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Protective Effects of Humanin on Okadaic Acid-Induced Neurotoxicities in Cultured Cortical Neurons

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Abstract

Neurofibrillary tangles are pathological hallmarks of Alzheimer’s disease (AD), which are mostly composed of hyperphosphorylated tau and directly correlate with dementia in AD patients. Okadaic acid (OA), a toxin extracted from marine life, can specifically inhibit protein phosphatases (PPs), including PP1 and Protein phosphatase 2A (PP2A), resulting in tau hyperphosphorylation. Humanin (HN), a peptide of 24 amino acids, was initially reported to protect neurons from AD-related cell toxicities. The present study was designed to test if HN could attenuate OA-induced neurotoxicities, including neural insults, apoptosis, autophagy, and tau hyperphosphorylation. We found that administration of OA for 24 h induced neuronal insults, including lactate dehydrogenase released, decreased of cell viability and numbers of living cells, neuronal apoptosis, cells autophagy and tau protein hyperphosphorylation. Pretreatment of cells with HN produced significant protective effects against OA-induced neural insults, apoptosis, autophagy and tau hyperphosphorylation. We also found that OA treatment inhibited PP2A activity and HN pretreatment significantly attenuated the inhibitory effects of OA. This study demonstrated for the first time that HN protected cortical neurons against OA-induced neurotoxicities, including neuronal insults, apoptosis, autophagy, and tau hyperphosphorylation. The mechanisms underlying the protections of HN may involve restoration of PP2A activity.

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Abbreviations

AD:

Alzheimer’s disease

NFTs:

Neurofibrillary tangles

PHF:

Paired helical filaments

Aβ:

Amyloid-β

AVs:

Autophagic vacuoles

PPs:

Protein phosphatases

PP2A:

Protein phosphatase 2A

OA:

Okadaic acid

HN:

Humanin

UP:

Unrelated peptide

LDH:

Lactate dehydrogenase

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

Ac-DEVD-pNA:

Acetyl-Asp-Glu-Val-Asp p-nitroaniline

TUNEL:

Terminal-deoxynucleoitidyl transferase mediated nick end labeling

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Acknowledgments

The study was supported by National Natural Science Foundation of China (30572085).

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Author notes

  1. Jinfeng Zhao

    Present address: College of Physical Education, Shanxi University, Taiyuan, 030006, People’s Republic of China

Authors and Affiliations

  1. Department of Neurobiology, Shanxi Medical University, 56# Xin Jian South Road, Taiyuan, 030001, Shanxi, People’s Republic of China

    Jinfeng Zhao, Dan Wang, Lingmin Li, Wenhui Zhao & Ce Zhang

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  1. Jinfeng Zhao
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  2. Dan Wang
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  3. Lingmin Li
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  4. Wenhui Zhao
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Corresponding author

Correspondence to Ce Zhang.

Additional information

Jinfeng Zhao and Dan Wang have contributed equally to this work.

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Zhao, J., Wang, D., Li, L. et al. Protective Effects of Humanin on Okadaic Acid-Induced Neurotoxicities in Cultured Cortical Neurons. Neurochem Res 39, 2150–2159 (2014). https://doi.org/10.1007/s11064-014-1410-3

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  • DOI: https://doi.org/10.1007/s11064-014-1410-3

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