3 November 2006. Of all the Aβ proteases, the matrix metalloproteinases (MMPs) may be the ones that degrade extracellular Aβ and thus keep the brain clear of plaques. As we first reported last year, Jin-Moo Lee and colleagues at Washington University School of Medicine, St. Louis, Missouri, presented data at the Society for Neuroscience meeting in Washington showing that both MMP-2 and MMP-9 can degrade not only soluble but also fibrillar Aβ. The proteases appear to be secreted by astrocytes that surround and possibly help gobble up plaques (see ARF SfN news story).
That work was just published in the October 25 Journal of Neuroscience. In addition, Lee and colleagues reveal that MMP-2 and MMP-9 knockout mice have higher levels of endogenous Aβ than do wild-type animals. First author Ke-Jie Yin and colleagues also report that these MMP knockouts have normal levels of APP C-terminal fragments, indicating that it is truly attenuated degradation that explains the increase in Aβ, rather than any spurious effects on APP or Aβ production. The findings lend in-vivo support to the hypothesis that the two MMPs help clear extracellular deposits of Aβ. In fact, using laser capture microscopy to extract astrocytes from the brains of APP/PS1 double transgenic mice, Yin and colleagues could show that mRNA levels for the two proteinases were about 10-fold higher in cortical astrocytes surrounding plaques than in comparable astrocytes that were distant from plaques.
If upregulation of these MMPs is a response to increased Aβ and/or plaque load, then loss of MMP-2 and/or MMP-9 could spell trouble for the aging brain. Indeed, by using microdialysis to pump tiny amounts of the MMP inhibitor GM6001 into the hippocampus of APPsw transgenic mice, the authors found that the half-life of Aβ in the hippocampal interstitial fluid increased by 50 percent. Because Aβ fibril formation is most likely a concentration-dependent process, such an increase in the half-life of soluble Aβ would undoubtedly lead to increased formation of plaques, too.
The MMPs are just one type of protease that has been found to degrade Aβ. Others include insulin-degrading enzyme (IDE), neprilysin, endothelin-converting enzyme, angiotensin-converting enzyme, plasminogen activators, and most recently cathepsin B (see ARF related news story). The list may not stop there. Yin and colleagues found that the MMP inhibitor failed to completely block degradation of Aβ by astrocyte-conditioned medium despite the absence of other likely Aβ-degrading enzymes. That finding suggests that there are more Aβ-degrading proteases released by astrocytes that are yet to be discovered.—Tom Fagan.
Yin K-J, Cirrito JR, Yan P, Hu X, Xiao Q, Pan X, Bateman R, Song H, Hsu F-F, Turk J, Xu J, Hsu CY, Mills JC, Holtzman DM, Lee J-M. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J. Neurosci. October 25, 2006;26:10939-10948. Abstract