HIV-1 Tat Interacts with and Regulates the Localization and Processing of Amyloid Precursor Protein

Abstract

HIV-1 Tat protein plays various roles in virus proliferation and in the regulation of numerous host cell functions. Accumulating evidence suggests that HIV-1 Tat also plays an important role in HIV-associated neurocognitive disorders (HAND) by disrupting intracellular communication. Amyloid beta (Aβ) is generated from amyloid precursor protein (APP) and accumulates in the senile plaques of Alzheimer's disease patients. This study demonstrates that Tat interacts with APP both in vitro and in vivo, and increases the level of Aβ42 by recruiting APP into lipid rafts. Co-localization of Tat with APP in the cytosol was observed in U-87 MG cells that expressed high levels of Tat, and redistribution of APP into lipid rafts, a site of increased β- and γ-secretase activity, was demonstrated by discontinuous sucrose density gradient ultracentrifugation in the presence of Tat. Furthermore, Tat enhanced the cleavage of APP by β-secretase in vitro, resulting in 5.5-fold higher levels of Aβ42. This was consistent with increased levels of β-C-terminal fragment (β-CTF) and reduced levels of α-CTF. Moreover, stereotaxic injection of a lentiviral Tat expression construct into the hippocampus of APP/presenilin-1 (PS1) transgenic mice resulted in increased Tat-mediated production and processing of Aβ in vivo. Increased levels of Aβ42, as well as an increase in the number and size of Aβ plaques, were observed in the hippocampus following injection of Tat virus compared with mock virus. These results suggest that HIV-1 Tat may contribute to HAND by interacting with and modifying APP processing, thereby increasing Aβ production.

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

“…Tat increases Aβ secretion in neuron cultures [187]. Injection of lentiviral Tat construct into the hippocampus of mice results in elevated levels of Aβ production and increases the size and number of Aβ plaques [190]. Moreover, Tat further increases the burden of Aβ in AβPP/PS1 mice crossed with HIV-1Tattransgenicmice[191].…”

“…Tat also binds to heparan sulfate proteoglycan receptors on the microglia surface and decreases the transfer of Aβ to LRP1, thereby inhibiting phagocytosis [193]. Tat enhances Aβ burden by promoting the accumulation of AβPP into lipid rafts [190]. Tat and peptides derived from Tat decrease the activity of neprisylin, a major Aβ-degrading enzyme [187, 194].…”

Role of HIV in Amyloid Metabolism

“…Insulin degrading enzyme (IDE) or neprilysin can proteolyze Aβ42 and prevent deleterious Aβ42 aggregations in neurons (Madani et al 2006). In order to evacuate Aβ42 from neural tissue, active shuttling of Aβ42 from the brain into the bloodstream occurs through receptors for advanced glycation end-products (RAGE) and lipoprotein 1 receptors (LRP1) located on endothelial cells in the brain vasculature (Hickman et al 2008; Kim et al 2013). Altogether these systems help regulate Aβ42 levels in a sustainable balance that is necessary for normal cellular metabolism.…”

“…While the current diagnostic value of CSF and 11 C-PiB measurements of amyloid remain less clear for HIV compared to AD, many in-vitro studies still suggest that neuro-inflammation, as seen with HIV, can affect amyloid metabolism (Kim et al 2013a). A promising method to investigate differences is CSF proteomics.…”

Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND

“…Similarly, astrocytic tumor growth factor β-mediated neuroprotection was demonstrated in a mouse model for subacute neuroinflammation (Cekanaviciute et al , 2014). Although deleterious effects of intracellular accumulation of amyloid beta (Aβ) is well known in AD, a recent study using an amyloid precursor protein/presenilin-1 transgenic mouse model revealed that HIV-1 Tat can contribute to HAND by modifying amyloid precursor protein processing to increase Aβ production (Kim et al , 2013). …”