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P2‐138: Inhibition of plasminogen activator activity may be critical in the loss of cognitive function and amyloid‐beta accumulation in Alzheimer's disease brain
Author(s) -
Seeds Nicholas,
Fabbro Shay
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.04.449
Subject(s) - plasmin , alzheimer's disease , tissue plasminogen activator , plasminogen activator , amyloid beta , chemistry , endocrinology , neuroscience , medicine , biochemistry , biology , enzyme , peptide , disease
Background: Amyloid-beta (Ab) plaques are a pathological hallmark of Alzheimer’s disease. Several proteases are known to cleave/remove Ab, including plasmin, the product of tissue plasminogen activator (tPA) cleavage of the pro-enzyme plasminogen. Although plasmin levels are lower in Alzheimer brain, there has been little analysis of the plasminogen activator(PA)/plasmin system in the brains of Alzheimer patients. Methods: In this study, zymography, immunocapture and ELISA assays were utilized to show that tPA activity in frontal cortex tissue of Alzheimer patients is dramatically reduced compared to age-matched controls, while tPA and plasminogen protein levels are unchanged; suggesting that tPA activity is inhibited in the Alzheimer brain. Results: Analysis of endogenous PA inhibitors shows that while PAI-1 and PN-1 levels are unchanged, the neuroserpin levels are significantly elevated in brains of Alzheimer patients. Furthermore, elevated amounts of tPA-neuroserpin complexes are seen in the Alzheimer brain, and immunohistochemical studies demonstrate that both tPA and neuroserpin are associated with Ab plaques in Alzheimer brain tissue. Thus, neuroserpin inhibition of tPA activity may lead to reduced plasmin and reduced clearance of Ab in the Alzheimer disease brain. Furthermore, decreased tPA activity in the Alzheimer brain may directly influence synaptic activity and impair cognitive function. Animal models where Ab1-42 is injected into the frontal cortex of PA system knockout mice show that the absence of tPA leads to slow clearance of the peptide, while absence of neuroserpin leads to rapid clearance of Ab. More importantly, cognitive deficits in spatial memory characteristic of the mutant APP transgenic mice that develop amyloid plaques are dramatically minimized when this APP transgene is expressed in a neuroserpin knockout mouse. Conclusions: thus, demonstrating that neuroserpin inhibition of tPA plays an important role both in the loss of cognitive abilities and accumulation of brain amyloid plaques. We are currently exploring inhibitors of neuroserpin that may be useful therapeutic agents to slow the progression of Alzheimer Disease.