Indole compound NC009-1 augments APOE and TRKA in Alzheimer's disease cell and mouse models for neuroprotection and cognitive improvement

Yi Chun Chen, Ya Jen Chiu, Chih Hsin Lin, Wen Chuin Hsu, Jia Lu Wu, Chen Hsiang Huang, Chia Wei Lin, Ching Fa Yao, Hei Jen Huang, Yen Shi Lo, Chiung Mei Chen, Yih Ru Wu, Kuo Hsuan Chang*, Guey Jen Lee-Chen, Hsiu Mei Hsieh-Li

*此作品的通信作者

研究成果: 雜誌貢獻期刊論文同行評審

14 引文 斯高帕斯(Scopus)

摘要

Alzheimer's disease (AD), associated with abnormal accumulation of amyloid-β (Aβ), is the most common cause of dementia among older people. A few studies have identified substantial AD biomarkers in blood but their results were inconsistent. Here we screened gene expression alterations on Aβ-GFP SH-SY5Y neuronal model for AD, and evaluated the findings on peripheral leukocytes from 78 patients with AD and 56 healthy controls. The therapeutic responses of identified biomarker candidates were further examined in Aβ-GFP SH-SY5Y neuronal and APP/PS1/Tau triple transgenic (3×Tg-AD) mouse models. Downregulation of apolipoprotein E (APOE) and tropomyosin receptor kinase A (TRKA) were detected in Aβ-GFP SH-SY5Y cells and validated by peripheral leukocytes from AD patients. Treatment with an in-house indole compound NC009-1 upregulated the expression of APOE and TRKA accompanied with improvement of neurite outgrowth in Aβ-GFP SH-SY5Y cells. NC009-1 further rescued the downregulated APOE and TRKA and reduced Aβ and tau levels in hippocampus and cortex, and ameliorated cognitive deficits in streptozocin-induced hyperglycemic 3×Tg-AD mice. These results suggest the role of APOE and TRKA as potential peripheral biomarkers in AD, and offer a new drug development target of AD treatment. Further studies of a large series of AD patients will be warranted to verify the findings and confirm the correlation between these markers and therapeutic efficacy.

原文英語
頁(從 - 到)737-756
頁數20
期刊Journal of Alzheimer's Disease
67
發行號2
DOIs
出版狀態已發佈 - 2019

ASJC Scopus subject areas

  • 一般神經科學
  • 臨床心理學
  • 老年病學和老年學
  • 精神病學和心理健康

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