Date Published:
2020 05

Publication Type:
Journal Article

Authors:

S. Sil
G. Hu
K. Liao
F. Niu
S. Callen
P. Periyasamy
H.S. Fox
S. Buch

Secondary:
PLoS Biol

Volume:
18

Pagination:
e3000660

Issue:
5

PMID:
32453744

URL:
https://pubmed.ncbi.nlm.nih.gov/32453744

DOI:
10.1371/journal.pbio.3000660

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:
<p>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.</p>