Gfap -antisense prevents disease with early treatment and reverses clinical phenotypes with late treatment in a rat model of Alexander disease.

IF (intermediate filament) proteins can be cleaved by caspases to generate proapoptotic fragments as shown for desmin. These fragments can also cause filament a...

Neuroinflammation plays a central role in the pathophysiology of Alzheimer’s disease (AD). Compounds that suppress neuroinflammation have been identified as potential therapeutic targets for AD. Rhinacanthin C (RC), a naphthoquinone ester found in Rhinacanthus nasutus Kurz (Acanthaceae), is currently proposed as an effective molecule against inflammation. However, the exact role of RC on neuroinflammation remains to be elucidated. In the present study, we investigated RC effect on modulating lipopolysaccharides (LPS), amyloid‐β peptide (Aβ), or interferon‐γ‐ (IFN‐γ‐) evoked pathological events in neurons and glia. Our findings demonstrated that RC prevented Aβ‐induced toxicity in rat hippocampal neurons and attenuated LPS‐activated nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) expression, and NF‐κB signaling in rat glia. Likewise, RC suppressed LPS‐induced neuroinflammation by reducing NO production and iNOS, IL‐1β, CCL‐2, and CCL‐5 mRNA levels in rat microglia. Further studies using BV‐2 microglia revealed that RC inhibited LPS‐, Aβ‐, and IFN‐γ‐stimulated IL‐6 and TNF‐α secretion. Of note, NF‐κB and ERK activation was abrogated by RC in BV‐2 cell response to Aβ or IFN‐γ. Moreover, RC protected neurons from Aβ‐stimulated microglial conditioned media‐dependent toxicity. Collectively, these data highlight the beneficial effects of RC on neuroprotection and support the therapeutic implications of RC to neuroinflammation‐mediated conditions.

Alexander disease (AxD) is a primary genetic disorder of astrocytes caused by dominant mutations in the gene encoding the intermediate filament (IF) protein GFAP. This disease is characterized by excessive accumulation of GFAP, known as Rosenthal fibers, within astrocytes. Abnormal GFAP aggregation also occurs in giant axon neuropathy (GAN), which is caused by recessive mutations in the gene encoding gigaxonin. Given that one of the functions of gigaxonin is to facilitate proteasomal degradation of several IF proteins, we sought to determine whether gigaxonin is involved in the degradation of GFAP. Using a lentiviral transduction system, we demonstrated that gigaxonin levels influence the degradation of GFAP in primary astrocytes and in cell lines that express this IF protein. Gigaxonin was similarly involved in the degradation of some but not all AxD-associated GFAP mutants. In addition, gigaxonin directly bound to GFAP, and inhibition of proteasome reversed the clearance of GFAP in cells achieved by overexpressing gigaxonin. These studies identify gigaxonin as an important factor that targets GFAP for degradation through the proteasome pathway. Our findings provide a critical foundation for future studies aimed at reducing or reversing pathological accumulation of GFAP as a potential therapeutic strategy for AxD and related diseases.