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

Abstract

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.

• Authors: Ching-Chia Huang, Kuo-Hsuan Chang, Ya-Jen Chiu, Yi-Ru Chen, Tsai-Hui Lung, Hsiu Mei Hsieh-Li, Ming-Tsan Su, Ying-Chieh Sun, Chiung-Mei Chen, Wenwei Lin, Guey-Jen Lee-Chen
• Journal: Cells (Cells) Vol. 10 Issue 11 (11 09 2021) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 34831318 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Coumarins
• Neuroprotective Agents
• Protein Aggregates
• Reactive Oxygen Species
• Green Fluorescent Proteins
• Receptor, trkB
• Acetylcholinesterase
• Caspase 1

Topics

• Acetylcholinesterase (metabolism)
• Amyloid beta-Peptides (toxicity)
• Biological Availability
• Blood-Brain Barrier (drug effects, metabolism)
• Caspase 1 (metabolism)
• Cell Line, Tumor
• Cell Membrane Permeability (drug effects)
• Coumarins (chemistry, pharmacology)
• Gene Knockdown Techniques
• Green Fluorescent Proteins (toxicity)
• Humans
• Neuronal Outgrowth (drug effects)
• Neuroprotective Agents (pharmacology)
• Protein Aggregates
• Reactive Oxygen Species (metabolism)
• Receptor, trkB (metabolism)