The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP), also called alpha-synuclein, is a major component of Lewy bodies in Parkinson's disease (PD) as well as of neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy. We previously reported argyrophilic, tau-negative glial inclusions in the midbrains of patients with PD and have now conducted immunocytochemical and ultrastructural examinations. The PD glial inclusions also are immunoreactive for NACP/alpha-synuclein, but not for beta-synuclein, and ultrastructurally are composed of filamentous structures about 25-40 nm in diameter. Double immunolabeling showed that the inclusions were present in both astrocytic and oligodendroglial cells. They were located within the substantia nigra in 13 of 30 patients with PD and outside the nigra in 24. The number of inclusions was correlated with the severity of nigral neuronal loss. These findings indicate that abnormal accumulation of NACP/alpha-synuclein in glial cells is a pathological feature of PD related to its progression.
To test the hypothesis that the frequencies of normal alleles (ANs) with a relatively large number of CAG repeats (large ANs) are related to the prevalences of the dominant spinocerebellar ataxias (SCAs)-SCA types 1, 2, 3 (Machado-Joseph disease), 6, and dentatorubral-pallidoluysian atrophy (DRPLA)-we investigated the relative prevalences of these diseases in 202 Japanese and 177 Caucasian families and distributions of the number of CAG repeats of ANs at these disease loci in normal individuals in each population. The relative prevalences of SCA1 and SCA2 were significantly higher in Caucasian pedigrees (15% and 14%, respectively) than in Japanese pedigrees (3% and 5%, respectively), corresponding to the observation that the frequencies of large ANs of SCA1 (alleles >30 repeats) and of SCA2 (alleles >22 repeats) were significantly higher in Caucasians than in Japanese. The relative prevalences of MJD/SCA3, SCA6, and DRPLA were significantly higher in Japanese pedigrees (43%, 11%, and 20%, respectively) than in Caucasian pedigrees (30%, 5%, and 0%, respectively), corresponding to the observation that the frequencies of large ANs of MJD/SCA3 (>27 repeats), SCA6 (>13 repeats), and DRPLA (>17 repeats) were significantly higher in Japanese than in Caucasians. The close correlations of the relative prevalences of the dominant SCAs with the distributions of large ANs strongly support the assumption that large ANs contribute to generation of expanded alleles (AEs) and the relative prevalences of the dominant SCAs.
Recently, we have shown that the precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP), also known as alpha-synuclein, is a major component of Lewy bodies (LBs) as well as neuronal and glial cytoplasmic inclusions in multiple system atrophy (MSA). To elucidate whether the accumulation of NACP is specific to LB disease and MSA, we further studied 83 autopsied cases with various neurological disorders, using anti-NACP antibodies. In LB disease, NACP immunoreactivity was present in all of the LBs and Lewy neurites in both the central and peripheral nervous systems, the pale bodies in the substantia nigra, and dystrophic neurites in the hippocampal CA2/3 region. Immunoelectron microscopy revealed that the reaction product was localized within filamentous structures and associated granular structures. In MSA, NACP immunoreactivity was found in the intracytoplasmic inclusions of both neuronal and oligodendroglial cells, neuronal intranuclear inclusions, and swollen neuronal processes. No NACP immunoreactivity was found in a variety of other neuronal or glial inclusions in other disorders, including Alzheimer's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, motor neuron disease and triplet-repeat diseases. These findings strongly suggest that the accumulation of NACP is a cytopathological feature common to LB disease and MSA.
Estrogen may mediate some of its effects on hippocampal function through the alpha isoform of the estrogen receptor (ERalpha). By light microscopy, ERalpha-immunoreactivity (-I) is found in the nuclei of scattered inhibitory gamma-aminobutyric acid (GABA)ergic interneurons. However, several lines of evidence indicate that estrogen also may exert some of its effects through rapid nongenomic mechanisms, possibly by binding to plasma membranes. Thus, to determine whether ERalpha is found in extranuclear sites in the hippocampal formation (HF), four different antibodies to ERalpha were localized by immunoelectron microscopy in proestrous rats. Ultrastructural analysis revealed that in addition to interneuronal nuclei, ERalpha-I was affiliated with the cytoplasmic plasmalemma of select interneurons and with endosomes of a subset of principal (pyramidal and granule) cells. Moreover, ERalpha labeling was found in profiles dispersed throughout the HF, but slightly more numerous in CA1 stratum radiatum. Approximately 50% of the ERalpha-labeled profiles were unmyelinated axons and axon terminals that contained numerous small, synaptic vesicles. ERalpha-labeled terminals formed both asymmetric and symmetric synapses on dendritic shafts and spines, suggesting that ERalphas arise from sources in addition to inhibitory interneurons. About 25% of the ERalpha-I was found in dendritic spines, many originating from principal cells. Within spines, ERalpha-I often was associated with spine apparati and/or polyribosomes, suggesting that estrogen might act locally through the ERalpha to influence calcium availability, protein translation, or synaptic growth. The remaining 25% of ERalpha-labeled profiles were astrocytes, often located near the spines of principal cells. Collectively, these results suggest that ERalpha may serve as both a genomic and nongenomic transducer of estrogen action in the HF.
Some humans develop the axonal form of Guillain-Barré syndrome after receiving bovine brain ganglioside. On sensitization with the ganglioside mixture, all of a group of rabbits injected developed high anti-GM1 IgG antibody titers, flaccid limb weakness of acute onset, and a monophasic illness course. Pathological findings for the peripheral nerves showed predominant Wallerian-like degeneration, with neither lymphocytic infiltration nor demyelination. IgG was deposited on the axons of the anterior roots, and GM1 was proved to be present on the axons of peripheral nerves. Sensitization with purified GM1 also induced axonal neuropathy, indicating that GM1 was the immunogen in the mixture. A model of human axonal Guillain-Barré syndrome has been established that uses inoculation with a bovine brain ganglioside mixture or isolated GM1. This model may help to clarify the molecular pathogenesis of the syndrome and to develop new treatments for it.
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