Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Mutations in the gene (Mtapt) encoding tau protein cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby proving that tau dysfunction can directly result in neurodegeneration. Expression of human tau containing the most common FTDP-17 mutation (P301L) results in motor and behavioural deficits in transgenic mice, with age- and gene-dose-dependent development of NFT. This phenotype occurred as early as 6.5 months in hemizygous and 4.5 months in homozygous animals. NFT and Pick-body-like neuronal lesions occurred in the amygdala, septal nuclei, pre-optic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord, with tau-immunoreactive pre-tangles in the cortex, hippocampus and basal ganglia. Areas with the most NFT had reactive gliosis. Spinal cord had axonal spheroids, anterior horn cell loss and axonal degeneration in anterior spinal roots. We also saw peripheral neuropathy and skeletal muscle with neurogenic atrophy. Brain and spinal cord contained insoluble tau that co-migrated with insoluble tau from AD and FTDP-17 brains. The phenotype of mice expressing P301L mutant tau mimics features of human tauopathies and provides a model for investigating the pathogenesis of diseases with NFT.

To elucidate the role cAMP-dependent protein kinase (PKA) phosphorylations on tau play in Alzheimer's disease, we have generated highly specific monoclonal antibodies, CP-3 and PG-5, which recognize the PKA-dependent phosphorylations of ser214 and ser409 in tau respectively. The present study demonstrates by immunohistochemical analysis, CP-3 and PG-5 immunoreactivity with neurofibrillary pathology in both early and advanced Alzheimer's disease, but not in normal brain tissue and demonstrates that cAMP-dependent protein kinase phosphorylations on tau precede or are coincident with the initial appearance of filamentous aggregates of tau. Studies using heat-stable preparations demonstrate that neither site appears to be phosphorylated to any appreciable extent in normal rodent or human brain. Further analysis demonstrates that the ␤ catalytic subunit of PKA (C␤), the ␤ II regulatory subunit of PKA (RII␤), and the 79 kDa A-kinase-anchoringprotein (AKAP79), are tightly associated with the neurofibrillary pathology, positioning cAMP-dependent protein kinase to participate directly in the pathological hyperphosphorylation of tau seen in Alzheimer's disease.

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Regulation of cytoplasmic calcium is crucial both for proper neuronal function and cell survival. The concentration of Ca2+ in cytoplasm of a neuron at rest is 10,000 times lower than in the extracellular space, pointing to the importance of the transporters that extrude intracellular Ca2+. The family of plasma membrane calcium-dependent ATPases (PMCAs) represent a major component of the Ca2+ regulatory system. However, little information is available on the regional and cellular distribution of these calcium pumps. We used immunohistochemistry to investigate the distribution of each of the four PMCA isoforms (PMCA1-4) in the rat brain. Each isoform exhibited a remarkably precise and distinct pattern of distribution. In many cases, PMCA isoforms in a single brain structure were differentially expressed within different classes of neurons, and within different subcellular compartments. These data show that each isoform is independently organized and suggest that PMCAs may play a more complex role in calcium homeostasis than generally recognized.

This study attempts to determine whether the pathways from the guinea pig dorsal nucleus of the lateral lemniscus (DNLL) to the inferior colliculus (IC) use gamma-aminobutyric acid (GABA) as a transmitter. Injections of kainic acid (KA) were used to destroy neurons in the left DNLL. Two to 4 days after the injection, Nissl-stained sections through the lesion site showed destruction of the DNLL neurons. The lesions varied in size; 12-100% of the DNLL neurons were destroyed on the injected side without damage to the ipsilateral IC. Two to 4 days after the injection, the electrically evoked, Ca(2+)-dependent release and high-affinity uptake of [3H]GABA were measured in dissected pieces of the left and right IC. These activities were compared with those in the IC taken from unlesioned controls and from sham controls, which received injections of saline instead of KA. Each IC was divided into a dorsal piece, which contained the dorsal cortex and dorsomedial nucleus, and a ventral piece, which contained the central and lateral nuclei. Lesions of the left DNLL depressed the release and uptake of [3H]GABA in the ventral pieces of the IC, but there was a greater depression in the ventral IC contralateral to the lesioned DNLL. There were good correlations between the percentage of neuronal loss in the left DNLL and deficits in [3H]GABA release and uptake activities in the ipsi- and contralateral ventral IC. By contrast, there was no depression of [3H]GABA release and uptake in the dorsal pieces of the IC. The localization of the deficits in release and uptake appears to match the distribution of the synaptic endings of the DNLL pathways in the IC. This correspondence associates GABA release and uptake activities with the DNLL projections to the IC and, therefore, suggests that GABA may be a transmitter of these pathways. The release and uptake of [14C]glycine was also measured to determine whether glycine might be a transmitter of the DNLL pathways to the IC. Lesions of the left DNLL failed to alter the Ca(2+)-dependent release or the uptake of [14C]-glycine, suggesting that DNLL neurons are unlikely to use this compound as a transmitter.

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We have identified a developmentally regulated, oligodendrocyte-specific protein, designated microtubule-associated protein-2 expressing exon 13 (MAP-2+13), in the human central nervous system (CNS). Monoclonal antibodies directed against MAP-2+13 labeled oligodendrocytes in the white matter of human fetal spinal cord. Double-label immunofluorescence and confocal microscopy, and immunoelectron microscopy localized MAP-2+13 to the soma and extending processes of fetal oligodendrocytes, but not to the myelin sheath. The immunoreactivity was throughout the perikarya. Ultrastructural examination of the fetal myelin sheaths showed them to be thin and not fully compacted, indicating that myelination was in progress. There was no overlap in staining of GFAP+ astrocytes and MAP-2+13+ oligodendrocytes. MAP-2+13 was also expressed in intermediate filament-negative "radial glia" extending from the central canal to the subpial surface. In the mature CNS, MAP-2+13 also marked cells of oligodendroglial morphology, but these cells were rare. These finding demonstrate that in the human CNS, MAP-2+13 is a novel protein transiently expressed in cells of oligodendroglial lineage.

No abstract