Aβ may also be cleaved into smaller peptides before being transported from the brain. According to a second report in the October 1 Journal of Neuroscience by Sidney Strickland and colleagues at Rockefeller University in New York, tissue-type plasminogen activator (tPA) and plasmin may be crucial players in this potential clearance mechanism.
First author Jerry Melchor and colleagues found that in mouse models of AD, tPA activity is significantly reduced in the hippocampus and amygdala as compared to levels in wild-type mice. This, the authors show, correlates with increased levels of plasminogen activator inhibitor-1 (PAI-1), which can inactivate tPA.
To test the relationship between tPA/plasmin and Aβ clearance, the authors injected some Aβ into the brains of both normal mice and those lacking tPA or plasmin. In controls, the Aβ was cleared within three days, but in both tPA- and plasmin-negative mice analyzed at the same time, Aβ immunoreactivity was 10-fold higher. Furthermore, in the mutant mice, the Aβ injection provoked activation of microglia and a degeneration of neurons that were not observed in wild type animals.
This paper extends a recent report by this group implicating tPA and tPA blockers in AD pathogenesis and therapy (Melchor et al., 2003). Its experiments provide in-vivo support for earlier in-vitro experiments showing that plasmin cleaves Aβ (Tucker et al., 2000), and they follow a paper suggesting that plasmin is downregulated in AD brain (Ledesma et al., 2000). Plasmin cleavage of Aβ "may be important for slowing the progression of Alzheimer's disease," write the authors, but they caution that tPA has also been shown to be deleterious to neurons under conditions of excitotoxicity. Nevertheless, plasmin now appears ready to be added to the list of proteases that degrade Aβ in vivo (see ARF related news story).
Interestingly, the gene PLAU, which encodes the urokinase variant of plasminogen activator (uPA), is among the candidate risk factor genes for AD currently pursued by several labs. Steve Younkin’s group reported initial data on PLAU last year at a conference in Stockholm and again this year (see Younkin section in ARF conference report), while German and Swiss researchers published similar data this summer in Neurogenetics (Finckh et al., 2003).-Tom Fagan.
Cirrito JR, May PC, O'Dell MA, Taylor JW, Parsadanian M, Cramer JW, Audia JE, Nissen JS, Bales KR, Paul SM, DeMattos RB, Holtzman DM. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J. Neurosci. October 1;23:8844-8853. Abstract
Banks WA, Robinson SM, Verma S, and Morley JE. Efflux of human and mouse amyloid beta proteins 1-40 and 1-42 from brain: impairment in a mouse model of Alzheimer's disease. Neurosci. 2003. October 6;121:487-492. Abstract
Melchor JP, Pawlak R, Strickland S. The tissue plasminogen activator-plasminogen proteolytic cascade accelerates amyloid-beta (Abeta) degradation and inhibits Abeta-induced neurodegeneration. J. Neurosci. 2003. Oct 1;23:8867-8871. Abstract