The Potential of Indole/Indolylquinoline Compounds in Tau Misfolding Reduction by Enhancement of HSPB1

Kuo Hsuan Chang, Chih Hsin Lin, Hsuan Chiang Chen, Hsin Yu Huang, Shu Ling Chen, Te Hsien Lin, Chintakunta Ramesh, Chin Chang Huang, Hon Chung Fung, Yih Ru Wu, Hei Jen Huang, Guey-Jen Lee, Hsiu Mei Hsieh, Ching-Fa Yao

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Neurofibrillary tangles formed from tau misfolding have long been considered one of the pathological hallmarks of Alzheimer's disease (AD). The misfolding of tau in AD correlates with the clinical progression of AD and inhibition or reversal of tau misfolding may protect the affected neurons. Methods: We generated 293 and SH-SY5Y cells expressing DsRed-tagged pro-aggregation mutant of repeat domain of tau (ΔK280 tauRD) to test indole/indolylquinoline derivatives for reducing tau misfolding and neuroprotection. Results: Four of the 10 derivatives tested displayed good misfolding-inhibitory effects on Tet-On 293 cells. Among them, NC009-1 and NC009-7 enhanced heat-shock 27 kDa protein 1 (HSPB1) expression to increase ∆K280 tauRD-DsRed solubility and promoted neurite outgrowth in Tet-On SH-SY5Y cells. Knockdown of HSPB1 resulted in decreased ∆K280 tauRD-DsRed solubility and reduced neurite outgrowth, which were rescued by addition of NC009-1/NC009-7. Treatment with indole/indolylquinoline derivatives also improved neuronal cell viability and neurite outgrowth in mouse hippocampal primary culture under tau cytotoxicity. Conclusion: Our results demonstrate how indole/indolylquinoline derivatives are likely to work in tau misfolding reduction, providing insight into the possible working mechanism of indole and indolylquinoline derivatives in AD treatment.

Original languageEnglish
Pages (from-to)45-56
Number of pages12
JournalCNS Neuroscience and Therapeutics
Volume23
Issue number1
DOIs
Publication statusPublished - 2017 Jan 1

Fingerprint

Alzheimer Disease
Solubility
HSP27 Heat-Shock Proteins
Neurofibrillary Tangles
Cell Survival
Neurons
indole
fluorescent protein 583
Neuronal Outgrowth

Keywords

  • Alzheimer's disease
  • HSPB1
  • Indole/indolylquinoline compounds
  • Tau misfolding
  • Therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Physiology (medical)
  • Pharmacology (medical)

Cite this

The Potential of Indole/Indolylquinoline Compounds in Tau Misfolding Reduction by Enhancement of HSPB1. / Chang, Kuo Hsuan; Lin, Chih Hsin; Chen, Hsuan Chiang; Huang, Hsin Yu; Chen, Shu Ling; Lin, Te Hsien; Ramesh, Chintakunta; Huang, Chin Chang; Fung, Hon Chung; Wu, Yih Ru; Huang, Hei Jen; Lee, Guey-Jen; Hsieh, Hsiu Mei; Yao, Ching-Fa.

In: CNS Neuroscience and Therapeutics, Vol. 23, No. 1, 01.01.2017, p. 45-56.

Research output: Contribution to journalArticle

Chang, KH, Lin, CH, Chen, HC, Huang, HY, Chen, SL, Lin, TH, Ramesh, C, Huang, CC, Fung, HC, Wu, YR, Huang, HJ, Lee, G-J, Hsieh, HM & Yao, C-F 2017, 'The Potential of Indole/Indolylquinoline Compounds in Tau Misfolding Reduction by Enhancement of HSPB1', CNS Neuroscience and Therapeutics, vol. 23, no. 1, pp. 45-56. https://doi.org/10.1111/cns.12592
Chang, Kuo Hsuan ; Lin, Chih Hsin ; Chen, Hsuan Chiang ; Huang, Hsin Yu ; Chen, Shu Ling ; Lin, Te Hsien ; Ramesh, Chintakunta ; Huang, Chin Chang ; Fung, Hon Chung ; Wu, Yih Ru ; Huang, Hei Jen ; Lee, Guey-Jen ; Hsieh, Hsiu Mei ; Yao, Ching-Fa. / The Potential of Indole/Indolylquinoline Compounds in Tau Misfolding Reduction by Enhancement of HSPB1. In: CNS Neuroscience and Therapeutics. 2017 ; Vol. 23, No. 1. pp. 45-56.
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AU - Chen, Shu Ling

AU - Lin, Te Hsien

AU - Ramesh, Chintakunta

AU - Huang, Chin Chang

AU - Fung, Hon Chung

AU - Wu, Yih Ru

AU - Huang, Hei Jen

AU - Lee, Guey-Jen

AU - Hsieh, Hsiu Mei

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N2 - Background: Neurofibrillary tangles formed from tau misfolding have long been considered one of the pathological hallmarks of Alzheimer's disease (AD). The misfolding of tau in AD correlates with the clinical progression of AD and inhibition or reversal of tau misfolding may protect the affected neurons. Methods: We generated 293 and SH-SY5Y cells expressing DsRed-tagged pro-aggregation mutant of repeat domain of tau (ΔK280 tauRD) to test indole/indolylquinoline derivatives for reducing tau misfolding and neuroprotection. Results: Four of the 10 derivatives tested displayed good misfolding-inhibitory effects on Tet-On 293 cells. Among them, NC009-1 and NC009-7 enhanced heat-shock 27 kDa protein 1 (HSPB1) expression to increase ∆K280 tauRD-DsRed solubility and promoted neurite outgrowth in Tet-On SH-SY5Y cells. Knockdown of HSPB1 resulted in decreased ∆K280 tauRD-DsRed solubility and reduced neurite outgrowth, which were rescued by addition of NC009-1/NC009-7. Treatment with indole/indolylquinoline derivatives also improved neuronal cell viability and neurite outgrowth in mouse hippocampal primary culture under tau cytotoxicity. Conclusion: Our results demonstrate how indole/indolylquinoline derivatives are likely to work in tau misfolding reduction, providing insight into the possible working mechanism of indole and indolylquinoline derivatives in AD treatment.

AB - Background: Neurofibrillary tangles formed from tau misfolding have long been considered one of the pathological hallmarks of Alzheimer's disease (AD). The misfolding of tau in AD correlates with the clinical progression of AD and inhibition or reversal of tau misfolding may protect the affected neurons. Methods: We generated 293 and SH-SY5Y cells expressing DsRed-tagged pro-aggregation mutant of repeat domain of tau (ΔK280 tauRD) to test indole/indolylquinoline derivatives for reducing tau misfolding and neuroprotection. Results: Four of the 10 derivatives tested displayed good misfolding-inhibitory effects on Tet-On 293 cells. Among them, NC009-1 and NC009-7 enhanced heat-shock 27 kDa protein 1 (HSPB1) expression to increase ∆K280 tauRD-DsRed solubility and promoted neurite outgrowth in Tet-On SH-SY5Y cells. Knockdown of HSPB1 resulted in decreased ∆K280 tauRD-DsRed solubility and reduced neurite outgrowth, which were rescued by addition of NC009-1/NC009-7. Treatment with indole/indolylquinoline derivatives also improved neuronal cell viability and neurite outgrowth in mouse hippocampal primary culture under tau cytotoxicity. Conclusion: Our results demonstrate how indole/indolylquinoline derivatives are likely to work in tau misfolding reduction, providing insight into the possible working mechanism of indole and indolylquinoline derivatives in AD treatment.

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