| Summary: | 碩士 === 國立臺灣師範大學 === 生命科學系 === 105 === Alzheimer's disease (AD), the most common type of dementia in humans, is characterized as a progressive decline in cognitive function and loss of the long-term memory. The prominent pathological features of AD are aggregation of β-amyloid (Aβ) peptide in plaques and hyperphosphorylated tau protein in neurofibrillary tangles (NFTs). The Aβ deposition causes neuronal death via mechanisms including oxidative stress, excitotoxicity, energy depletion and apoptosis. Therefore, identifying novel Aβ aggregate inhibitor is essential to the disease treatment. Licochalcone A and coumarin are two natural compounds from plants with enhancing mitochondrial biogenesis and/or antioxidant activity. To improve therapeutic effects of licochalcone A and coumarin, chemical modification was applied and five licochalcone A and/or coumarin derivatives inhibiting SCA3 polyQ aggregation and reducing tau misfolding were obtained. In this study, biochemical tests were firstly used to examine the free radical scavenging and Aβ aggregation inhibition activities of licochalcone A, coumarin and the five synthetic derivatives. Tet-On Aβ-GFP 293/SH-SY5Y cells were then used to examine the ability of the tested compounds to reduce Aβ misfolding and neuroprotection. Among the tested compounds, derivative LM-031 had the lowest cytotoxicity and displayed the potentials of radical-scavenging and Aβ aggregation inhibition in biochemical tests, in addition to reducing Aβ misfolding and associated reactive oxygen species and caspase-3 activity in Aβ-GFP 293 cells and promoting neurite outgrowth in Aβ-GFP SH-SY5Y cells. LM-031, licochalcone A and coumarin enhanced heat-shock 27 kDa protein 1 (HSPB1) expression to increase the solubility of Aβ-GFP fusion protein and upregulated nuclear factor erythroid 2-like factor 2 (NRF2) to promote antioxidant-responsive element-dependent NAD(P)H quinone dehydrogenase 1 (NQO1) and glutamate-cysteine ligase catalytic subunit (GCLC) expression. The expression of factors involved in cell survival, growth and anti-apoptosis, such as brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate response element binding protein (CREB), B-cell leukemia protein 2 (BCL2), extracellular signal-regulated kinase (ERK) 1/2, and AKT serine/threonine kinase 1 (AKT) were also increased in Aβ-GFP SH-SY5Y cells by LM-031, licochalcone A and coumarin. The study results demonstrated that licochalcone A, coumarin and novel chalcone-coumarin hybrid LM-031 are likely to work in Aβ aggregation reduction and neuroprotection, providing insight into the possible application in AD treatment.
Keywords: Alzheimer’s disease, amyloid β, chalcone-coumarin hybrid, anti-oxidation, anti-apoptosis.
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