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Tumor necrosis factor ␣ (TNF-␣) is a potent cytokine in neurodegenerative disorders, but its precise role in particular brain disorders is ambiguous. In motor neuron (MN) disease of the mouse, exemplified by the model wobbler (WR), TNF-␣ causes upregulation of the metalloprotease-disintegrin ADAM8 (A8) in affected brain regions, spinal cord, and brainstem. The functional role of A8 during MN degeneration in the wobbler CNS was investigated by crossing WR with A8-deficient mice: a severely aggravated neuropathology was observed for A8-deficient WR compared with WR A8 ϩ/Ϫ mice, judged by drastically reduced survival [7 vs 81% survival at postnatal day 50 (P50)], accelerated force loss in the forelimbs, and terminal akinesis. In vitro protease assays using soluble A8 indicated specific cleavage of a TNF-␣ receptor 1 (p55 TNF-R1) but not a TNF-R2 peptide. Cleavage of TNF-R1 was confirmed in situ, because levels of soluble TNF-R1 were increased in spinal cords of standard WR compared with wild-type mice but not in A8-deficient WR mice. In isolated primary neurons and microglia, TNF-␣-induced TNF-R1 shedding was dependent on the A8 gene dosage. Furthermore, exogenous TNF-␣ showed higher toxicity for cultured neurons from A8-deficient than for those from wild-type mice, demonstrating that TNF-R1 shedding by A8 is neuroprotective. Our results indicate an essential role for ADAM8 in modulating TNF-␣ signaling in CNS diseases: a feedback loop integrating TNF-␣, ADAM8, and TNF-R1 shedding as a plausible mechanism for TNF-␣ mediated neuroprotection in situ and a rationale for therapeutic intervention.

Laser-induced fluorescence spectroscopy and batch experiments were combined to study the sorbed species of Eu(III) on amorphous silica and montmorillonite. In the silica system, more than six water molecules were removed from the first coordination sphere of Eu(III) above pH 7, suggesting that Eu(III) was incorporated into the silica. This fact was confirmed through the dependence on aging time and the desorption behavior after acidification. In the montmorillonite system, the Eu(III) aquo ion was sorbed as an outer-sphere complex on montmorillonite below pH 6. Two species with different fluorescence lifetimes were separately detected in higher pH regions in montmorillonite system. The faster component may be Eu(III)-hydroxide precipitates or Eu(III) surface precipitates, while for the slower component, the number of water molecules in the first coordination sphere of Eu(III) was 2-3. Similar studies on Eu(III) sorbed on kaolinite was also conducted for comparison with the results on montmorillonite.studies have employed LIF to study the aqueous and solid species of Eu(III).In this study, LIF was applied to Eu(III) sorbed on unporous silica (aerosil) and montmorillonite. Europium(III) is a member of the lanthanide(III) elements which include various fission products and is also regarded as an analogue of actinide(III) ions; unporous silica represents the surface of silicate minerals and montmorillonite is an important buffer material in repositories. In some parts of this study, kaolinite has also been employed, for comparison. The fluorescence lifetime (mainly 5 D 0 -• 7 F 2 ) and the emission spectrum of Eu(III) were employed to obtain structural information on the sorbed species. The lifetime often contains information on N U20 , the number of water molecules in the first coordination sphere of Eu(III). Based on the results of LIF and batch experiments using Eu-152 tracer, characterization of the sorbed species of Eu(III) was investigated.