Date Published:
2019 05 29

Publication Type:
Journal Article

Authors:

Y.M. Cantres-Rosario
S.C. Ortiz-Rodríguez
A.G. Santos-Figueroa
M. Plaud
K. Negron
B. Cotto
D. Langford
L.M. Meléndez

Secondary:
Sci Rep

Volume:
9

Pagination:
8006

Issue:
1

PMID:
31142756

URL:
https://pubmed.ncbi.nlm.nih.gov/31142756

DOI:
10.1038/s41598-019-44463-1

Keywords:
AIDS Dementia Complex;Apoptosis;Blood-Brain Barrier;Caspase 3;Cathepsin B;Cell Line;Cells, Cultured;Culture Media, Conditioned;Deoxyribonucleases, Type II Site-Specific;Endoribonucleases;Extracellular vesicles;Flow Cytometry;Hippocampus;Histidine;HIV Infections;HIV-1;Humans;Macrophages;Neoplasm Proteins;Neurons;Synaptophysin

Abstract:
<p>HIV-associated neurocognitive disorders prevail in 20-50 percent of infected individuals. Macrophages transmigrate through the blood brain barrier during HIV-1 infection, triggering neuronal dysfunction. HIV-infected macrophages secrete cathepsin B (CATB), and serum amyloid p component (SAPC), inducing neuronal apoptosis by an unknown mechanism. We hypothesized that HIV infection facilitates CATB/SAPC secretion from macrophages followed by neuronal internalization, promoting dysfunction. 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. Macrophage-derived extracellular vesicles (EVs) were tested for the presence of CATB and SAPC. 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. Neurons exposed to macrophage-conditioned media differentially internalized His-CATB, dependent on the HIV replication levels. Finally, CATB and SAPC were secreted in EVs. We report for the first time that CATB is secreted from macrophages both free and in EVs, and is internalized by neurons. Moreover, HIV-replication levels modulate the amount of CATB neuronal uptake, and neuronal dysfunction can be decreased with CATB antibodies. In conclusion, the CATB/SAPC complex represents a novel target against HIV-associated neurocognitive disorders.</p>