Inflammation and microglial activation are associated with Alzheimer's disease (AD) pathology. Somewhat surprisingly, injection of a prototypical inflammatory agent, lipopolysaccharide (LPS) into brains of amyloid precursor protein (APP) transgenic mice clears some of the pre-existing amyloid deposits. It is less well understood how brain inflammation modulates tau pathology in the absence of Aβ. These studies examined the role of LPS-induced inflammation on tau pathology. We used transgenic rTg4510 mice, which express the P301L mutation (4R0N TauP301L) and initiate tau pathology between 3-5 months of age. First, we found an age-dependent increase in several markers of microglial activation as these rTg4510 mice aged and tau tangles accumulated. LPS injections into the frontal cortex and hippocampus induced significant activation of CD45 and arginase 1 in rTg4510 and non-transgenic mice. In addition, activation of YM1 by LPS was exaggerated in transgenic mice relative to non-transgenic animals. Expression of Ser199/202 and phospho-tau Ser396 was increased in rTg4510 mice that received LPS compared to vehicle injections. However, the numbers of silver-positive neurons, implying presence of more pre- and mature tangles, was not significantly affected by LPS administration. These data suggest that inflammatory stimuli can facilitate tau phosphorylation. Coupled with prior results demonstrating clearance of Aβ by similar LPS injections, these results suggest that brain inflammation may have opposing effects on amyloid and tau pathology, possibly explaining the failures (to date) of anti-inflammatory therapies in AD patients.

The levels of plasma PTX3 were increased in patients with arterial inflammation, especially UAP. This PTX3 detection system will be useful for the prediction of UAP.

Wilms' tumor 1-associating protein (WTAP) has been reported to be a ubiquitously expressed nuclear protein. Although a relation to splicing factors has been postulated, its actual physiological function still remains to be elucidated. To investigate the role of WTAP, we generated WTAP-knockout mice and performed small interfering RNA (siRNA)-mediated knockdown analyses in primary cultured cells. In DNA microarrays using human umbilical vein endothelial cells, WTAP-targeted siRNA treatment resulted in markedly reduced expression of cell-cycle-related genes. siRNA-mediated WTAP knockdown down-regulated the stability of cyclin A2 mRNA through a nine-nucleotide essential sequence in cyclin A2 mRNA 3 UTR. WTAP knockdown induced G 2 accumulation, which is partially rescued by adenoviral overexpression of cyclin A2. Moreover, WTAP-null mice exhibited proliferative failure with death resulting at approximately embryonic day 6.5, an etiology almost identical to cyclin A2-null mice. Collectively, these findings establish WTAP as an essential factor for the stabilization of cyclin A2 mRNA, thereby regulating G 2͞M cell-cycle transition.mRNA stability ͉ cell-cycle regulation W ilms' tumor 1-associating protein (WTAP) was identified as a protein that specifically interacts with Wilms' tumor 1 (WT1) in both in vitro and in vivo assays (1). The Wilms tumor suppressor gene WT1 is essential for the normal development of the bipotential gonad, and the primordial kidney (2-4) and is associated with a common form of pediatric kidney cancer (5). WTAP and WT1 are present together throughout the nucleoplasm as well as in nuclear speckles and partially colocalize with splicing factors (1). WTAP was also identified as the mammalian homologue of the Drosophila female-lethal-2-D [fl(2)D]. fl(2)D is required for the female developmental pathway because of its activation of female-specific patterns of alternative splicing on SXL and transformer (tra) premRNA (6, 7). The presence of the lethal phenotype of the fl(2)D mutation in both sexes suggests an additional function for the gene (8). In vitro splicing assays demonstrated that depletion of WTAP from HeLa nuclear extracts affects tra but not AdML (a model adenovirus RNA) splicing, suggesting a biochemical function in female-specific splicing regulation (9). Furthermore, proteomic studies isolated WTAP as one of 145 spliceosomal proteins assembled on two distinct premRNAs, adenovirus major late and Fushi tarazu (10). While investigating GATA function in vascular endothelial cells, we serendipitously identified WTAP, in addition to GATAassociating proteins and hematopoietically expressed homeobox, from a yeast two-hybrid screen (11). In spite of these refined studies, the exact function of WTAP remains unknown.In the present study, we investigated the function of WTAP in vitro by using RNAi in primary cultured cells and in vivo by generating WTAP-knockout mice. Here, we demonstrate that WTAP is a factor essential for cyclin A2 mRNA stabilization and G 2 ͞M transition, the understanding of w...