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

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 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: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.11.2021; MDPI
• 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; United States > US; Aβ; therapeutics; TRKB agonist; Alzheimer’s disease; coumarins; neuroprotection
• 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.