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

Ching-Chia Huang,Kuo-Hsuan Chang,Guey-Jen Lee-Chen,Hsiu Mei Hsieh-Li,Wenwei Lin,Chiung-Mei Chen,Ming-Tsan Su,Yi-Ru Chen,Ying-Chieh Sun,Ya-Jen Chiu,Tsai-Hui Lung

doi:10.3390/cells10113095

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.

Highlights

Alzheimer’s disease (AD), the most prevalent type of neurodegenerative dementia, is characterized by progressive memory and cognitive impairments [1]
We found the neuroprotective potential of two new coumarin derivatives, ZN014 and ZN015, against amyloid β (Aβ) neurotoxicity via the inhibition of oxidative stress, caspase-1, and AChE activities and the activation of tropomyosin-related kinase B (TRKB) signaling in the Aβ-GFP SHSY5Y cell model (Figure 6)
As AD has complex neurodegenerative pathogenesis, the pleiotropic mechanism of ZN014 and ZN015 make these compounds promising for drug development

Summary

Introduction

Alzheimer’s disease (AD), the most prevalent type of neurodegenerative dementia, is characterized by progressive memory and cognitive impairments [1]. Extracellular accumulation of misfolded amyloid β (Aβ) in the brain (amyloid plaques) contributes to neuronal apoptosis, eventually leading to the shrinkage of the cortex and hippocampus. The Aβ tends to form oligomers and fibrils, which cause neuronal death by increasing oxidative stress, neuroinflammation, excitotoxicity, and apoptosis [3]. Among these mechanisms, Aβ-induced oxidative stress modifies proteins to perturb their biological function and impairs key biochemical and metabolic pathways in which these proteins normally play a role [4]. Selective loss of acetylcholine-containing neurons in the brain contributes substantially to the cognitive decline in AD [5], and acetylcholinesterase (AChE) inhibitors modulating acetylcholine hydrolysis can increase the level and action duration of acetylcholine [6]. Accumulation of Aβ has been proposed to be an activator to induce sequential pathological events such as the downregulation of the brain-derived neurotrophic factor (BDNF) signaling pathway [7,8]

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