Article

Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice.

Laboratory of Oral Aging Science, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Molecular and Cellular Neuroscience (impact factor: 3.66). 09/2007; 35(4):573-84. DOI:10.1016/j.mcn.2007.05.002 pp.573-84
Source: PubMed

ABSTRACT Nitric oxide (NO) and peroxynitrite, which are produced by activated microglia, are responsible for accelerated neurodegeneration in cathepsin D-deficient (CD-/-) mice. To elucidate the mechanisms by which microglia are initially activated in CD-/- mice, we analyzed the possible relationship between lysosomal storage and microglial activation. In CD-/- mice, the microglial NO-generating activity that was closely associated with the induction of inducible NO synthase and the cationic amino acid transporter-2 (CAT-2) coincided well with the lysosomal storage of subunit c of mitochondrial F0F1ATPase and the formation of ceroid/lipofuscin. Furthermore, activated microglia, which are often accumulating subunit c and ceroid/lipofuscin, showed proliferation activity and an activation of p38 mitogen-activated protein (MAP) kinase. In the primary cultured microglia, pepstatin A was found to enhance the generation of NO and superoxide anion radicals. In these pepstatin A-treated microglia, both an increased generation of the intracellular reactive oxygen species (ROS) and an activation of p38 MAP kinase were observed. These results suggest that the ceroid/lipofuscin which form in microglia activate the p38 MAP kinase cascade through the increased intracellular generation of ROS in CD-/- mice. The activated p38 MAP kinase cascade then promotes the expression of iNOS and CAT-2, thereby inducing the overproduction of NO.

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Keywords

accumulating subunit c
 
activated microglia
 
activated p38 MAP kinase cascade
 
cationic amino acid transporter-2
 
CD-/- mice
 
increased intracellular generation
 
intracellular reactive oxygen species
 
microglia activate
 
microglial activation
 
microglial NO-generating activity
 
mitochondrial F0F1ATPase
 
p38 MAP kinase
 
p38 MAP kinase cascade
 
p38 mitogen-activated protein
 
pepstatin A-treated microglia
 
possible relationship
 
primary cultured microglia
 
proliferation activity
 
subunit c
 
superoxide anion radicals