Metalloproteinase shedding of Fas ligand regulates β-amyloid neurotoxicity

Extracellular deposits of beta-amyloid (Abeta) peptide closely match areas of neuronal loss in, and are a postmortem diagnostic indicator of, Alzheimer's disease. Neuronal cultures treated with fibrillar Abeta can be protected from neurotoxicity by caspase-8 inhibition or the expression of dominant-negative FADD, both of which are components of the Fas death receptor pathway [1, 2], and neurons with defective Fas and FasL are resistant to Abeta neurotoxicity [3]. The receptor binding region of FasL can be shed from cells by metalloproteinases, and this process greatly reduces its proapoptotic activity [4, 5]. Here, we show that factors affecting the shedding of membrane-bound Fast- significantly impact Abeta neurotoxicity. A broad-spectrum metalloproteinase inhibitor, GM6001/Ilomastat, acted synergistically with Abeta to enhance neurotoxicity through a FasL-dependent mechanism. The disruption of ADAM-based metalloproteinase activity was likely responsible, as MMP-inhibiting TIMPs had no such effect. In contrast, enhanced FasL shedding, by recombinant MMP-7, completely protected neurons from Abeta neurotoxicity. These findings suggest that factors that affect metalloproteinase-mediated shedding of FasL may play a role in the etiology of Alzheimer's disease and may provide an avenue for therapeutic intervention.