Cooexpression of FTDP-17 tau and GSK-3β in transgenic mice induce tau polymerization and neurodegeneration

Background/Aims: TREM2 plays a crucial role in modulating microglial function through interaction with DAP12, the adapter for TREM2. Emerging evidence has demonstrated that TREM2 could suppress neuroinflammatory responses by repression of microglia-mediated cytokine production. This study investigated the potential role of TREM2 in surgery-induced cognitive deficits and neuroinflammatory responses in wild-type (WT) and APPswe/PS1dE9 mice. Methods: Adult APPswe/PS1dE9 transgenic male mice (a classic transgenic model of Alzheimer’s disease, 3 months old) and their age-matched WT mice received intracerebral lentiviral particles encoding the mouse TREM2 gene and then were subjected to partial hepatectomy at 1 month after the lentiviral particle injection. The behavioral changes were evaluated with an open-field test and Morris water maze test on postoperative days 3, 7, and 14. Hippocampal TREM2, DAP12, and interleukin (IL)-1β were measured at each time point. Ionized calcium-binding adapter molecule 1 (Iba-1), microglial M2 phenotype marker Arg1, synaptophysin, tau hyperphosphorylation (T396), and glycogen synthase kinase-3β (GSK-3β) were also examined in the hippocampus. Results: Surgical trauma induced an exacerbated cognitive impairment and enhanced hippocampal IL-1β expression in the transgenic mice on postoperative days 3 and 7. A corresponding decline in the levels of TREM2 was also found on postoperative days 3, 7, and 14. Overexpression of TREM2 downregulated the levels of IL-1β, ameliorated T396 expression, inhibited the activity of GSK-3β, and improved sickness behavior. Increased Arg1 expression and a high level of synaptophysin were also observed in the transgenic mice following TREM2 overexpression. Conclusion: The downregulation of TREM2 exacerbated surgery-induced cognitive deficits and exaggerated neuroinflammatory responses in this rodent model. Overexpression of TREM2 potentially attenuated these effects by decreasing the associated production of proinflammatory cytokines, inhibiting tau hyperphosphorylation, and enhancing synaptophysin expression.

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Abstract 187: Overexpression of Calpastatin Enhances Cardiotoxicity Induced by Doxorubicin

Circulation Research ◽

10.1161/res.111.suppl_1.a187 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Tianqing Peng ◽

Yanpeng Wang ◽

Jian Ma

Keyword(s):

Transgenic Mice ◽

Glycogen Synthase ◽

Myocardial Dysfunction ◽

Effective Prevention ◽

Doxorubicin Treatment ◽

Over Expression ◽

Calcium Dependent ◽

Gsk 3Β ◽

Calpain Inhibition

Background: Doxorubicin causes damage to the heart, which may present as cardiomyopathy. However, the mechanisms by which doxorubicin induces cardiotoxicity remain not fully understood and no effective prevention for doxorubicin cardiomyopathy is available. Calpains, a family of calcium-dependent thiol-proteases, have been implicated in cardiovascular diseases. Their activities are tightly controlled by calpastatin. This study employed transgenic mice over-expressing calpastatin to investigate the role of calpain in doxorubicin-induced cardiotoxicity. Methods and Results: Doxorubicin treatment decreased calpain activities in cultured neonatal mouse cardiomyocytes and in vivo mouse hearts. Over-expression of calpastatin or incubation with pharmacological calpain inhibitors enhanced caspase-3 activity and DNA fragmentation in both neonatal and adult cardiomyocytes induced by doxorubicin. Inhibition of calpain also induced down-regulation of phosphorylated protein kinase B (AKT, Thr308), and a concomitant reduction in glycogen synthase kinase-3beta (GSK-3β) phosphorylation (Ser9) in doxorubicin-treated cardiomyocytes. Blocking AKT further increased doxorubicin-induced cardiac injuries, suggesting the effects of calpain inhibition may be mediated by inactivating the AKT/GSK-3β signaling. In an in vivo model of doxorubicin-induced cardiotoxicity, over-expression of calpastatin decreased calpain activities and exacerbated myocardial dysfunction as assessed by echocardiography and hemodynamic measurement in transgenic mice (C57BL/6) 5 days after doxorubicin injection. The five-day mortality was higher in transgenic mice (29.16%) compared with their wild-type littermates (8%) after doxorubicin treatment. Conclusions: Over-expression of calpastatin enhances doxorubicin-induced cardiac injuries through inhibiting calpain and compromising AKT survival signaling. Thus, calpains may protect cardiomyocytes against doxorubicin-induced cardiotoxicity.

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