Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-β peptide catabolism

It has been postulated that the development of amyloid plaques in Alzheimer's disease ( AD) may result from an imbalance between the generation and clearance of the amyloid-beta peptide (A beta). Although familial AD appears to be caused by A beta overproduction, sporadic AD ( the most prevalent form) may result from impairment in clearance. Recent evidence suggests that several proteases may contribute to the degradation of A beta. Furthermore, astrocytes have recently been implicated as a potential cellular mediator of A beta degradation. In this study, we examined the possibility that matrix metalloproteinases ( MMPs), proteases known to be expressed and secreted by astrocytes, could play a role in extracellular A beta degradation. We found that astrocytes surrounding amyloid plaques showed enhanced expression of MMP-2 and MMP-9 in aged amyloid precursor protein (APP)/presenilin 1 mice. Moreover, astrocyte-conditioned medium (ACM) degraded A beta, lowering levels and producing several fragments after incubation with synthetic human A beta 1-40 and A beta 1-42. This activity was attenuated with specific inhibitors of MMP-2 and -9, as well as in ACM derived from mmp- 2 or -9 knock-out ( KO) mice. In vivo, significant increases in the steady-state levels of A beta were found in the brains of mmp- 2 and -9K0 mice compared with wild-type controls. Furthermore, pharmacological inhibition of the MMPs with N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide ( GM 6001) increased brain interstitial fluid A beta levels and elimination of half-life in APPsw mice. These results suggest that MMP-2 and - 9 may contribute to extracellular brain A beta clearance by promoting A beta catabolism.