HIV-Associated Insults Modulate ADAM10 and Its Regulator Sirtuin1 in an NMDA Receptor-Dependent Manner

Area of Science:

• Neuroscience
• Virology
• Cell Biology

Background:

• Human immunodeficiency virus (HIV) infection affects 50% of individuals, leading to HIV-associated neurocognitive disorders (HAND).
• HAND shares neuropathological features with Alzheimer's disease (AD), including amyloid-beta (Aβ) aggregates.
• Aβ is produced by BACE1 cleavage of amyloid precursor protein (APP), but can be prevented by ADAM10 cleavage.

Purpose of the Study:

• To investigate the role of ADAM10 and its regulatory mechanisms in in vitro models of HAND.
• To examine how HIV-associated insults affect APP secretase pathways.

Main Methods:

• Primary rat cortical neurons were exposed to supernatants from HIV-infected human macrophages (HIV/MDMs).
• The effects of NMDA receptor activation and inhibition were studied.
• Protein levels of ADAM10 and Sirtuin1 (SIRT1) were analyzed.
• Proteasome activity was assessed using MG132.

Main Results:

• HIV/MDMs reduced levels of both ADAM10 and SIRT1.
• NMDA receptor antagonists blocked these decreases.
• NMDA treatment alone decreased ADAM10 and SIRT1 protein levels.
• SIRT1 levels decreased before ADAM10, and this decrease was reversible with MG132.

Conclusions:

• HIV-associated insults, particularly excitotoxicity, downregulate ADAM10 and its regulator SIRT1.
• This suggests a mechanism by which HIV impacts APP secretase activity and contributes to HAND pathogenesis.