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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)737-756
Number of pages20
JournalJournal of Alzheimer's Disease
Volume67
Issue number2
DOIs
Publication statusPublished - 2019 Jan 1

Fingerprint

Low Density Lipoprotein Receptor-Related Protein-1
Alzheimer Disease
Biomarkers
Leukocytes
Down-Regulation
indole
tropomyosin kinase
Neuroprotection
Therapeutics
Streptozocin
Amyloid
Dementia
Hippocampus

Keywords

  • Alzheimer's disease
  • amyloid
  • APOE
  • biomarker
  • indole compound
  • TRKA

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

Indole compound NC009-1 augments APOE and TRKA in Alzheimer's disease cell and mouse models for neuroprotection and cognitive improvement. / Chen, Yi Chun; Chiu, Ya Jen; Lin, Chih Hsin; Hsu, Wen Chuin; Wu, Jia Lu; Huang, Chen Hsiang; Lin, Chia Wei; Yao, Ching Fa; Huang, Hei Jen; Lo, Yen Shi; Chen, Chiung Mei; Wu, Yih Ru; Chang, Kuo Hsuan; Lee-Chen, Guey Jen; Hsieh-Li, Hsiu Mei.

In: Journal of Alzheimer's Disease, Vol. 67, No. 2, 01.01.2019, p. 737-756.

Research output: Contribution to journalArticle

Chen, Yi Chun ; Chiu, Ya Jen ; Lin, Chih Hsin ; Hsu, Wen Chuin ; Wu, Jia Lu ; Huang, Chen Hsiang ; Lin, Chia Wei ; Yao, Ching Fa ; Huang, Hei Jen ; Lo, Yen Shi ; Chen, Chiung Mei ; Wu, Yih Ru ; Chang, Kuo Hsuan ; Lee-Chen, Guey Jen ; Hsieh-Li, Hsiu Mei. / Indole compound NC009-1 augments APOE and TRKA in Alzheimer's disease cell and mouse models for neuroprotection and cognitive improvement. In: Journal of Alzheimer's Disease. 2019 ; Vol. 67, No. 2. pp. 737-756.
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AU - Chiu, Ya Jen

AU - Lin, Chih Hsin

AU - Hsu, Wen Chuin

AU - Wu, Jia Lu

AU - Huang, Chen Hsiang

AU - Lin, Chia Wei

AU - Yao, Ching Fa

AU - Huang, Hei Jen

AU - Lo, Yen Shi

AU - Chen, Chiung Mei

AU - Wu, Yih Ru

AU - Chang, Kuo Hsuan

AU - Lee-Chen, Guey Jen

AU - Hsieh-Li, Hsiu Mei

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N2 - 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.

AB - 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.

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KW - indole compound

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