Modification of lipid rafts by extracellular vesicles carrying HIV-1 protein Nef induces redistribution of amyloid precursor protein and Tau, causing neuronal dysfunction.
Title | Modification of lipid rafts by extracellular vesicles carrying HIV-1 protein Nef induces redistribution of amyloid precursor protein and Tau, causing neuronal dysfunction. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Ditiatkovski, M, Mukhamedova, N, Dragoljevic, D, Hoang, A, Low, H, Pushkarsky, T, Fu, Y, Carmichael, I, Hill, AF, Murphy, AJ, Bukrinsky, M, Sviridov, D |
Journal | J Biol Chem |
Volume | 295 |
Issue | 38 |
Pagination | 13377-13392 |
Date Published | 2020 Sep 18 |
ISSN | 1083-351X |
Keywords | Internal |
Abstract | HIV-associated neurocognitive disorders (HANDs) are a frequent outcome of HIV infection. Effective treatment of HIV infection has reduced the rate of progression and severity but not the overall prevalence of HANDs, suggesting ongoing pathological process even when viral replication is suppressed. In this study, we investigated how HIV-1 protein Nef secreted in extracellular vesicles (exNef) impairs neuronal functionality. ExNef were rapidly taken up by neural cells , reducing the abundance of ABC transporter A1 (ABCA1) and thus cholesterol efflux and increasing the abundance and modifying lipid rafts in neuronal plasma membranes. ExNef caused a redistribution of amyloid precursor protein (APP) and Tau to lipid rafts and increased the abundance of these proteins, as well as of Aβ ExNef further potentiated phosphorylation of Tau and activation of inflammatory pathways. These changes were accompanied by neuronal functional impairment. Disruption of lipid rafts with cyclodextrin reversed the phenotype. Short-term treatment of C57BL/6 mice with either purified recombinant Nef or exNef similarly resulted in reduced abundance of ABCA1 and elevated abundance of APP in brain tissue. The abundance of ABCA1 in brain tissue of HIV-infected human subjects diagnosed with HAND was lower, and the abundance of lipid rafts was higher compared with HIV-negative individuals. Levels of APP and Tau in brain tissue correlated with the abundance of Nef. Thus, modification of neuronal cholesterol trafficking and of lipid rafts by Nef may contribute to early stages of neurodegeneration and pathogenesis in HAND. |
DOI | 10.1074/jbc.RA120.014642 |
Alternate Journal | J Biol Chem |
PubMed ID | 32732283 |
PubMed Central ID | PMC7504931 |
Grant List | U24 MH100929 / MH / NIMH NIH HHS / United States U24 MH100925 / MH / NIMH NIH HHS / United States U24 MH100931 / MH / NIMH NIH HHS / United States P30 AI117970 / AI / NIAID NIH HHS / United States R01 NS102163 / NS / NINDS NIH HHS / United States U24 MH100930 / MH / NIMH NIH HHS / United States R01 HL131473 / HL / NHLBI NIH HHS / United States U24 MH100928 / MH / NIMH NIH HHS / United States |