title: Tissue plasminogen activator arrests Alzheimer's disease pathogenesis.
abstract: The progressive deposition of amyloid-β (Aβ) in the brain is a pathologic feature of Alzheimer's disease (AD). This study was aimed to determine whether endogenous tissue plasminogen activator (tPA) modulates the pathogenic process of AD. tPA expression and activity developed around amyloid plaques in the brains of human amyloid precursor protein-overexpressing Tg2576 mice, which were weakened by the genetic ablation of tPA. Although the complete loss of tPA was developmentally fatal to Tg2576 mice, tPA-heterozygous Tg2576 mice expressed the more severe degenerative phenotypes than tPA wild-type Tg2576 mice, including abnormal and unhealthy growth, shorter life spans, significantly enhanced Aβ levels, and the deposition of more and larger amyloid plaques in the brain. In addition, the expression of synaptic function-associated proteins was significantly reduced, which in turn caused a more severe impairment in learning and memory performance in Tg2576 mice. Thus, endogenous tPA, preferentially its aggregate form, could degrade Aβ molecules and maintain low levels of brain Aβ, resulting in the delay of AD pathogenesis.
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Shin Bi
authors.initials: SB
authors.lastname: Oh
authors.forename: Catherine Jeonghae
authors.initials: CJ
authors.lastname: Byun
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Yun
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D018450:Disease Progression; D007858:Learning; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D010959:Tissue Plasminogen Activator
keywords: Amyloid degrading enzymes; Amyloid plaques; Amyloid-β (Aβ); Tg2576 mice