Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity

• Published in: Cells (Basel, Switzerland) Switzerland), 2021-11, Vol.10 (11), p.3095
• Main Authors: Huang, Ching-Chia, Chang, Kuo-Hsuan, Chiu, Ya-Jen, Chen, Yi-Ru, Lung, Tsai-Hui, Hsieh-Li, Hsiu Mei, Su, Ming-Tsan, Sun, Ying-Chieh, Chen, Chiung-Mei, Lin, Wenwei, Lee-Chen, Guey-Jen
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Acetylcholinesterase - metabolism; Acids; AKT protein; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - toxicity; Animal cognition; Apoptosis; Axonogenesis; B-cell lymphoma; Biological Availability; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain-derived neurotrophic factor; Caspase 1 - metabolism; Caspase-1; Cell culture; Cell Line, Tumor; Cell Membrane Permeability - drug effects; Cognitive ability; Coumarin; coumarins; Coumarins - chemistry; Coumarins - pharmacology; Cyclic AMP response element-binding protein; Extracellular signal-regulated kinase; Gene Knockdown Techniques; Green Fluorescent Proteins - toxicity; Humans; Immunological memory; Kinases; Lymphocytes B; Membrane permeability; Memory; Neurodegenerative diseases; Neuronal Outgrowth - drug effects; Neurons; Neuroprotection; Neuroprotective Agents - pharmacology; Neurotoxicity; Oxidative stress; Peptides; Phosphorylation; Protein Aggregates; Protein-serine/threonine kinase; Proteins; Reactive Oxygen Species - metabolism; Receptor, trkB - metabolism; therapeutics; TRKB agonist; TrkB receptors
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10113095

Alzheimer's disease (AD) is a common neurodegenerative disease presenting with progressive memory and cognitive impairments. One of the pathogenic mechanisms of AD is attributed to the aggregation of misfolded amyloid β (Aβ), which induces neurotoxicity by reducing the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (TRKB) and increasing oxidative stress, caspase-1, and acetylcholinesterase (AChE) activities. Here, we have found the potential of two novel synthetic coumarin derivatives, ZN014 and ZN015, for the inhibition of Aβ and neuroprotection in SH-SY5Y neuroblastoma cell models for AD. In SH-SY5Y cells expressing the GFP-tagged Aβ-folding reporter, both ZN compounds reduced Aβ aggregation, oxidative stress, activities of caspase-1 and AChE, as well as increased neurite outgrowth. By activating TRKB-mediated extracellular signal-regulated kinase (ERK) and AKT serine/threonine kinase 1 (AKT) signaling, these two ZN compounds also upregulated the cAMP-response-element binding protein (CREB) and its downstream BDNF and anti-apoptotic B-cell lymphoma 2 (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of ZN014 and ZN015. A parallel artificial membrane permeability assay showed that ZN014 and ZN015 could be characterized as blood-brain barrier permeable. Our results suggest ZN014 and ZN015 as novel therapeutic candidates for AD and demonstrate that ZN014 and ZN015 reduce Aβ neurotoxicity via pleiotropic mechanisms.