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The Role of Secretory Phospholipase A2 in the Central Nervous System and Neurological Diseases

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Abstract

Secretory phospholipase A2 (sPLA2s) are small secreted proteins (14–18 kDa) and require submillimolar levels of Ca2+ for liberating arachidonic acid from cell membrane lipids. In addition to the enzymatic function, sPLA2 can exert various biological responses by binding to specific receptors. Physiologically, sPLA2s play important roles on the neurotransmission in the central nervous system and the neuritogenesis in the peripheral nervous system. Pathologically, sPLA2s are involved in the neurodegenerative diseases (e.g., Alzheimer’s disease) and cerebrovascular diseases (e.g., stoke). The common pathology (e.g., neuronal apoptosis) of Alzheimer’s disease and stroke coexists in the mixed dementia, suggesting common pathogenic mechanisms of the two neurological diseases. Among mammalian sPLA2s, sPLA2-IB and sPLA2-IIA induce neuronal apoptosis in rat cortical neurons. The excess influx of calcium into neurons via l-type voltage-dependent Ca2+ channels mediates the two sPLA2-induced apoptosis. The elevated concentration of intracellular calcium activates PKC, MAPK and cytosolic PLA2. Moreover, it is linked with the production of reactive oxygen species and apoptosis through activation of the superoxide producing enzyme NADPH oxidase. NADPH oxidase is involved in the neurotoxicity of amyloid β peptide, which impairs synaptic plasticity long before its deposition in the form of amyloid plaques of Alzheimer’s disease. In turn, reactive oxygen species from NADPH oxidase can stimulate ERK1/2 phosphorylation and activation of cPLA2 and result in a release of arachidonic acid. sPLA2 is up-regulated in both Alzheimer’s disease and cerebrovascular disease, suggesting the involvement of sPLA2 in the common pathogenic mechanisms of the two diseases. Thus, our review presents evidences for pathophysiological roles of sPLA2 in the central nervous system and neurological diseases.

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Abbreviations

AA:

Arachidonic acid

AD:

Alzheimer’s disease

AMPA:

Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

APP:

Amyloid precursor protein

CaMK II:

Calcium/calmodulin-dependent protein kinase II

COX:

Cyclooxygenase

CVD:

Cerebrovascular disease

iPLA2 :

Ca2+-independent cytosolic phospholipase A2

ER:

Endoplasmic reticulum

FAβ:

Fibrillar Aβ

[Ca2+]i :

Intracellular Ca2+ concentration

IL-1β:

Interleukin-1β

LGCC:

Ligand-gated calcium channel

LTP:

Long-term potentiation

l-VDCC:

l-Type voltage-dependent Ca2+ channels

MAPK:

Mitogen-activated protein kinases

NMDA:

N-Methyl-d-aspartate

NFTs:

Neurofibrillary tangles

PAF:

Platelet activating factor

PLA2 :

Phospholipase A2

PG:

Prostaglandin

ROS:

Reactive oxygen species

sPLA2 :

Secreted phospholipase A2

sPLA2R:

Secretory phospholipase A2 receptor

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  1. Division of Physiology, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 2-1-7, Kami-ohno, Himeji, Hyogo, 670-8524, Japan

    Tatsurou Yagami, Yasuhiro Yamamoto & Hiromi Koma

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  1. Tatsurou Yagami
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  2. Yasuhiro Yamamoto
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  3. Hiromi Koma
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Correspondence to Tatsurou Yagami.

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Yagami, T., Yamamoto, Y. & Koma, H. The Role of Secretory Phospholipase A2 in the Central Nervous System and Neurological Diseases. Mol Neurobiol 49, 863–876 (2014). https://doi.org/10.1007/s12035-013-8565-9

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  • DOI: https://doi.org/10.1007/s12035-013-8565-9

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