Recent studies suggest that transplantation of mesenchymal stem cells might have therapeutic effects in preventing pathogenesis of several neurodegenerative disorders. Adipose-derived mesenchymal stem cells (ADSCs) are a promising new cell source for regenerative therapy. However, whether transplantation of ADSCs could actually ameliorate the neuropathological deficits in Alzheimer's disease (AD) and the mechanisms involved has not yet been established. Here, we evaluated the therapeutic effects of intracerebral ADSC transplantation on AD pathology and spatial learning/memory of APP/PS1 double transgenic AD model mice. Results showed that ADSC transplantation dramatically reduced b-amyloid (Ab) peptide deposition and significantly restored the learning/memory function in APP/PS1 transgenic mice. It was observed that in both regions of the hippocampus and the cortex there were more activated microglia, which preferentially surrounded and infiltrated into plaques after ADSC transplantation. The activated microglia exhibited an alternatively activated phenotype, as indicated by their decreased expression levels of proinflammatory factors and elevated expression levels of alternative activation markers, as well as Ab-degrading enzymes. In conclusion, ADSC transplantation could modulate microglial activation in AD mice, mitigate AD symptoms, and alleviate cognitive decline, all of which suggest ADSC transplantation as a promising choice for AD therapy. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation.

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RESULTSIn DI bladder muscle, spontaneous contractile activity persisted in the presence of blockers for known neurotransmitter receptors in the bladder wall. The RyR blocker ryanodine significantly increased the spontaneous contractile frequency in normal bladder strips, but failed to affect spontaneous contractions in DI muscle. Caffeine inhibited spontaneous contractile activity in both the DI and normal strips. After administering the L -type Ca 2 + channel antagonist nimodipine, the myogenic contractile activity was abolished in normal strips; in contrast, in DI strips, the amplitude of contractions was reduced but the frequency of contractions was unchanged. Western blot analysis showed that RyR expression was lower in DI muscle than in normal bladder muscle. CONCLUSIONThese results provide the first characterization of a loss of regulation of spontaneous contractile activity by RyRs in DI muscle associated with a significant decrease in RyR expression. RyRs in normal detrusor muscle act as negative-feedback regulators of spontaneous contractile activity, presumably by releasing Ca 2 + that activates Ca 2 + -dependent K + channels to decrease contractility. This mechanism might be weakened in DI muscle, resulting in spontaneous contractile overactivity.

To evaluate the changes in intercellular communication through gap junctions in detrusor overactivity (DO), we studied 23 adult female Wistar rats with DO after partial outflow obstruction (DO group) and 13 sham-operated rats (control group). The two groups were compared by means of urodynamics, light and electron microscopy, expression of Cx40, Cx43, and Cx45 mRNA genes with RT-PCR, Cx43 protein with Western blot analysis, and functional intercellular communication with scrape loading dye transfer (SLDT) and fluorescence recovery after photobleaching (FRAP). The number of gap junctions and the expression of connexin mRNA and Cx43 protein were increased in DO rats, and intercellular communication through gap junctions increased after 6 wk of partial outflow obstruction as assessed with SLDT and FRAP techniques. The findings provide a theoretical rationale for using Cx43 antagonists and gap junction inhibitors in the treatment of patients with overactive detrusor secondary to partial bladder outflow obstruction.

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It is widely acknowledged that E2F1 and GSK3␤ are both involved in the process of cell differentiation. However, the relationship between E2F1 and GSK3␤ in cell differentiation has yet to be discovered. Here, we provide evidence that in the differentiation of PC12 cells induced by nerve growth factor (NGF), GSK3␤ was increased at both the mRNA and protein levels, whereas E2F1 at these two levels was decreased. Both wild-type GSK3␤ and its kinase-defective mutant GSK3␤ KM can inhibit E2F1 by promoting its ubiquitination through physical interaction. In addition, the colocalization of GSK3␤ and E2F1 and their subcellular distribution, regulated by NGF, were observed in the process of PC12 differentiation. At the tissue level, GSK3␤ colocalized and interacted with E2F1 in mouse hippocampus. Furthermore, GSK3␤ facilitated neurite outgrowth by rescuing the promoter activities of Cdk inhibitors p21 and p15 from the inhibition caused by E2F1. To summarize, our findings suggest that GSK3␤ can promote the ubiquitination of E2F1 via physical interaction and thus inhibit its transcription activity in a kinase activity independent manner, which plays an important role in the NGF-induced PC12 differentiation.GSK3␤, a multifunctional serine/threonine (Ser/Thr) kinase that was originally identified as a regulator of glycogen metabolism, is now known to be a key kinase in several important signaling pathways. The kinase activity of GSK3␤ is positively regulated by phosphorylation of its Tyr 216 and negatively regulated by N-terminal phosphorylation of its Ser 9 (1). GSK3␤ is involved in several signaling pathways important for early central nervous system patterning and neuronal differentiation. For example, GSK3␤ down-regulates ␤-catenin via phosphorylation through the forming of a multicomponent complex with adenomatous polyposis coli and Axin, and thus inhibits the transcription of downstream genes in Wnt signaling (2). In addition, GSK3␤ regulates cell cycle by phosphorylating cyclin D1 and p21 (3-5). Also, it activates MRP2, an actin-binding protein of the kelch-related protein family, and promotes neurite outgrowth in NGF 3 -stimulated PC12 cells. Treatment of PC12 cells with GSK3␤-interfering RNAs results in the inhibition of neurite outgrowth (6). Moreover, GSK3␤ promotes dendrite formation through the ILK-GSK3␤ pathway in sympathetic neurons (7), and it regulates the phosphorylation of CRMP-2, adenomatous polyposis coli, and MAP1B, which are separately related to the polymerization, stabilization, and dynamics of microtubules, principal cytoskeletal components of axons (8).The E2F family has at least 10 members, classified as E2Fs (E2F1 to -8) and DPs (DP1 and -2). Physiological E2F exists as E2F/DP heterodimers in mammalian cells, binding and regulating E2F-targeted genes (9, 10). The E2F family plays a crucial role in regulating cell cycle progression at the G 1 -S transition mediated by pRB, a retinoblastoma tumor suppressor protein. pRB is phosphorylated in a cell cycle-dependent manner by cyclin-dependent kinases ...