No abstract

PrP C -deficient mice expressing prion protein variants with large amino-proximal deletions (termed PrP DF ) suffer from neurodegeneration, which is rescued by full-length PrP C . We now report that expression of PrP DCD , a PrP variant lacking 40 central residues (94-134), induces a rapidly progressive, lethal phenotype with extensive central and peripheral myelin degeneration. This phenotype was rescued dose-dependently by coexpression of full-length PrP C or PrP C lacking all octarepeats. Expression of a PrP C variant lacking eight residues (114-121) was innocuous in the presence or absence of full-length PrP C , yet enhanced the toxicity of PrP DCD and diminished that of PrP DF . Therefore, deletion of the entire central domain generates a strong recessive-negative mutant of PrP C , whereas removal of residues 114-121 creates a partial agonist with context-dependent action. These findings suggest that myelin integrity is maintained by a constitutively active neurotrophic protein complex involving PrP C , whose effector domain encompasses residues 94-134.

Deposition of the beta-amyloid peptide (Abeta) in the brain occurs during normal ageing and is substantially accelerated in patients with Alzheimer's disease. Since Abeta is continuously produced in the brain, it has been suggested that a clearance mechanism should exist to prevent its accumulation and subsequent aggregation. Until now, little attention has been paid to the possible role of P-glycoprotein (P-gp), a member of the ATP binding cassette superfamily of transporter proteins, in the pathogenesis of Alzheimer's disease. A recent study demonstrated that Abeta40 and Abeta42 interact directly with P-gp. We therefore hypothesized that Abeta accumulation in the brain would correlate inversely with the degree of vascular P-gp expression. To study early pathogenetic factors that influence the deposition of Abeta, at routine autopsies, brain tissue samples were taken from 243 non-demented subjects who died between the ages of 50 and 91 years. Vascular P-gp expression and the number of Abeta40- and Abeta42-positive senile plaques were assessed immunohistochemically in the medial temporal lobe. In addition, the apolipoprotein E (apoE) genotypes, as well as multiple drug resistance gene 1 ( ) polymorphisms (exon 2, G-1A; exon 21, G2677T/A; exon 26, C3436T), were also determined for each case. P-gp expression was not correlated with genotypes, but we found a significant inverse correlation between P-gp expression and the deposition of both Abeta40 and Abeta42 in the medial temporal lobe. Our results provide the first evidence in human brain tissue that the accumulation of Abeta may be influenced by the expression of P-gp in blood vessels, and suggest that P-gp may influence the elimination of Abeta from brain.

Neuronal subthreshold excitability and firing behaviour are markedly influenced by the activation and deactivation of the somato-dendritic hyperpolarization-activated cation current (Ih). Here, we evaluated possible contributions of Ih to hyperexcitability in an animal model of absence seizures (WAG/Rij rats). We investigated pyramidal neurons of the somatosensory neocortex, the site of generation of spike-wave discharges. Ih-mediated functions in neurons from WAG/Rij rats, Wistar rats (sharing the same genetic background with WAG/Rij, but less epilepsy-prone) and ACI rats (an inbred strain, virtually free of seizures) were compared. We complemented whole-cell recordings from layer 2-3 pyramidal neurons with immunohistochemistry, Western blot and RT-PCR analysis of the h-channel subunits HCN1-4. The fast component of Ih activation in WAG/Rij neurons was significantly reduced (50% reduction in the h-current density) and four times slower than in neurons from nonepileptic Wistar or ACI rats. The results showing decreases in currents corresponded to a 34% reduction in HCN1 protein in the WAG/Rij compared to the Wistar neocortex, but HCN1 mRNA showed stable expression. The other three Ih subunit mRNAs and proteins (HCN2-4) were not affected. The alterations in Ih magnitude and kinetics of gating in WAG/Rij neurons may contribute to augmented excitatory postsynaptic potentials, the increase in their temporal summation and the facilitation of burst firing of these neurons because each of these effects could be mimicked by the selective Ih antagonist ZD 7288. We suggest that the deficit in Ih-mediated functions may contribute to the development and onset of spontaneously occurring hyperexcitability in a rat model of absence seizures.

Flowers sensu lato are short, specialized axes bearing closely aggregated sporophylls. They are typical for seed plants (spermatophytes) and are prominent in f lowering plants sensu stricto (angiosperms), where they often comprise an attractive perianth. There is evidence that spermatophytes evolved from gymnosperm-like plants with a fern-like mode of reproduction called progymnosperms. It seems plausible, therefore, that the stamens͞carpels and pollen sacs͞nucelli of spermatophytes are homologous to fern sporophylls and sporangia, respectively. However, the exact mode and molecular basis of early seed and f lower evolution is not yet known. Comparing f lower developmental control genes to their homologs from lower plants that do not f lower may help to clarify the issue. We have isolated and characterized MADS-box genes expressed in gametophytes and sporophytes of the fern Ceratopteris. The data indicate that at least two different MADS-box genes homologous to f loral homeotic genes existed in the last common ancestor of contemporary vascular plants, some descendants of which underwent multiple duplications and diversifications and were recruited into novel developmental networks during the evolution of f loral organs.