People infected with the human immunodeficiency virus type 1 (HIV-1) may develop dementia due to the death of neurons in the brain. However, HIV-1 does not infect neurons, suggesting that an indirect process is at work. A potent neurotoxin produced by a complex interaction of signals from non-neuronal brain cells may be the answer, reports a study in the October issue of Nature Neuroscience. This work suggests that drugs already in clinical trials for another disease may be effective for treating HIV-associated dementia.
The authors found that when certain immune cells (called macrophages) were infected with HIV-1, they released a substance toxic to neurons. Further examination revealed that the substance, an inactive form of a protein called matrix metalloprotease 2 (MMP2), was itself not the killer, but rather was converted by neurons into an enzyme that cleaves another protein, called stromal-derived factor (SDF) 1. SDF-1 has a number of normal functions in the brain, but the shortened form of SDF-1 was highly toxic to neurons. Rats given the inactive MMP2 showed loss of neurons and exhibited behavioral problems. By using drugs that block the activation of MMP2 (and thus the cleavage of SDF-1), the researchers could diminish the toxic effects. Such MMP2 inhibitors are already in clinical trials for cancer.
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