IKKβ regulates endothelial thrombomodulin in a Klf2-dependent manner.

Background: Endothelial thrombomodulin (TM) is critically involved in anticoagulation, anti-inflammation, cytoprotection and normal fetal development. Tumor necrosis factor alpha (TNFα) suppresses TM expression.

Objective: TNFα has been shown to down-regulate TM partly via activation of nuclear factor kappa B (NF-κB).

Pharmacological tuning of heat shock protein 70 modulates polyglutamine toxicity and aggregation.

Nine neurodegenerative disorders are caused by the abnormal expansion of polyglutamine (polyQ) regions within distinct proteins. Genetic and biochemical evidence has documented that the molecular chaperone, heat shock protein 70 (Hsp70), modulates polyQ toxicity and aggregation, yet it remains unclear how Hsp70 might be used as a potential therapeutic target in polyQ-related diseases. We have utilized a pair of membrane-permeable compounds that tune the activity of Hsp70 by either stimulating or by inhibiting its ATPase functions.

Impaired heat shock response in cells expressing full-length polyglutamine-expanded huntingtin.

The molecular mechanisms by which polyglutamine (polyQ)-expanded huntingtin (Htt) causes neurodegeneration in Huntington's disease (HD) remain unclear. The malfunction of cellular proteostasis has been suggested as central in HD pathogenesis and also as a target of therapeutic interventions for the treatment of HD. We present results that offer a previously unexplored perspective regarding impaired proteostasis in HD.

Increased Abeta1-42 production sensitizes neuroblastoma cells for ER stress toxicity.

Alzheimer's disease (AD) is characterized by the aggregation and subsequent deposition of misfolded beta-amyloid (Abeta) peptide. The unfolded protein response (UPR) is activated by misfolded protein stress in the endoplasmic reticulum (ER). In previous studies we demonstrated mild activation of the UPR by extracellularly applied oligomeric but not fibrillar Abeta1-42.

Oligomer-specific Abeta toxicity in cell models is mediated by selective uptake.

Alzheimer's disease (AD) is characterized by the aggregation and subsequent deposition of misfolded beta-amyloid (Abeta) peptide. Previous studies show that aggregated Abeta is more toxic in oligomeric than in fibrillar form, and that each aggregation form activates specific molecular pathways in the cell. We hypothesize that these differences between oligomers and fibrils are related to their different accessibility to the intracellular space.