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K284-6111 prevents the amyloid beta-induced neuroinflammation and impairment of recognition memory through inhibition of NF-κB-mediated CHI3L1 expression.
- Source :
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Journal of Neuroinflammation . 8/11/2018, Vol. 15 Issue 1, pN.PAG-N.PAG. 1p. - Publication Year :
- 2018
-
Abstract
- <bold>Background: </bold>Alzheimer's disease, which is pathologically characterized by an excessive accumulation of amyloid beta (Aβ) fibrils, is a degenerative brain disease and the most common cause of dementia. In a previous study, it was reported that an increased level of CHI3L1 in plasma was found in AD patients. We investigated the inhibitory effect of 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), an inhibitor of chitinase 3 like 1 (CHI3L1), on memory impairment in Aβ1-42-infused mice, and microglial BV-2 cells and astrocytes.<bold>Methods: </bold>We examined whether K284-6111 (3 mg/kg given orally for 4 weeks) prevents amyloidogenesis and memory loss in Aβ1-42-induced AD mice model. After intracerebroventrical (ICV) infusion of Aβ1-42 for 14 days, the cognitive function was assessed by the Morris water maze test and passive avoidance test. K284-6111 treatment was found to reduce Aβ1-42-induced memory loss.<bold>Results: </bold>A memory recovery effect was found to be associated with the reduction of Aβ1-42-induced expression of inflammatory proteins (iNOS, COX-2, GFAP, and Iba-1) and the suppression of CHI3L1 expression in the brain. Additionally, K284-6111 reduced Aβ1-42-induced β-secretase activity and Aβ generation. Lipopolysaccharide (LPS)-induced (1 μg/mL) expression of inflammatory (COX-2, iNOS, GFAP, Iba-1) and amyloidogenic proteins (APP, BACE1) were decreased in microglial BV-2 cells and cultured astrocytes by the K284-6111 treatment (0.5, 1, and 2 μM). Moreover, K284-6111 treatment suppressed p50 and p65 translocation into the nucleus, and phosphorylation of IκB in vivo and in vitro.<bold>Conclusion: </bold>These results suggest that CHI3L1 inhibitor could be an applicable intervention drug in amyloidogenesis and neuroinflammation, thereby preventing memory dysfunction via inhibition of NF-κB. [ABSTRACT FROM AUTHOR]
- Subjects :
- *AMYLOID
*ALZHEIMER'S disease
*IMMUNE recognition
*MEMORY loss
*LIPOPOLYSACCHARIDES
Subjects
Details
- Language :
- English
- ISSN :
- 17422094
- Volume :
- 15
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Journal of Neuroinflammation
- Publication Type :
- Academic Journal
- Accession number :
- 131197369
- Full Text :
- https://doi.org/10.1186/s12974-018-1269-3