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Abstract
BackgroundAlzheimer’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-(1-cyclohexene-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), 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.MethodsIn 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.ResultsAdministration 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.ConclusionThese results suggest that K284-6111 could improve memory dysfunction by alleviating neuroinflammation through inhibiting CHI3L1 enhancing ERK-dependent PTX3 pathway.
Highlights
Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders characterized by gradual memory loss and neuropsychiatric symptoms
K284-6111 alleviates memory impairment in Tg2576 mice To investigate if there is a difference in Chitinase-3-like 1 (CHI3L1) levels between Tg2576 and WT mice, the CHI3L1 levels in serum and brain were determined by ELISA assay
To verify the combination effect of Extracellular signal-regulated kinases (ERK) inhibitor (U0126) and K284-6111 on neuroinflammation, the microglial BV-2 cells were treated with accumulation of βamyloid (Aβ) (5 μM), U0126 (20 μM), and K284-6111 (2 μM), and the Inhibitory effect of K284-6111 on neuroinflammatory responses induced by CHI3L1 In our previous study, we demonstrated that K284-6111 directly binds to CHI3L1 using a computational docking study and that K284-6111 has an anti-inflammatory effect on the Aβ-infusion AD mouse model and BV-2 cells [34]
Summary
Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders characterized by gradual memory loss and neuropsychiatric symptoms. The pathological features of AD are accumulation of βamyloid (Aβ) plaques, neurofibrillary tangles, cerebral atrophy, and neuroinflammation [5, 6] It is known that neuroinflammatory responses occur in the AD brain, such as changes in morphology and distribution of microglia and astrocytes, and increased expression of inflammatory mediators [7]. The M1 phenotype is the proinflammatory microglia, the main characteristic of which is the production of pro-inflammatory mediators such as pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and inflammatory proteins [11, 12]. The M2 phenotype is the anti-inflammatory microglia, the main characteristic of which is the production of anti-inflammatory mediators such as anti-inflammatory cytokines including arginase-1 (Arg1), transforming growth factor β1 (TGFβ1), and mannose receptor C-type 1 (MRC1), and immunosuppressive proteins [11, 12]. In the brain of AD patients, apoptotic and pro-inflammatory signaling including M1 microglia phenotypes such as IFN-γ, and IL-1β are upregulated [8]
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