Alpha-synuclein accumulates in the brain of scrapie-affected sheep and goats.

Immunohistochemical examination demonstrated widespread granular deposits of alpha-synuclein (alphaSN) in the brains of sheep and goats with natural scrapie, especially in the cornu ammonis and subiculum of the hippocampus; this contrasted with the diffuse and non-granular immunolabelling seen in healthy controls. There was non-regular "co-localization" of PrP(Sc) and alphaSN. The findings resembled those reported in Creutzfeldt-Jakob disease and in experimental prion disease in hamsters and mice. The results suggest that perturbation of alphaSN metabolism plays a role in human and animal prion diseases.

[Familial fronto-temporal dementia with brain stem ubiquitin-positive neuronal inclusions]. / Démence fronto-temporale familiale avec inclusions marquées par l'anti-ubiquitine dans le tronc cérébral.

INTRODUCTION: Fronto-temporal dementias (FTD) were described a century ago on the macroscopic basis of frontal and/or temporal lobe atrophy. Progress in neuropathology, immunohistochemistry, biochemistry and genetics has since shown that they are heterogeneous entities, encompassing many different diseases with similar clinical presentations. A few, such as tauopathies due to mutations of the gene coding for tau protein (MAPtau form a well-defined group. Definition and grouping of other types of FTD is still problematic. MATERIAL AND METHOD: We studied a family where the mother and 4/8 children were affected with FTD. Clinical presentation was typical of FTD. Onset was ill-defined with early (at age 40 years or less) personality changes. The clinical course was protracted (about 30 years). For a long period, the patients were able to live in the community in spite of obvious signs such as hyperorality and loss of verbal initiative; operative orientation as to place was preserved for a long time: a mute patient was still able to drive. Signs of extrapyramidal or motoneuron involvement were not observed. RESULTS: The genetic study failed to detect any mutation in MAPtau; the lod score for flanking markers was positive but not significant. Biochemical study showed no qualitative abnormality in tau protein. Neuropathological study of one affected subject showed brain atrophy (962 g), with elective frontal lobe involvement. Cortical nerve cell loss was more marked in superficial layers and in frontal areas; glia was inconspicuous; pseudolaminar spongiosis was present in the more severely affected zones. No argentophilic "Pick bodies" were seen; ubiquitin-positive, tau-negative round inclusions were present in the cytoplasm of fascia dentata neurones. "Tangles" were mostly restricted to the entorhinal cortex, partly correlated with tau immunoreactivity, but better with ubiquitin immunoreactivity. Large, ovoid or reniform, moderately dense, spongy, granular or filamentous argentophilic cytoplasmic nerve cell inclusions were observed. They were ubiquitin-positive, but did not react with other antibodies, particularly anti-tau. They were present in swollen nerve cells in the deeper cortical layers but were most conspicuous in the brain stem: in the magnocellular reticular nuclei (e.g. nucleus centralis pontis), in the pes pontis, in the inferior olive and in motor nuclei, especially in the trigeminal motor nucleus. They were not associated with nerve cell loss, atrophy nor pycnosis. Cerebellar relay nuclei neurones were swollen, and their cytoplasm contained argentophilic filaments. CONCLUSION: In our opinion, "ubiquitinopathy" would be non-specific and "Motor Neuron Disease-Inclusion Dementia" (MNDID) would not be satisfactory as a diagnosis for the present cases of FTD. Hopefully, progress in genetics may allow a causal, and thence definitive, classification.

Ultrastructural localization of parkin in the rat brainstem, thalamus and basal ganglia.

The parkin gene encodes a 52 kd putative E3 ubiquitin-protein ligase involved in an autosomal recessive form of early onset parkinsonism. Parkin ultrastructural localization was studied by immunohistochemistry in the adult rat brain and in a parkin inducible PC12 cell line (HS22). In the rat brain, parkin immunoreactivity was detected in neuronal and glial cell bodies and in nerve processes. In the neurons, it was mostly localized on the periphery of large vesicles, some rare mitochondria and endoplasmic reticulum in the cell bodies, and on the periphery of large vesicles in the dendrites and terminals of the neurons. In addition, parkin immunoreactivity was also found around synaptic vesicles in the presynaptic elements of some axons. In HS22 cells over-expressing parkin, the distribution of the protein was similar to that observed in the perikarya of the labeled neurons.

Similarities between spinocerebellar ataxia type 7 (SCA7) cell models and human brain: proteins recruited in inclusions and activation of caspase-3.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant polyglutamine disorder presenting with progressive cerebellar ataxia and blindness. The molecular mechanisms underlying the selective neuronal death typical of SCA7 are unknown. We have established SCA7 cell culture models in HEK293 and SH-SY5Y cells, in order to analyse the effects of overexpression of the mutant ataxin-7 protein. The cells readily formed anti-ataxin-7 positive, fibrillar inclusions and small, nuclear electron dense structures. We have compared the inclusions in cells expressing mutant ataxin-7 and in human SCA7 brain tissue. There were consistent signs of ongoing abnormal protein folding, including the recruitment of heat-shock proteins and proteasome subunits. Occasionally, sequestered transcription factors were found. Activated caspase-3 was recruited into the inclusions in both the cell models and human SCA7 brain and its expression was upregulated in cortical neurones, suggesting that it may play a role in the disease process. Finally, on the ultrastructural level, there were signs of autophagy and nuclear indentations, indicative of a major stress response in cells expressing mutant ataxin-7.

FE65 in Alzheimer's disease: neuronal distribution and association with neurofibrillary tangles.

FE65, a protein expressed in the nervous system, has the ability to bind the C-terminal domain of the amyloid precursor protein. This suggests a role for FE65 in the pathogenesis of Alzheimer's disease (AD). The present study was conducted to find out if the distribution of FE65 immunoreactivity was affected during the course of AD, and to determine the degree of co-localization of FE65 with other proteins known to be involved in AD. Single immunoperoxidase-labeling experiments, conducted on six sporadic AD patients and six nondemented age-matched controls, showed that the proportion of volume occupied by FE65 immunoreactivity was not modified in the isocortex of AD patients. However, in hippocampal area CA4, increased FE65 immunoreactivity seemed to be associated with the severity of the disease. Double-immunofluorescent labeling did not show any clear co-localization of FE65 with the amyloid precursor protein. FE65 immunoreactivity was also absent from focal and diffuse deposits of the beta-amyloid peptide. Unexpectedly double labeling experiments showed a co-localization of FE65 and tau proteins in intracellular tangles. Ultrastructural observations confirmed that FE65 was associated with paired helical filaments.

Comparison of clinical and pathological phenotypes in two ethnically and geographically unrelated pedigrees segregating an equivalent presenilin 1 mutation.

At least 30 different missense mutations have been identified within the presenilin 1 (PS1) gene in pedigrees transmitting familial Alzheimer's disease. The authors investigated the clinical and pathological features of affected members of two pedigrees segregating a PS1 Met146Leu mutation. Genetic relationships between these pedigrees can be effectively excluded on the basis of genealogical data and the fact that although the amino acid substitution is identical, the nucleotide mutations are different. The clinical picture shows remarkable similarities in the neurological and the neuropathological findings between the two pedigrees. This general clinical and pathological concordance argues that much of the disease phenotype arises directly from the effects of the amino acid substitution within the PS1 protein itself. Clinical differences could arise from a direct effect of the difference in base sequence or, alternatively, from the effect of genetic or environmental modifiers.

Modifications of oligodendroglial cells in spongiform encephalopathies.

Although gray matter lesions involving neurones and astrocytes are prominent in human transmissible spongiform encephalopathies (TSE), white matter lesions have also been occasionally observed. Secondary (Wallerian) degeneration and direct myelin damage have been invoked, but the physiopathology of white matter involvement is still debated. We performed an immunohistochemistry study with anti-PrP antibodies of autopsy material of four patients with Creutzfeldt-Jakob disease (CJD), together with transmission electron microscopy (TEM) studies of conventionally processed biopsy specimens of the same patients. Light microscopy immunolabeling was observed as arrays adjacent to myelinic fibers and as a clumps adjacent to oligodendroglial nuclei; both cerebrum and cerebellum were involved. At the ultrastructural level, two types of intracellular inclusions were seen in the white matter. They were associated with dense lysosomes in oligodendroglial perikarya and in their processes. The inclusions were made of finely fibrillar, paracrystalline, amorphous, or densely osmophilic material. Thus, our findings may suggest that white matter involvement in spongiform encephalopathy is due to direct modifications of oligodendroglial cell associated with abnormal metabolism of PrP.

Putative neurosurgical transmission of Creutzfeldt-Jakob disease with analysis of donor and recipient: agent strains.

A woman, aged 59 years, underwent a cortical biopsy that led to the diagnosis of Creutzfeldt-Jakob disease (CJD). A man, aged 46 years, underwent cranial surgery in the same department 3 days later for brain contusion, with an uneventful recovery. Twenty six months later, he developed clinical signs of CJD with a typical EEG pattern. Both cases exhibited features of the 'ataxic' form of the disease with depletion of cerebellar granule cells, without kuru plaques or PrP deposits. PrP deposits were immuno-histochemically observed in the cerebrum, spinal cord and peripheral nerve. Molecular genetic analysis performed on brain tissue revealed the codon 129 polymorphism to be Met129Met in the donor and Met129Val in the recipient. The shared 'cerebellar' phenotype and the genotypic discrepancy between the two patients lead us to postulate that the 'cerebellar' agent strain plays a major role in CJD phenotype and transmission.

Do microglial cells phagocyte the beta/A4-amyloid senile plaque core of Alzheimer disease?

We performed EM, immuno-EM and light microscope immunohistochemistry studies on the topographic and functional relationships between microglial cells and amyloid senile plaque core in Alzheimer's disease. Microglial cells with cytologic characteristics of phagocytic function were associated to amyloid fibrils and to other neuropathological degenerative processes. On the periphery of the amyloid plaque core, microglial cells contain intracytoplasmic bundles of membrane bound fibrils. These fibrils, like plaque core fibrils, are immunodecorated. Immunostaining was observed neither in secretory organelles nor in hyalaplasm. Preamyloid deposits in superficial layers were not associated to microglial cells. These data lead us to conclude that the microglial cells participate to phagocytosis of beta/A4 amyloid and do not secrete this substance in Alzheimer's disease.

Alzheimer's disease: a model from the quantitative study of a large kindred.

In an Italian kindred (family N), early onset Alzheimer's disease has been transmitted in a Mendelian autosomal fashion since the early 18th century. The age at death of affected members of the family varies widely, and was taken as an index of the age of expression, a measure of phenotypic variability. Either a gamma or a log-normal algorithm provides the best fit for the age at death distribution. Subsets of family N widely different as to time and place have the same age at death of patients: Environment appears to play a negligible role in the expression of disease. Pairwise correlation between an affected parent and child is zero: The disease is monogenic (no major expression gene). The same stochastic distribution of age of expression, but with late onset, and after correction for death from other causes, is compatible with the epidemiology of Alzheimer's disease in general. Mendelian genetics is a possible model for Alzheimer's disease etiology.

Relationship between non-fibrillary amyloid precursors and cell processes in the cortical neuropil of Alzheimer patients.

We examined the ultrastructural localization of amyloid beta-protein in 8 Alzheimer neocortical biopsies. Intense immunoreactivity was located extracellularly on amyloid fibrils and amorphous material. Amorphous labelled material was also found in cell processes. No ultrastructural cell marker, such as glial fibrils, glycogen, tubules, paired helical filaments (PFHs) or synaptic vesicles could be seen in these processes that could allow their identification as glial processes, neurites or presynaptic terminals, respectively; occasional membrane stacks were observed. These findings suggest that preamyloid deposits are related to cell processes and, by elimination, that postsynaptic terminals may be involved in abnormal metabolism of the amyloid fibril precursors.

[Intradural extramedullary neuro-enteric cysts without associated malformation. 3 cases with magnetic resonance imaging]. / Kystes neurentériques intraduraux extramédullaires sans malformation associée. Trois cas avec imagerie en résonance magnétique.

We report 3 cases of extramedullary neurenteric cyst without associated dysraphic lesions. One of the cases had an ultrastructural study. Magnetic resonance imaging provided a preoperative diagnosis. The embryogenesis of neurenteric cysts, their main clinical aspects and their surgical treatment are reviewed.

[Loss of dendritic spines in Alzheimer's disease]. / Perte des épines dendritiques dans la maladie d'Alzheimer.

Neurones from five patients with Alzheimer's disease were studied semi-quantitatively on Golgi impregnated samples of cerebral cortex. They showed a dramatic reduction in dendritic spine number of pyramidal and non-pyramidal cells of all neocortical layers, as compared with control samples matched for age. Dendritic spine loss could be an initial phenomenon in Alzheimer's disease pathology.