HIV-1 Tat-mediated astrocytic amyloidosis involves the HIF-1α/lncRNA BACE1-AS axis.
Title | HIV-1 Tat-mediated astrocytic amyloidosis involves the HIF-1α/lncRNA BACE1-AS axis. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Sil, S, Hu, G, Liao, K, Niu, F, Callen, S, Periyasamy, P, Fox, HS, Buch, S |
Journal | PLoS Biol |
Volume | 18 |
Issue | 5 |
Pagination | e3000660 |
Date Published | 2020 05 |
ISSN | 1545-7885 |
Keywords | Amyloid beta-Peptides, Amyloidosis, Animals, Astrocytes, Brain, Cells, Cultured, External, HIV Infections, HIV-1, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Macaca mulatta, Middle Aged, neurocognitive disorders, Peptide Fragments, RNA, Long Noncoding, tat Gene Products, Human Immunodeficiency Virus, Up-Regulation |
Abstract | Increased life expectancy of patients diagnosed with HIV in the current era of antiretroviral therapy is unfortunately accompanied with the prevalence of HIV-associated neurocognitive disorders (HANDs) and risk of comorbidities such as Alzheimer-like pathology. HIV-1 transactivator of transcription (Tat) protein has been shown to induce the production of toxic neuronal amyloid protein and also enhance neurotoxicity. The contribution of astrocytes in Tat-mediated amyloidosis remains an enigma. We report here, in simian immunodeficiency virus (SIV)+ rhesus macaques and patients diagnosed with HIV, brain region-specific up-regulation of amyloid precursor protein (APP) and Aβ (40 and 42) in astrocytes. In addition, we find increased expression of β-site cleaving enzyme (BACE1), APP, and Aβ in human primary astrocytes (HPAs) exposed to Tat. Mechanisms involved up-regulation of hypoxia-inducible factor (HIF-1α), its translocation and binding to the long noncoding RNA (lncRNA) BACE1-antisense transcript (BACE1-AS), resulting, in turn, in the formation of the BACE1-AS/BACE1 RNA complex, subsequently leading to increased BACE1 protein, and activity and generation of Aβ-42. Gene silencing approaches confirmed the regulatory role of HIF-1α in BACE1-AS/BACE1 in Tat-mediated amyloidosis. This is the first report implicating the role of the HIF-1α/lncRNABACE1-AS/BACE1 axis in Tat-mediated induction of astrocytic amyloidosis, which could be targeted as adjunctive therapies for HAND-associated Alzheimer-like comorbidity. |
DOI | 10.1371/journal.pbio.3000660 |
Alternate Journal | PLoS Biol |
PubMed ID | 32453744 |
PubMed Central ID | PMC7274476 |
Grant List | R01 MH106425 / MH / NIMH NIH HHS / United States R25 MH080661 / MH / NIMH NIH HHS / United States |