Novel Synthetic Coumarin-Chalcone Derivative (E)-3-(3-(4-(Dimethylamino)Phenyl)Acryloyl)-4-Hydroxy-2H-Chromen-2-One Activates CREB-Mediated Neuroprotection in Aβ and Tau Cell Models of Alzheimer's Disease.

Ya-Jen Chiu,Chiung-Mei Chen,Ming-Tsan Su,Chih-Hsin Lin,Kuo-Hsuan Chang,Yu-Shan Teng,Chung-Yin Lin,Guey-Jen Lee-Chen,Ying-Chieh Sun,Hsiu Mei Hsieh-Li,Te-Hsien Lin,Wenwei Lin,Kai Wang

doi:10.1155/2021/3058861

Abstract

Abnormal accumulations of misfolded Aβ and tau proteins are major components of the hallmark plaques and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients. These abnormal protein deposits cause neurodegeneration through a number of proposed mechanisms, including downregulation of the cAMP-response-element (CRE) binding protein 1 (CREB) signaling pathway. Using CRE-GFP reporter cells, we investigated the effects of three coumarin-chalcone derivatives synthesized in our lab on CREB-mediated gene expression. Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells were used to evaluate these agents for possible antiaggregative, antioxidative, and neuroprotective effects. Blood-brain barrier (BBB) penetration was assessed by pharmacokinetic studies in mice. Of the three tested compounds, (E)-3-(3-(4-(dimethylamino)phenyl)acryloyl)-4-hydroxy-2H-chromen-2-one (LM-021) was observed to increase CREB-mediated gene expression through protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and extracellular signal-regulated kinase (ERK) in CRE-GFP reporter cells. LM-021 exhibited antiaggregative, antioxidative, and neuroprotective effects mediated by the upregulation of CREB phosphorylation and its downstream brain-derived neurotrophic factor and BCL2 apoptosis regulator genes in Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells. Blockage of the PKA, CaMKII, or ERK pathway counteracted the beneficial effects of LM-021. LM-021 also exhibited good BBB penetration ability, with brain to plasma ratio of 5.3%, in in vivo pharmacokinetic assessment. Our results indicate that LM-021 works as a CREB enhancer to reduce Aβ and tau aggregation and provide neuroprotection. These findings suggest the therapeutic potential of LM-021 in treating AD.

Highlights

Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disease that gradually impairs memory and cognitive function [1]
Senile plaques are caused by the aggregation and deposition of amyloid β peptides (Aβ) [2], fragments of the amyloid peptide precursor protein (APP) that result from its cleavage by β- and γ-secretases [3]
We show that the CREB signaling pathway in Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SHSY5Y cells is compromised, which leads to decreased BCL2 and BDNF, elevated BAX and oxidative stress, and subsequent neurite outgrowth deficits

Summary

Introduction

Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disease that gradually impairs memory and cognitive function [1]. The pathological hallmarks of AD include deposits of the extracellular senile plaques and intracellular neurofibrillary tangles, which eventually lead to extensive loss of neurons and synapses and brain atrophy. Senile plaques are caused by the aggregation and deposition of amyloid β peptides (Aβ) [2], fragments of the amyloid peptide precursor protein (APP) that result from its cleavage by β- and γ-secretases [3]. Neurofibrillary tangles are composed of abnormally hyperphosphorylated microtubule-associated protein tau (MAPT) [5, 6], which are involved in the neurodegenerative process [7]. Accumulation of Aβ is considered to be an early event and could trigger or accelerate tau pathology in AD [8]

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Conclusion