AbstactThe effect of V 2 O 5 addition on molybdates crystallization tendency, glass structure and chemical durability of aluminoborosilicate glass belonging to SiO 2 -B 2 O 3 -CaO-Na 2 O-Al 2 O 3 -MoO 3 system has been studied. The results confirm that V 2 O 5 addition can effectively suppress the crystallization tendency of powellite and enhance the molybdenum solubility in the glass. The MoO 3 solubility limit is found to be 2.8 mol% in the V 2 O 5 -containing aluminoborosilicate glass. Raman results reveal that V 2 O 5 addition seems to modify the local structural environment of isolated MoO 4 units and increase their chemical disorder in the glass, which is favored for molybdenum incorporation in the glass. The molar volume and glass transition temperature of samples are found to depend on V 2 O 5 content. Product consistency test (PCT) results show that the normalized leaching rates of the V 2 O 5 -containing aluminoborosilicate glass maintain at a fairly low level compared with standard borosilicate glassy waste form.
Soluble amyloid-β-protein (Aβ) oligomers, a major hallmark of AD, trigger the integrated stress response (ISR) via multiple pathologies including neuronal hyperactivation, microvascular hypoxia, and neuroinflammation. Increasing eIF2α phosphorylation, the core event of ISR, facilitates metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), and suppressing its phosphorylation has the opposite effect. Having found the facilitation of mGluR5-LTD by Aβ in live rats, we wondered if suppressing eIF2α phosphorylation cascade would protect against the synaptic plasticity and cognitive disrupting effects of Aβ. We demonstrate here that the facilitation of mGluR5-LTD in a delayed rat model by single i.c.v. injection of synthetic Aβ1–42. Systemic administration of the small-molecule inhibitor of the ISR called ISRIB (trans-isomer) prevents Aβ-facilitated LTD and abrogates spatial learning and memory deficits in the hippocampus in exogenous synthetic Aβ-injected rats. Moreover, ex vivo evidence indicates that ISRIB normalizes protein synthesis in the hippocampus. Targeting the ISR by suppressing the eIF2α phosphorylation cascade with the eIF2B activator ISRIB may provide protective effects against the synaptic and cognitive disruptive effects of Aβ which likely mediate the early stage of sporadic AD.
Background: Cognitive decline in Alzheimer’s disease (AD) correlates with the extent of tau pathology, in particular tau hyperphosphorylation, which is strongly age-associated. Although elevation of cerebrospinal fluid or blood levels of phosphorylated tau (p-Tau) at residues Thr181 (p-Tau181), Thr217 (p-Tau217), and Thr231 (p-Tau231) are proposed to be particularly sensitive markers of preclinical AD, the generation of p-Tau during brain activity is poorly understood. Objective: To study whether the expression levels of p-Tau181, p-Tau217, and p-Tau231 can be enhanced by physiological synaptic long-term depression (LTD) which has been linked to the enhancement of p-Tau in hippocampus. Methods: In vivo electrophysiology was performed in urethane anesthetized young adult and aged male rats. Low frequency electrical stimulation (LFS) was used to induce LTD at CA3 to CA1 synapses. The expression level of p-Tau and total tau was measured in dorsal hippocampus using immunofluorescent staining and/or western blotting. Results: We found that LFS enhanced p-Tau181 and p-Tau217 in an age-dependent manner in the hippocampus of live rats. In contrast, phosphorylation at residues Thr231, Ser202/Thr205, and Ser396 appeared less sensitive to LFS. Pharmacological antagonism of either N-methyl-D-aspartate or metabotropic glutamate 5 receptors inhibited the elevation of both p-Tau181 and p-Tau217. Targeting the integrated stress response, which increases with aging, using a small molecule inhibitor ISRIB, prevented the enhancement of p-Tau by LFS in aged rats. Conclusion: Together, our data provide a novel in vivo means to uncover brain plasticity-related cellular and molecular processes of tau phosphorylation at key sites in health and aging.
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