Tissue plasminogen activator arrests Alzheimer's disease pathogenesis

The progressive deposition of amyloid-beta (A beta) 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 A beta 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 Ab molecules and maintain low levels of brain A beta, resulting in the delay of AD pathogenesis. (C) 2014 Elsevier Inc. All rights reserved.