K284-6111 alleviates memory impairment and neuroinflammation in Tg2576 mice by inhibition of Chitinase-3-like 1 regulati
- PDF / 8,656,345 Bytes
- 16 Pages / 595.276 x 790.866 pts Page_size
- 4 Downloads / 183 Views
RESEARCH
Open Access
K284-6111 alleviates memory impairment and neuroinflammation in Tg2576 mice by inhibition of Chitinase-3-like 1 regulating ERK-dependent PTX3 pathway Hyeon Joo Ham, Yong Sun Lee, Jaesuk Yun, Dong Ju Son, Hee Pom Lee, Sang-Bae Han and Jin Tae Hong*
Abstract Background: Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders characterized by gradual memory loss and neuropsychiatric symptoms. We have previously demonstrated that the 2-({3-[2-(1cyclohexene-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K2846111), the inhibitor of CHI3L1, has the inhibitory effect on memory impairment in Αβ infusion mouse model and on LPS-induced neuroinflammation in the murine BV-2 microglia and primary cultured astrocyte. Methods: In the present study, we investigated the inhibitory effect of K284-6111 on memory dysfunction and neuroinflammation in Tg2576 transgenic mice, and a more detailed correlation of CHI3L1 and AD. To investigate the effects of K284-6111 on memory dysfunction, we administered K284-6111 (3 mg/kg, p.o.) daily for 4 weeks to Tg2576 mice, followed by behavioral tests of water maze test, probe test, and passive avoidance test. Results: Administration of K284-6111 alleviated memory impairment in Tg2576 mice and had the effect of reducing the accumulation of Aβ and neuroinflammatory responses in the mouse brain. K284-6111 treatment also selectively inactivated ERK and NF-κB pathways, which were activated when CHI3L1 was overexpressed, in the mouse brain and in BV-2 cells. Web-based gene network analysis and our results of gene expression level in BV-2 cells showed that CHI3L1 is closely correlated with PTX3. Our result revealed that knockdown of PTX3 has an inhibitory effect on the production of inflammatory proteins and cytokines, and on the phosphorylation of ERK and IκBα. Conclusion: These results suggest that K284-6111 could improve memory dysfunction by alleviating neuroinflammation through inhibiting CHI3L1 enhancing ERK-dependent PTX3 pathway. Keywords: Alzheimer’s disease, Neuroinflammation, CHI3L1, ERK, NF-κB
Background Alzheimer’s disease (AD) is the most common neurodegenerative disease, with 46.8 million people currently suffering from AD worldwide, and the number is expected to reach 131.5 million by 2050 [1]. AD is * Correspondence: [email protected] College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 28160, Republic of Korea
generally characterized by reduced cognitive function, including memory loss, but it is also characterized by behavioral or psychological symptoms such as anxiety, depression, and delusions [2]. Despite decades of research, AD is still one of the major human medical challenges that are incurable [3]. Currently, there are six FDAapproved drugs for treating AD, but none of them stop the progression or provide any fundamental treatment for AD [4].
© The Author(s). 2020 Open Access This
Data Loading...
