Abstract
BackgroundAlzheimer’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.MethodsWe 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.ResultsA 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.ConclusionThese results suggest that CHI3L1 inhibitor could be an applicable intervention drug in amyloidogenesis and neuroinflammation, thereby preventing memory dysfunction via inhibition of NF-κB.
Highlights
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
A two-way ANOVA showed that the Aβ1–42-infused mice (44.29 ± 4.08 s) learned more slowly than control mice (18.70 ± 76 s), and K284-6111-treated mice (26.56 ± 4.36 s) showed a great reduction in escape latency on day 6 (Fig. 1b)
We found that K284-6111 treatment decreased Aβ-induced mRNA levels of chitinase 3 like 1 (CHI3L1) (Fig. 2d), Tumor necrosis factor alpha (TNF-α) (Fig. 2e), Interleukin 1 beta (IL-1β) (Fig. 2f ), and Interleukin 6 (IL-6) (Fig. 2g) in brain tissues
Summary
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. It was reported that an increased level of CHI3L1 in plasma was found in AD patients. Alzheimer’s disease (AD), the most common cause of dementia, can be characterized by difficulties in memory, language, problem-solving, and other cognitive abilities to perform everyday activities [1]. The neuropathological hallmark of AD, leads to synaptic dysfunction and neurodegeneration in critical brain regions involved in cognition and memory [5, 6]. It was notably reported that intraneuronal Aβ accumulation was detected in the brain tissue of AD patients [7, 8]. There has been extensive effort to find a cure for AD through the reduction of Aβ
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