Alonso et al. (Abstract 590) reviewed the role of tau proteins in tubulin polymerization. There are six tau isoforms in the human brain. Three have three microtubule-binding domains (3R) and the three others have four microtubule-binding domains (4R). In Alzheimer's disease (AD), all six tau isoforms are found abnormally phosphorylated in paired helical filaments (PHF) and referred to as AD-P-tau. 4R isoforms bind better to microtubules than 3R isoforms. AD-P-tau induces microtubule depolymerization. AD-P-tau binds to normal tau isoforms (2+3+10+>2+3-10>2-3-10+>2+3+10->2+3-10->2-3-10-). AD-P-tau inhibits microtubule polymerization induced by normal tau isoforms by binding to them. This may be useful in developing new therapeutic strategies.

By immunoblotting using specific tau antibodies, Buée et al. (Abstract 591) demonstrated that all six hyperphosphorylated tau isoforms aggregate into PHF. Tau isoforms without the exon 10 sequence (3R) are hyperphosphorylated in Pick's disease, with the exception of the 12E8 epitope, and aggregate into Pick bodies in particular subsets of neurons. In corticobasal degeneration and progressive supranuclear palsy, 4R tau isoforms are hyperphosphorylated and aggregate into straight filaments. Similar conclusions were obtained using tau cDNAs with or w/o exon 10 and COS cell transfection followed by OA treatment. These data suggest that different subsets of neurons expressed tau isoforms at different levels.

Brion et al. (Abstract 592) obtained transgenic mice for the shortest tau isoform (fetal). They used the promoter of 3-hydroxy-methyl-glutaryl CoA reductase gene. The transgene was expressed preferentially in the brain. Somatodendritic domain in neurons was strongly labeled by AT180 and AT270 antibodies. Astrocytic structures were labeled by PHF-1 and AD2 antibodies. No labeling was obtained with Ubiquitin, TG3, AP22, AT100 and AT8 antibodies. These mice display a neuronal pathology similar as that described for pretangles.

Wang et al. (Abstract 593) studied tau phosphorylation and its effects on tubulin polymerization. Tau isoform was phosphorylated using CK-1, GSKß and pKA. Phosphorylated tau isoform inhibited tubulin polymerization. The weakest effect was observed when tau was phosphorylated by CK-1. The inhibition was much more severe with GSK3, then pKA, CK-1 + GSK3 and dramatic with pKA +GSK3. The phosphorylation sites dscribed in the present work are different from those found by Zheng-Fishhöfer (Abstract 914). Vincent et al. (Abstract 594) nicely demonstrated the importance of mitotic mechanisms in AD. Cdk2 activity slightly increases in AD. Cyclin A is not detected in controls and is present in AD. Cyclin A complex activity increases in AD. Upstream regulators of cdc2 (cdc25 A and B isoforms, cdk7) were analyzed. As an example, cdc25A data were presented. Cdc25A is expressed in NFT and dystrophic neurites but also present in neurons in controls. Equivalent amounts are found in AD and C. Surprisingly, cdc25A is constitutively active in differentiated neurons of human brain. Expression of mitotic kinase/cyclin is an initiating step in NFD.

Arendt et al. (Abstract 595) brought more arguments about the high degree of plasticity in neurons predispose to tangle formation by studying cdk inhibitors. Cdk inhibitors are elevated in AD and are closely associated with neurofibrillary degeneration. It is true for p15 INK4b, p16INK4a, p18INK4c and p19INK4d. However, no alteration of altered expression of p21Cip1 and p27Kip1. Finally, INK4 and NFD have similar regional distribution patterns.

Takashima et al. (Abstract 596). confirmed that PS1 mutations increased Aß42 formation. They have also analyzed the interactions Tau-PS1 and GSK3ß-PS1. They found that both GSK3ß and Tau bind to the same region on PS1 [250-298]. PS1 mutations (C263R and P264L) increase by about three times the association PS1-GSK3ß. They do not increase the association PS1-Tau. However, tau hyperphosphorylation was increased. These data suggest that there may be a physiological connection between tau, GSK3 and PS1.

Lee et al. (Abstract 597) demonstrated in a very complete study that tau proteins bind to SH3 (Src homology 3) domains of Fyn. SH3 (from Fyn, Lek and src) usually binds PXXP proline-rich motives. Fyn is expressed in brain and thymus. In brain, it is localized in developing axonal tracts and promotes neurite growth in response to specific cell adhesion molecules. Fyn is also required in cytokinesis in B cells. They found that a subpool of tau binds Fyn. When Tau and Fyn are co-transfected, they colocalized in 3T3 cells. Furthermore, cell morphology is completly modified: cells are spherical. After Fyn transfection, Tau is found Tyr phosphorylated. Tau protein is more than a MAP...—Luc Buee

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