HIV-1 Tat-mediated astrocytic amyloidosis involves the HIF-1α/lncRNA BACE1-AS axis.

TitleHIV-1 Tat-mediated astrocytic amyloidosis involves the HIF-1α/lncRNA BACE1-AS axis.
Publication TypeJournal Article
Year of Publication2020
AuthorsSil, S, Hu, G, Liao, K, Niu, F, Callen, S, Periyasamy, P, Fox, HS, Buch, S
JournalPLoS Biol
Date Published2020 05
KeywordsAmyloid 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

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.

Alternate JournalPLoS Biol
PubMed ID32453744
PubMed Central IDPMC7274476
Grant ListR01 MH106425 / MH / NIMH NIH HHS / United States
R25 MH080661 / MH / NIMH NIH HHS / United States