Estrogen activates matrix metalloproteinases-2 and -9 to increase beta amyloid degradation

Estrogen is known to affect different aspects of β-amyloid (Aβ) synthesis and degradation. The present work was undertaken to evaluate specifically whether matrix metalloproteinases (MMP) -2 and -9 are involved in Aβ degradation induced by estrogen and whether this is relevant to estrogen-induced neuroprotection. In SH-SY5Y human neuroblastoma cells, 10 nM 17β-estradiol (17β-E2) increases mRNA and intracellular protein expression of MMP-2 and -9, as well as the levels of the active forms of both enzymes released in the medium. Specificity of the effect is proved by prevention with the estrogen receptor (ER) antagonist ICI 182,780 (1 μM) and involvement of the ERα subtype is confirmed by the use of selective ERα or ERβ agonists (PPT, DPN) and antagonists (MPP, PHTPP). 17β-E2 significantly increases the degradation of Aβ, either transferred with the conditioned medium of H4-APPSw human neuroglioma cells, engineered to overproduce Aβ1-40 and Aβ1-42, or exogenously added as 2 μM Aβ1-42. Both these effects are completely prevented by preexposure to the broad spectrum MMP inhibitor GM6001 (5 μM). Importantly, the 17β-E2-induced rescue of neuroblastoma cells challenged with 2 μM Aβ1-42, an effect prevented by ICI 182,780 (1 μM), is mediated by MMPs, as it appears significantly reduced by GM6001 (5 μM) as well as by both MMP-2 (200 nM) and MMP-9 (200 nM) selective inhibitors. In conclusion, the present study shows for the first time that MMP-2 and -9 give a main contribution to estrogen's neuroprotective effect.