Transglutaminases derived from astrocytes might accelerate amyloid-beta aggregation

[Speaker] Katsura Takano:1
[Co-author] Kenji Kawabe:2, Mitsuaki Moriyama:1, Yoichi Nakamura:1
1:Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, Japan, 2:Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan

Transglutaminase (TG) is a crosslinking enzyme and contributes to cell adhesion, cytoskeleton construct, extracellular matrix formation, and so on. TG has eight isozymes and tissue-type TG (TG2), one of the isozymes, is reported to be involved in inflammation and neurodegenerative diseases including Alzheimer's disease (AD). Amyloid-beta (Abeta), which is aggregated and the aggregation is detected as characteristic pathology in AD brain, is known to be a substrate of TG2. Activation of glia also has been observed in various neurodegenerative diseases. Excessive production of NO, as a consequence of increased inducible NO synthase (iNOS) in glia, contributes to the neurodegeneration. In the previous study, we presented in cultured astrocytes that lipopolysaccharide (LPS) increased TG2 expression and that TG2 might be involved in LPS-induced NO production. In the present study, we investigated the effects of TGs expressed in cultured astrocytes on Abeta aggregation. When freshly prepared Abeta was added to cultured astrocytes for 7 days, Abeta monomer decreased and Abeta oligomer unchanged. On the other hand, when Abeta monomer was diluted with astrocytes conditioned medium, Abeta oligomer increased time-dependently, and cystamine, a competitive inhibitor of TG enzymatic activity, blocked it. By western blotting analysis, TG1, TG2, TG3, and coagulation factor XIII (FXIII) were expressed in cultured astrocytes, and TG1, TG2, and FXIII were contained in astrocytes conditioned medium. Furthermore, when cultured astrocytes were stimulated with aggregated Abeta, TG2 expression significantly increased. These results suggest that astrocytes could incorporate Abeta monomer to eliminate from brain; however, TGs derived from astrocytes might accelerate Abeta aggregation and the aggregated Abeta might enhance TG2 in astrocytes as a vicious cycle in pathological conditions. Regulation of glial function targeting to TGs could be a therapeutic candidate for the treatment of neurodegenerative diseases.
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