Dysregulation of macrophage-secreted cathepsin B contirbutes to HIV-linked neuronal apoptosis

Author(s): Loyda M Melendez

Chronic human immunodeficiency virus type one (HIV-1) infection leads to a spectrum of neurological and cognitive abnormalities, termed HIV-associated neurocognitive disorders (HAND). HAND remains prevalent, particularly in its milder forms, despite effective combination antiretroviral therapy (cART). The pathogenesis of HAND is caused by HIV-infected perivascular macrophages and microglia, whose activation leads to the release of pro-inflammatory cytokines and other soluble factors toxic to neurons. One factor that may be involved in macrophage-mediated HIV neurotoxicity is cathepsin B (CATB), a cysteine protease. We recently demonstrated that monocyte-derived macrophages (MDM) secreted, CATB has increased neurotoxic activity in vitro. Our studies demonstrate that cathepsin B interacts with MMP-9 in uninfected cells but this interaction disappears in HIV infection and develops a new interaction with serum amyloid P component (SAPC), related to amyloid deposition in Alzheimer’s disease (AD). Studies in the literature also suggest that CATB might be involved in amyloid-beta (Aβ)- related inflammatory response, which results in neuronal death. Our hypothesis is that increased secretion of monocyte-derived cathepsin B and SAPC after HIV infection causes neuronal dysfunction and death, and contributes to the pathogenesis of HAND. SK-N-SH neuronal cells were exposed to active recombinant histidine-tagged cathepsin B (His- CATB). His-CATB entry was tracked by intracellular flow cytometry, and neuronal dysfunction was verified by western blot. Neurons internalized His-CATB, an effect that was partially decreased by pre-treatment with anti-CATB antibody. Pre-treatment with CATB and SAPC antibodies decreased cleavage of caspase-3 and restored synaptophysin in neurons. CATB secreted both free and in EVs, is internalized by neurons. HIV-replication levels modulate the amount of CATB neuronal uptake, and neuronal dysfunction can be decreased with CATB antibodies or with CATB inhibitor CA074. In conclusion, the CATB/SAPC complex represents a novel target against HAND and current studies will test this approach in a small animal model.