Upregulation of tPA/plasminogen proteolytic system in the periphery of amyloid deposits in the Tg2576 mouse model of Alzheimer's disease.
Although the tissue plasminogen activator (tPA)/plasminogen/plasmin proteolytic system is thought to modulate the catabolism of amyloid-beta (Abeta), in vivo evidence remains insufficient. In the brain of human amyloid precursor protein transgenic Tg2576 mice, we found co-accumulation of tPA and plasminogen at the periphery of compact amyloid deposits, mainly Abeta42-cored plaques, as well as in the walls of blood vessels with cerebral amyloid angiopathy (CAA). This tPA/plasminogen system contained high levels of proteolytic activity. High levels of tPA were also found in reactive astrocytes with increased Abeta42 expression, whereas plasminogen was found only in neurons. When the brain sections of Tg2576 mice were treated with both tPA and plasminogen, levels of thioflavin-S fluorescence, congophilicity and birefringence in the compact amyloid plaques were significantly reduced, and the ultrastructure of Abeta42-fibrils was disrupted. These results suggest that the assembled Abeta42 may promote upregulation of the tPA/plasminogen proteolytic system, which can modulate the deposition of amyloid plaques in vivo.
Lee
Joo-Yong
JY
Asan Institute for Life Science, Department of Neurology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea. jlee@amc.seoul.kr
Kweon
Hee-Seok
HS
Cho
Eunsil
E
Lee
Jee-Young
JY
Byun
Hyae-Ran
HR
Kim
Dong Hou
DH
Kim
Yang-Hee
YH
Han
Pyung-Lim
PL
Koh
Jae-Young
JY
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D004396:Coloring Agents; D003224:Congo Red; D005456:Fluorescent Dyes; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004396:Coloring Agents; D005456:Fluorescent Dyes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D003224:Congo Red; D010958:Plasminogen; D010959:Tissue Plasminogen Activator