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-Chen; Hsiu Mei Hsieh-Li; Ching Fa Yao

doi:10.1111/cns.12592

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-Chen^*, Hsiu Mei Hsieh-Li, Ching Fa Yao

^*Corresponding author for this work

School of Medicine

Research output: Contribution to journal › Journal Article › peer-review

19 Scopus citations

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 tau_RD) 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 tau_RD-DsRed solubility and promoted neurite outgrowth in Tet-On SH-SY5Y cells. Knockdown of HSPB1 resulted in decreased ∆K280 tau_RD-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 language	English
Pages (from-to)	45-56
Number of pages	12
Journal	CNS Neuroscience and Therapeutics
Volume	23
Issue number	1
DOIs	https://doi.org/10.1111/cns.12592
State	Published - 01 01 2017

Bibliographical note

Publisher Copyright:
© 2016 John Wiley & Sons Ltd

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/cns.12592

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Chang, K. H., Lin, C. H., Chen, H. C., Huang, H. Y., Chen, S. L., Lin, T. H., Ramesh, C., Huang, C. C., Fung, H. C., Wu, Y. R., Huang, H. J., Lee-Chen, G. J., Hsieh-Li, H. M., & Yao, C. F. (2017). The Potential of Indole/Indolylquinoline Compounds in Tau Misfolding Reduction by Enhancement of HSPB1. CNS Neuroscience and Therapeutics, 23(1), 45-56. https://doi.org/10.1111/cns.12592

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title = "The Potential of Indole/Indolylquinoline Compounds in Tau Misfolding Reduction by Enhancement of HSPB1",

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.",

keywords = "Alzheimer's disease, HSPB1, Indole/indolylquinoline compounds, Tau misfolding, Therapeutics",

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

note = "Publisher Copyright: {\textcopyright} 2016 John Wiley & Sons Ltd",

year = "2017",

month = jan,

day = "1",

doi = "10.1111/cns.12592",

language = "英语",

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T1 - The Potential of Indole/Indolylquinoline Compounds in Tau Misfolding Reduction by Enhancement of HSPB1

AU - Chang, Kuo Hsuan

AU - Lin, Chih Hsin

AU - Chen, Hsuan Chiang

AU - Huang, Hsin Yu

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-Chen, Guey Jen

AU - Hsieh-Li, Hsiu Mei

AU - Yao, Ching Fa

PY - 2017/1/1

Y1 - 2017/1/1

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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KW - HSPB1

KW - Indole/indolylquinoline compounds

KW - Tau misfolding

KW - Therapeutics

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U2 - 10.1111/cns.12592

DO - 10.1111/cns.12592

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AN - SCOPUS:84978496139

SN - 1755-5930

VL - 23

SP - 45

EP - 56

JO - CNS Neuroscience and Therapeutics

JF - CNS Neuroscience and Therapeutics

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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