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Molecular Neurobiology

, Volume 50, Issue 3, pp 852–865 | Cite as

Molecular and Cellular Mechanism of Okadaic Acid (OKA)-Induced Neurotoxicity: A Novel Tool for Alzheimer’s Disease Therapeutic Application

  • Pradip K. KamatEmail author
  • Shivika Rai
  • Supriya Swarnkar
  • Rakesh Shukla
  • Chandishwar Nath
Article

Abstract

Okadaic acid (OKA), a polyether C38 fatty acid toxin extracted from a black sponge Hallichondria okadaii, is a potent and selective inhibitor of protein phosphatase, PP1 and PP2A. OKA has been proved to be a powerful probe for studying the various regulatory mechanisms and neurotoxicity. Because of its property to inhibit phosphatase activity, OKA is associated with protein phosphorylation; it is implicated in hyperphosphorylation of tau and in later stages causes Alzhiemer’s disease (AD)-like pathology. AD is a progressive neurodegenerative disorder, pathologically characterized by extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The density of tau tangles in AD pathology is associated with cognitive dysfunction. Recent studies have highlighted the importance of serine/threonine protein phosphatases in many processes including apoptosis and neurotoxicity. Although OKA causes neurotoxicity by various pathways, the exact mechanism is still not clear. The activation of major kinases, such as Ser/Thr, MAPK, ERK, PKA, JNK, PKC, CaMKII, Calpain, and GSK3β, in neurons is associated with AD pathology. These kinases, associated with abnormal hyperphosphorylation of tau, suggest that the cascade of these kinases could exclusively be involved in the pathogenesis of AD. The activity of serine/threonine protein phosphatases needs extensive study as these enzymes are potential targets for novel therapeutics with applications in many diseases including cancer, inflammatory diseases, and neurodegeneration. There is a need to pay ample attention on MAPK kinase pathways in AD, and OKA can be a better tool to study cellular and molecular mechanism for AD pathology. This review elucidates the regulatory mechanism of PP2A and MAPK kinase and their possible mechanisms involved in OKA-induced apoptosis, neurotoxicity, and AD-like pathology.

Keywords

Okadaic acid Kinases Neurotoxicity Alzheimer’s disease 

Abbreviations

AD

Alzhiemer’s disease

CaMKII

Calmodulin kinase

Ser/Thr

Serine threonine

OKA

Okadaic acid

PKC

Protein kinase C

PKA

Proten kinase A

ERK

Extracellular regulated kinases

MAPK

Mitogen-activated protein kinases

GSK3β

Glycogen synthase kinase

JNK

c-Jun N-terminal kinases

PP2A

Phosphatase 2A

Beta amyloid

NFT

Neuro fibrillary tangle

Notes

Acknowledgments

Financial support to Pradip Kumar Kamat from the Council of Scientific and Industrial Research (CSIR) New Delhi, India is gratefully acknowledged

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Pradip K. Kamat
    • 1
    Email author
  • Shivika Rai
    • 2
  • Supriya Swarnkar
    • 3
  • Rakesh Shukla
    • 2
  • Chandishwar Nath
    • 2
  1. 1.Division of Physiology and BiophysicsUniversity of Louisville School of MedicineLouisvilleUSA
  2. 2.Division of PharmacologyCentral Drug Research Institute (CDRI)LucknowIndia
  3. 3.Department of NeuroscienceThe Scripps Research InstituteJupiterUSA

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