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Abnormal accumulation of alpha-synuclein is regarded as a key pathological step in a wide range of neurodegenerative processes, not only in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) but also in multiple-system atrophy (MSA). Nevertheless, the mechanism of alpha-synuclein accumulation remains unclear. Leupeptin, a protease inhibitor, has been known to cause various neuropathological changes in vivo resembling those of aging or neurodegenerative processes in the human brain, including the accumulation of neuronal processes and neuronal cytoskeletal abnormalities leading to neurofibrillary tangle (NFT)-like formations. In the present study, we administered leupeptin into the rat ventricle and found that alpha-synuclein-positive structures appeared widely in the neuronal tissue, mainly in neuronal processes of the fimbria and alveus. Immunoelectron microscopic study revealed that alpha-synuclein immunoreactivity was located in the swollen axons of the fimbria and alveus, especially in the dilated presynaptic terminals. In addition colocalization of alpha-synuclein with ubiquitin was rarely observed in confocal laser-scan image. This is the first report of experimentally induced in vivo accumulation of alpha-synuclein in non-transgenic rodent brain injected with a well-characterized protease inhibitor by an infusion pump. The present finding suggests that the local accumulation of alpha-synuclein might be induced by the impaired metabolism of alpha-synuclein, which are likely related to lysosomal or ubiquitin-independent proteasomal systems.

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We report a rare familial case of dementia with Lewy bodies (DLB). The patient was a man who died at the age of 51. His parents were first cousins. Among three siblings, two were diagnosed as probable cases of DLB, and one was a possible case, according to the clinical diagnostic criteria of the consortium on DLB. Following the patient's autopsy, he was found to have had DLB without neurofibrillary tangles or senile plaques (pure form of diffuse Lewy body disease). His other siblings have been followed for more than ten years. Although these patients with familial DLB displayed clinical variability, all three siblings showed progressive dementia of early onset and progressive language disorder with paraphasia and difficulty in finding words. Psychotic features were also seen in the three siblings. The patient's sister showed compulsive behavior, and the other two siblings showed symptoms of parkinsonism. Neuropathologically, in addition to the usual neuropathology of DLB, the autopsy findings showed numerous small spheroids in the stratum pyramidale from the subiculum to CA1 of the hippocampus. Significant neuronal loss in CA2-3 of the hippocampus was detected. Axonal flow disturbance may be involved in the hippocampal formations of this incidence of familial DLB.

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We describe three sibling patients with autosomal dominantly inherited sensory neuropathy, sensorineural hearing loss and dementia. The features of cognitive-behavioral deficits in the patients, including executive dysfunction, apathy, indifference and inattention, were consistent with a frontal lobe dysfunction. Magnetic resonance imaging showed a diffuse brain atrophy. A fluorodeoxyglucose positron emission tomography in one patient and a single photon emission computed tomography in another demonstrated a glucose hypometabolism or a hypoperfusion in the medial frontal and thalamic regions. Primary frontal involvement or frontal dysfunction secondary to thalamic lesions may contribute to the nature of dementia in these patients.

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The A375 cell line, derived from human malignant melanoma, has characteristics of interleukin-6 (IL-6) production. By using this cell line, we have investigated a murine metastasis model of IL-6-producing tumors to the brain by injecting A375 cells directly into the left cardiac ventricle. Nude mice were anesthetized with intraperitoneal injection of pentobarbital sodium. Next, A375 cells suspended in phosphate-buffered saline (PBS) were injected into the left cardiac ventricle of mice. An intracardiac injection of 10(5) cells developed tumor colonies in the brain after 4 to 6 weeks. Metastatic cells were found in every lobe of the brain. An immunocytochemical study revealed IL-6 production by A375 cells at the metastatic sites in the brain. By the transfection of genes encoding proteins into A375 cells, a novel model of protein expression in the brain in vivo could be constructed. Our system does not require great skill. Our experimental model will facilitate future studies of the local effects of proteins in the brain.

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It is known that proteases participate in cellular protein turnover and eliminate abnormal and potentially toxic proteins. Disturbed proteolysis may be responsible for generating the pathological features of some neurodegenerative disorders. Alzheimer disease, for instance, is the most common neurodegenerative disorder and a condition in which proteins of the cell membrane and cytoskeleton are abnormally processed and accumulated in the brain. It is of interest to investigate the effect of protease inhibitors on neurons and neurotransmitter systems in the brain. We examined neurochemical and morphological neuronal changes in the rat brain following long-term intracerebroventricular infusion of leupeptin, a potent calcium-activated protease (calpain) inhibitor. Leupeptin (5 mg) was infused into the lateral ventricle using an osmotic minipump for 14 days. We found a significant reduction of regional choline acetyltransferase activities in the hippocampus, and of somatostatin concentrations in the hypothalamus and entorhinal cortex. Moreover, leupeptin caused a wide-spread, highly significant decrease in neuropeptide-Y concentrations. Leupeptin infusion produced severe degeneration of neuronal processes in both axons and dendrites, and accumulation of electron-dense bodies in the hippocampus. The results indicate that long-term intracerebroventricular infusion of leupeptin in the rat produces neurochemical and morphological changes resembling those of some neurodegenerative disease and aging. Abnormal proteolysis caused by either reduced protease or enhanced protease inhibitor activities might play an important role in these conditions.

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Attacks of gelastic (laughing) seizure are usually reported as complex partial seizures of temporal lobe epilepsy and seizures associated with hypothalamic hamartomas, but are rarely reported as complex partial seizures of frontal lobe origin. We recently encountered a 29-year-old woman who had gelastic seizure attacks from age 17. She had shown severe mental retardation with cerebral palsy at 7 months, and entered precocious puberty at age 7. Attacks of gelastic seizure with ipsilateral adversive seizures, ipsilateral oculogyric crisis, and horizontal epileptic nystagmus were observed until her death at age 29. Each gelastic seizure lasted 1 to 10 minutes. Her laughing was very strong and loud. Interictal spikes were observed over the right fronto-parietal lobe, but no ictal spike was detected. The neuropathological examinations of her brain revealed no hypothalamic lesions such as hamartomas, gliosis, and distinct neuronal loss. Her brain was severely affected with multicystic encephalopathy, and the bilateral temporal lobe tissues were almost replaced by the cystic changes. The right frontal lobe and occipital lobe were not cystic. From the clinicopathological examinations, the focus of her gelastic seizure was considered to be of the right frontal origin. The hippocampus and parahippocampal gyrus are major components of the limbic system, which is involved in affective emotions. Although the right hippocampus and parahippocampal gyrus were completely lost, and those of the left hemisphere were almost completely lost, by the multicystic replacements in this case, the gelastic seizure attacks were evoked from right frontal origin. The frontal lobe may play an important role in motor expressions of laughing. The motor expressions of the loud and strong laughing may be one of the characteristic features of frontal lobe-originated gelastic seizure of this case.

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We observed abundant Pick argentophilic inclusion bodies (PBs) as well as some atypical Lewy bodies (LBs) in the locus ceruleus (LC) from a patient with Pick's disease. In addition, there were a few neurons which contained both PBs and LBs. PBs in the LC frequently appeared multiple and had lobulated or irregular shapes, though their ultrastructural elements were the same as those of the PBs appearing in the cerebral cortex, and consisted of randomly arranged smooth-surfaced straight tubules of 15 nm in diameter, mixed with a small number of long-period constricted fibrils. The ultrastructure of the LB coexisting with PB was identical with that previously reported; a dense core was surrounded by concentric layers of radially oriented 10-nm filaments and was clearly distinguishable from the PB. Immunohistochemical examination with various antibodies related to neurofibrillar pathology demonstrated that anti-tau antibodies reacted positively with both PB and the rim portion of LB in the present case; an unusual finding for LB. The anti-neurofilament 200-kDa protein stained only LBs, even when PBs and LBs coexisted in the same neuron. These findings show that two kinds of neuronal fibrillar inclusions, whose underlying cytoskeletal abnormalities are thought to be different, can coexist in the same neuron. In addition, the formation of multiple, lobulated PBs may suggest some particularity of cytoskeletal composition of the LC neurons.

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Neurofibrillary tangles (NFTs), which are composed of paired helical filament (PHF)-like filaments, were induced by the long-term intraventricular infusion of leupeptin, a potent protease inhibitor. The fibrils composing the NFTs were 20 nm in maximal width and had periodic constrictions at 40-nm intervals. They were identical to the PHF that had been found in aged rat neurons. Dystrophic axons filled with mainly tubular structures were also abundantly found in the parietal and temporal isocortices, which were not affected in the acute or subacute phases of leupeptin treatment. An immunohistochemical study using antibodies related to the neuronal cytoskeleton showed that neuronal cytoskeletal changes accompanying ubiquitination occurred in dystrophic axons distributed widely in the isocortex as well as the hippocampal formation. The present findings suggest that long-term administration of leupeptin accelerates the neuronal ageing process in rats and causes other neuronal changes: NFT formation, such as seen in the aged brain or in neurodegenerative diseases including Alzheimer's disease, in addition to accumulation of lipofuscin granules and degeneration of neuronal processes. In other words, some disturbance of the balance between proteases and their inhibitors may play an important role in the neuronal ageing process, and some regulatory intervention in the intraneuronal protease activity may provide a new therapeutic strategy for the neurodegenerative diseases.

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The clinical and pathological features of a sporadic case of juvenile neuroaxonal dystrophy beginning at the age of 10 and leading to death at the age of 26 are described. Clinical manifestation began with cerebellar symptoms. The subject subsequently developed dementia, pes cavus (Friedreich's feet), epilepsy, myoclonus, and Parkinsonian syndrome, but demonstrated neither tremor nor choreoathetoid movement. Pathological examination showed typical generalized axonal dystrophy throughout the central nervous system (Seitelberger's disease). Iron-positive pigmentation was seen in the pallidonigral system, diffuse Lewy bodies (brainstem type and cerebral type) were demonstrated in the brainstem nuclei and cerebral cortex, and neurofibrillary tangles were observed.

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The neurotoxicity of acetyl-ethyl-tetramethyl-tetralin (AETT) was investigated following its percutaneous administration to rats. Animals exposed to a high-dose of AETT developed a gait abnormality that progressed to severe ataxia. Microscopic examinations revealed remarkable cerebellar changes in addition to a widespread accumulation of ceroid-like pigmentation in the neuronal cytoplasm. The cerebellar changes, especially in the vermis and intermediate part, were characterized by selective degeneration and depopulation of Purkinje cells, and a spongy state of the cerebellar white matter, which was formed in splits in the intraperiod lines within the myelin sheath. In contrast, there were only negligible changes of granule cells and other neuronal elements. Accumulation of ceroid-like pigments and selective damage to the Purkinje cells seen in the present study together provide a basis for understanding the pathogenesis of AETT intoxication and distinguish it from other experimentally induced conditions. Thus, high-dosage AETT intoxicated rats may constitute a new experimental model of cerebellar degeneration.

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Severe degeneration of neuronal processes, including axons and dendrites, as well as accumulation of lipofuscin-like dense bodies have been induced in rats by continuous intraventricular administration by infusion of a protase inhibitor, leupeptin. The aggregation of degenerated processes in neuropils mingled with glial cells and their processes resembled the aggregation of degenerated neurites that are important constituents of the senile plaque of Alzheimer's disease. The present findings provide morphological evidence supporting the hypothesis that protease inhibitors participate in the process of senile plaque formation.

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We report the results of an ultrastructural study of Pick bodies (PB). A histogram constructed with the maximal width of each filamentous component in PB revealed a wide range of sizes among the filaments, in contrast to the unique composition of the paired helical filaments (PHF) seen in the neurofibrillary tangle of Alzheimer type (NFT-AT). Morphologically, three groups of filaments could be distinguished. The first group consisted of straight smooth-surfaced filaments of 10-14 nm diameter, which were presumably altered neurofilaments. The second one was of straight smooth-surfaced "tubules" of 15-22 nm diameter, smaller than normal microtubules. The third one was of PHF thought to be formed by a pair of filaments of the first group. The PHF found in PB differed from PHF of NFT-AT in the distance between crossovers, and rather resembled the loosely interwinding PHF reported in NFT of progressive supranuclear palsy.

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Unusual paired helical filaments (PHF) coexisting with single filaments were observed in neurofibrillary degeneration (NFD) in the globus pallidus, subthalamic nucleus, substantia nigra, and pontine tegmentum of a typical case of progressive supra-nuclear palsy (PSP). Each filament had a diameter of 10-12 nm and showed central low density and a smooth contour. The thickest portion of a pair was 22-24 nm in diameter. The periodicity of twist varied from 150 nm to 300 nm, but each PHF had regular periodicity. The present ultrastructural finding is unusual in the neurofibrillary pathology of PSP, and is also different from the PHF found in Alzheimer type NFD.

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Spongy state and degeneration of the white matter in the 6-aminonicotinamide intoxicated rats were studied neuropathologically and electromicroscopically. Young albino rats, four weeks of age, received 0.1% of 6-aminonicotinamide solution intraperitoneally as a single dose of 10 mg/Kg of body weight. Four hours after the administration, paralysis of the hind limbs occurred in the rats. Neuropathological investigations revealed a characteristic spongy and degenerative change of white matter as well as gray matter of the central nervous system. Corpus callosum, cerebellar cortex, and optic nerves showed edematous and spongy degeneration in the early stage of the experiment. Ultrastructural changes of myelin sheath were initially seen in the vicinity of severely damaged oligodendrocytes. The vacuoles in the myelin, i.e. intramyelinic vacuoles, were formed by splitting between the innermost myelin lamellae and axon. Axons remained usually unchanged in the early stage. The pathogenesis of ultrastructural changes of the white matter in the 6-aminonicotinamide intoxication was discussed.

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(1) Accumulation of neuronal lipofuscin was clearly demonstrated in the chronic tellurium intoxication in young rats with histological, fluorescent and electron-microscopical methods; (2) The needle-shaped crystal in the neuronal lysosomes were demostrated to contain the tellurium with electron dispersive spectrophotometry analysis. (3) The vacuolation of the cytoplasm of Schwann cells was the initial pathological change noted in the tellurium peripheral neuropathy.

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