in the basal ganglia, thalamus and hypothalamus. In one of the most severely affected case, the NFT were even found in the neurons in the inferior olivary nucleus and in the spinal cord. The NFT were immunostained with Alz 50, and cosisted of paired helical filaments. The distribution of the neurons bearing the NFT was generally similar to that of the swollen storage neurons, and storage neurons often contained NFT in their perikarya and/or in the meganeurites. However, neurons with NFT could be noted without swollen perikarya. The coexistence of neuronal storage and NFT in NPC without amyloid deposits suggests that perturbed cholesterol metabolism and/or lysosomal membrane trafficking may play a role in the formation of NFT, and that amyloid deposits are not necessarily the prerequisite for NFT formation. The results of our study also suggest that NFT formation may be a rather nonspecific cellular reaction of neurons to certain slowly progressive metabolic perturbations of an as yet undefined nature.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0568
    Keywords: Cerebellar graft ; Deep cerebellar nuclei ; Neurological mutant mice ; “Purkinje cell degeneration” (pcd)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In transplanting embryonic cerebellar grafts to the cerebellar cortex of “Purkinje cell degeneration” (pcd) mutant mice to replace missing Purkinje cells (PC), donor PC leave the graft and migrate to the molecular layer of the host. However, PC axons do not always reach the deep cerebellar nuclei of the host, which would be a key element in restoring much of the necessary inhibitory cortico-nuclear projection associated with normal cerebellar function. Rather, grafted PC axons often innervate a region containing deep cerebellar nuclei neurons inside the transplant, while the perikaryon migrates to the host molecular layer. In the present study, aimed at re-establishing a PC innervation of the deep nuclei, we implanted E12 cerebellar cell suspensions intraparenchymally to the deep cerebellar mass of the hosts. The development of grafted PC was monitored with 28-kDa calcium-binding protein (CaBP) immunocytochemistry at various times after transplantation. At short survival times (5 days after grafting), grafts were confined to the site of the original injection. At longer survival times (7–32 days after grafting), grafted PC formed a migratory stream that reached the cerebellar cortex of the host. The most robust graft development was seen 1 month after grafting, the longest survival time allowed in this series of experiments. At that time, clusters of donor PC were found both in the deep nuclei parenchyma and aligned along cortical folia. The orientation of the dendritic trees of PC that had migrated to the cortex was toward the pia. A CaBP-immunoreactive fibre plexus innervated the host deep cerebellar nuclei. The stream of grafted PC extended from the deep cerebellar nuclei to the cerebellar cortex of the host, indicating that donor PC could establish their axonal contacts in the deep nuclei and then move to their final cortical locality, thus recapitulating a migratory path normally taken during cerebellar ontogeny. It appears therefore that both from the pathophysiological and ontogenetic standpoints, the deep cerebellar nuclei represent the appropriate site for PC implantation in cerebellocortical atrophy.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1573-6903
    Keywords: Cerebellar graft ; mouse, neurological mutant ; ‘Purkinje cell degeneration’ (pcd) ; serotonin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract One aspect of integration of implanted neurons into the neuronal circuitry of a defective host brain is the re-establishment of a host-to-graft afferent innervation. We addressed this issue by using the adult cerebellum of ‘Purkinje cell degeneration’ (pcd) mutant mice, which lack virtually all Purkinje cells after postnatal day (P) 45. Purkinje cells constitute one of the cerebellar cell types being innervated by axons of raphé serotonin (5-HT) neurons. In normal mice, 5-HT-immunoreactive fibers are distributed to all cerebellar folia. Following Purkinje cell loss inpcd mice, cerebellar 5-HT-immunoreactive fibers persist. Cerebellar cell suspensions were prepared from embryonic day (E) 11–13 normal mouse embryos and were intraparenchymally grafted into the cerebellum ofpcd mutants either directly or after pre-treatment with 5, 7-dihydroxytryptamine (5,7-DHT) to selectively remove 5-HT cells of donor origin. The state of Purkinje cells and 5-HT axons was monitored in alternate sections by 28-kDa Ca2+-binding protein (CaBP) and 5-HT immunocytochemistry, respectively. Serotonin-immunoreactive axons were seen in the grafts from 5 to 32 days after transplantation. In some of the grafts which had not been pre-treated with 5,7-DHT, a small number of 5-HT-immunoreactive cell bodies was found, indicating that part of the 5-HT fiber innervation of the graft could actually derive from donor cells. On the other hand, in grafts pre-treated with 5,7-DHT, no 5-HT cell bodies were seen in the grafted cerebellum; 5-HT fibre innervation of the grafts occurred, but it appeared to be slightly less robust compared to situations of co-grafted 5-HT cell bodies. These findings suggest that host 5-HT fibers are able to provide afferent innervation to donor cerebellar tissue; the presence of co-grafted 5-HT cells may augment such an innervation.
    Type of Medium: Electronic Resource
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