Affective dimensions as a diagnostic tool for bipolar disorder in first psychotic episodes.

OBJECTIVE: To examine the predictive diagnostic value of affective symptomatology in a first-episode psychosis (FEP) sample with 5 years' follow-up. METHOD: Affective dimensions (depressive, manic, activation, dysphoric) were measured at baseline and 5 years in 112 FEP patients based on a factor structure analysis using the Young Mania Rating Scale and Hamilton Depression Rating Scale. Patients were classified as having a diagnosis of bipolar disorder at baseline (BDi), bipolar disorder at 5 years (BDf), or "other psychosis". The ability of affective dimensions to discriminate between these diagnostic groups and to predict a bipolar disorder diagnosis was analysed. RESULTS: Manic dimension score was higher in BDi vs. BDf, and both groups had higher manic and activation scores vs. "other psychosis". Activation dimension predicted a bipolar diagnosis at 5 years (odds ratio=1.383; 95% confidence interval, 1.205-1.587; P=0.000), and showed high levels of sensitivity (86.2%), specificity (71.7%), positive (57.8%) and negative predictive value (90.5%). Absence of the manic dimension and presence of the depressive dimension were both significant predictors of an early misdiagnosis. CONCLUSION: The activation dimension is a diagnostic predictor for bipolar disorder in FEP. The manic dimension contributes to a bipolar diagnosis and its absence can lead to early misdiagnosis.

In vitro assembly of tau protein: mapping the regions involved in filament formation.

Unraveling the mechanism of self-assembly of the protein tau into paired helical filaments (PHFs) is a crucial step toward the understanding of Alzheimer's and other neuropathological diseases at the molecular level. In an effort to map the role of different regions of tau in the mechanism of self-assembly, we have studied the polymerization ability of different tau fragments using an in vitro assay. Our results indicate that the N-terminal domain interferes with tau's ability to polymerize in vitro. The effect seems to be size dependent. Particularly, an isoform of tau from the peripheral nervous system, which has a much larger N-terminal domain, was found unable to form filaments in our in vitro assay. This finding can explain why in Alzheimer's patients PHFs only accumulate in the neurons from the central nervous system. We also report that a short segment of tau located in the third microtubule binding repeat (residues 317 to 335, peptide 1/2R) is probably the minimal segment of that region able to grow into filaments in vitro and in the presence of heparin. In contrast with whole peptide 1/2R, peptides corresponding to either the N-terminal or C-terminal halves of this segment were unable to form filaments. Finally, our polymerization studies of peptides from the C-terminal domain reveal a short sequence spanning residues 391 to 407 that grows into filaments in vitro. This tau segment forms filaments regardless of whether is incubated with heparin. Moreover, such filaments differ in diameter and morphology, suggesting a different mechanism of self-assembly.

The FTDP-17-linked mutation R406W abolishes the interaction of phosphorylated tau with microtubules.

The recent finding that several point mutations in the gene encoding for the microtubule-binding protein tau correlate with neurological disorders has heightened interest in the mechanisms of destabilization of this protein. In this study the functional consequences of the tau mutation R406W on the interaction of the protein with microtubules have been analyzed. Mutated tau is less phosphorylated than its normal counterpart at serines 396 and 404. Furthermore, the phosphorylated mutant protein is unable to bind to microtubules, and, as a consequence, microtubules assembled after transient nocodazole treatment in the presence of this tau variant contain only unmodified tau and appear to form more and longer bundles than those assembled in the presence of wild-type tau. We propose that phosphorylated tau, unbound to microtubules, could accumulate in the cytoplasm.

Tau dephosphorylation at tau-1 site correlates with its association to cell membrane.

It has been considered that tau protein is mainly a cytoplasmic protein since it is a microtubule associated protein. However, it has also been suggested that tau could be located in the cell nucleus and membrane. In our work, the cellular distribution of tau has been studied by immunofluorescence and western blot analysis, after subcellular fractionation in neuroblastoma cells and in tau-transfected non neural cells using, mainly, two types of tau antibodies; antibody 7.51 (that recognizes tau independent of its phosphorylation level); and antibody Tau-1 (that recognizes tau only in its dephosphorylated form). Also, tau was expressed in COS-1 cells to test for the features involved in the sorting of tau to different cell localizations. Our results show that tau associated to cell membrane has a lower phosphorylation level in its proline-rich region. Additionally, in differentiated neuroblastoma cells, tau phosphorylation, at that region, decreases and the amount of tau associated to cell membrane increases.

Polymerization of tau peptides into fibrillar structures. The effect of FTDP-17 mutations.

The peptides corresponding to the four repeats found in the microtubule binding region of tau protein were synthesized and their ability for self-aggregation in presence of heparin or chondroitin sulfate was measured. Mainly, only the peptide containing the third tau repeat is able to form polymers in a high proportion. Additionally, the peptide containing the second repeat aggregates with a very low efficiency. However, when this peptide contains the mutation (P301L), described in a fronto temporal dementia, it is able to form polymers at a higher extent. Finally, it is suggested to have a role for the first and fourth tau repeats. It could be to decrease the ability of the third tau repeat for self-aggregation in the presence of heparin.

Ferritin is associated with the aberrant tau filaments present in progressive supranuclear palsy.

Tau-containing filaments purified from the brain of progressive supranuclear palsy (PSP) patients were isolated and characterized. These filaments co-purify with regular particles that biophysical and biochemical methods identified as ferritin shells. In vivo, brain tau accumulation in PSP co-localized with ferritin. These results suggest that ferritin/iron could modulate the formation of tau aggregates in PSP.

Role of glycosaminoglycans in determining the helicity of paired helical filaments.

It is known from previous work that tau is the main component of paired helical filaments (PHFs) and that it can assemble in vitro into polymers resembling PHFs when high concentrations of protein are used. In the search for molecules that can facilitate tau polymerization, a component of neurofibrillary tangles, heparan sulfate (or its more sulfated form, heparin), and other glycosaminoglycans have been tested. Glycosaminoglycans, in the sulfated but not in the unsulfated form, facilitate not only tau assembly but also the formation of polymers resembling PHFs. Conversely, PHFs were found to contain heparan sulfate and chondroitin sulfate. Heparinase or chondroitinase treatment of PHFs results in the formation of straight structures. All of these results suggest a role for sulfated glycosaminoglycans in determining the helicity of PHFs.