Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebral amyloid angiopathy, associated to most cases of Alzheimer's disease (AD), is characterized by the deposition of amyloid ss-peptide (Ass) in brain vessels, although the origin of the vascular amyloid deposits is still controversial: neuronal versus vascular. In the present work, we demonstrate that primary cultures of human cerebral vascular smooth muscle cells (HC-VSMCs) have all the secretases involved in amyloid ss-protein precursor (APP) cleavage and produce Ass(1-40) and Ass(1-42). Oxidative stress, a key factor in the etiology and pathophysiology of AD, up-regulates ss-site APP cleaving enzyme 1 (BACE1) expression, as well as Ass(1-40) and Ass(1-42) secretion in HC-VSMCs. This process is mediated by c-Jun N-terminal Kinase and p38 MAPK signaling and appears restricted to BACE1 regulation as no changes in the other secretases were observed. In conclusion, oxidative stress-mediated up-regulation of the amyloidogenic pathway in human cerebral vascular smooth muscle cells may contribute to the overall cerebrovascular amyloid angiopathy observed in AD patients.
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PMID:Oxidative stress triggers the amyloidogenic pathway in human vascular smooth muscle cells. 1730 21

Alzheimer's disease (AD) is characterized by accumulation and deposition of Abeta peptides in the brain. Abeta deposition in cerebral vessels occurs in many AD patients and results in cerebral amyloid angiopathy (AD/CAA). Abeta deposits evoke neuro- and neurovascular inflammation contributing to neurodegeneration. In this study, we found that exposure of cultured human brain endothelial cells (HBEC) to Abeta(1-40) elicited expression of inflammatory genes MCP-1, GRO, IL-1beta and IL-6. Up-regulation of these genes was confirmed in AD and AD/CAA brains by qRT-PCR. Profiling of 54 transcription factors indicated that AP-1 was strongly activated not only in Abeta-treated HBEC but also in AD and AD/CAA brains. AP-1 complex in nuclear extracts from Abeta-treated HBEC bound to AP-1 DNA-binding sequence and activated the reporter gene of a luciferase vector carrying AP-1-binding site from human MCP-1 gene. AP-1 is a dimeric protein complex and supershift assay identified c-Jun as a component of the activated AP-1 complex. Western blot analyses showed that c-Jun was activated via JNK-mediated phosphorylation, suggesting that as a result of c-Jun phosphorylation, AP-1 was activated and thus up-regulated MCP-1 expression. A JNK inhibitor SP600125 strongly inhibited Abeta-induced c-Jun phosphorylation, AP-1 activation, AP-1 reporter gene activity and MCP-1 expression in cells stimulated with Abeta peptides. The results suggested that JNK-AP1 signaling pathway is responsible for Abeta-induced neuroinflammation in HBEC and Alzheimer's brain and that this signaling pathway may serve as a therapeutic target for relieving Abeta-induced inflammation.
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PMID:Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer's brain is mediated by the JNK-AP1 signaling pathway. 1916 85