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.