Cerebrospinal fluid levels of MMP-2, 7, and 9 are elevated in association with human immunodeficiency virus dementia

Pathological evidence suggests that alterations of the blood-brain barrier (BBB) may occur in association with human immunodeficiency virus (HN) demen tia (HIVD). Increased BBB permeability could contribute to the development of dementia by facilitating the entry of activated and infected monocytes, as well as potentially toxic serum proteins, into the central nervous syste m. One mechanism by which BBB permeability may be altered is through increa sed activity of select matrix metalloproteinases (MMPs). In the present stu dy, we examined the possibility that MMPs that target critical BBB proteins , including laminin, entactin, and collagen type IV, are elevated in the ce rebrospinal fluid (CSF) of patients with HIVD. We also examined the possibi lity that such MMPs could be produced by brain-derived cells, and that MMP production by these cells might be increased by tumor necrosis factor-alpha , an inflammatory cytokine that is produced by HIV-infected monocytes/micro glia and is elevated in HIVD. By using western blot and enzyme-linked immun osorbent assay, we observed that CSF levels of pro-MMP-2 and pro-MMP-7 were increased in association with HIVD, In addition, through the use of gelati n substrate zymography, a sensitive functional assay for MMP-2 and MMP-9, w e observed that MMP-2 or pro-MMP-9 activity was more frequently detectable in the CSF of individuals with HIV dementia (9/16) than in the CSF from eit her nondemented seropositive (2/11) or seronegative (0/11) controls. Althou gh the presence of MMPs in the serum could contribute to elevated levels in the CSF, we also show that brain-derived cells release MMP-2, 7, and 9, an d that such release is increased after their stimulation with tumor necrosi s factor-alpha. Together, these results suggest that elevated CSF levels of select MMPs may reflect immune activation within the central nervous syste m. They also suggest that further studies may be warranted to determine whe ther these proteins may play a role in the development of symptomatic neuro logical disease.