Tam Thanh Nguyen Tran
Introduction: Creutzfeldt-Jakob Disease is a rare (1-1.5 cases per million worldwide), rapidly progressive, and inevitably fatal neurodegenerative prion disease involving abnormal protein aggregates that cause brain tissue deterioration (1,2). The normal prion protein PrPC (cellular) is mutated to the infectious form PrPSc (prototypical prion disease–scrapie) that contains an increase in beta-sheets, which is associated with increased protein aggregation potential (3) The insoluble misfolded proteins deposit in the form of plaques resistant to proteases, causing neuronal cell death and development of hole-like lesions in the brain (3). Treatment is directed towards symptomatic relief (1). A major symptom of CJD is myoclonic seizures associated with high brain levels of the inflammatory cytokine IL-1β seen in CJD patients (4). Therefore, targeting pathways that reduce or inhibit IL-1β activity could improve the prognosis for CJD patients (4). Methods: To assess the pathways involved in IL-1β activity, researchers used western blotting, ELISA, rapid electrical hippocampal kindling and invivo microdialysis on mice models of CJ (5-7). Western blotting was used to analyze the number of IL-1β-positive astrocytes in WT mice, mice with PrP gene knock-out, and mice that modeled CJD (5). The number of seizures in the respective experimental models was observed (5). Western blotting of members of the NFκB/IKK pathway allowed researchers to detect the activity in control mice, and MM1 subtype and VV2 subtype of sCJD (5). ELISA was used to analyze levels of phospho-STAT1 and phospho-STAT3 in brain lysates, relative to the JAK/STAT pathway (6). Rapid electrical hippocampal kindling and invivo microdialysis methods were used to observe the involvement of IL-1β and inflammatory mediator lipopolysaccharide (LPS) on mechanisms of kindling (7). Results: Levels of IL-1β-positive astrocytes and seizures were highest in mice modeling CJD. Phosphorylated (active) p-NFkB levels were highest in sCJD MM1 and sCJD VV2 in both the frontal cortex and cerebellum (5). The expression levels of IκBα (an inhibitory protein) were comparatively diminished (5). Both proteins phospho-STAT1 and phospho-STAT3 were phosphorylated and activated in the frontal cortex of sCJD MM1 samples (6). Both LPS and IL-1β when administered, accelerated the kindling process (7). Conclusion: These results conclude that there is an upregulation of inflammatory pathways such as the NFκB/IKK pathway, and JAK/STAT pathway in CJD patients along with an increase in IL-1β-positive astrocytes, LPS, and seizure activity (5-7). Therefore, targeting these pathways could potentially reduce seizure susceptibility in CJD patients.4 The studies provide information for further research that could include manipulation of these target pathways involved in CJD to provide therapeutic treatment for patients (4).
- Appleby BS., Yobs DR. Symptomatic treatment, care, and support of CJD patients.. Handb Clin Neurol. 2018;153:399-408. doi: 10.1016/B978-0-444-63945-5.00021-0.
- Manix M., Kalakoti P. Creutzfeldt-Jakob disease: updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy. Neurosurg Focus. 2015 Nov;39(5):E2. doi: 10.3171/2015.8.FOCUS15328.
- Vrentas CE., Greenlee JJ., et al. Effects of a naturally occurring amino acid substitution in bovine PrP: a model for inherited prion disease in a natural host species. BMC Res Notes. 2017 Dec 20;10(1):759. doi: 10.1186/s13104-017-3085-8.
- Bertani I., Iori V., et al. Inhibition of IL-1β Signaling Normalizes NMDA-Dependent Neurotransmission and Reduces Seizure Susceptibility in a Mouse Model of Creutzfeldt-Jakob Disease. J Neurosci. 2017 Oct 25;37(43):10278-10289. doi: 10.1523/JNEUROSCI.1301-17.2017. Epub 2017 Sep 18.
- Llorens F., López-González I., et al. Subtype and regional-specific neuroinflammation in sporadic creutzfeldt-jakob disease. Front Aging Neurosci. 2014 Aug 4;6:198. doi: 10.3389/fnagi.2014.00198. eCollection 2014.
- Kolosowska K., Maciejak P., et al. The role of IL-1β and glutamate in the effects of lipopolysaccharide on the hippocampal electrical kindling of seizures. J Neuroimmunol. 2016 Sep 15;298:146-52. doi: 10.1016/j.jneuroim.2016.07.018. Epub 2016 Jul 21.
- Sun Y., Ma J., et al. Interleukin-10 inhibits interleukin-1β production and inflammasome activation of microglia in epileptic seizures. J Neuroinflammation. 2019 Mar 28;16(1):66. doi: 10.1186/s12974-019-1452-1