SARS-CoV-2 Nsp7 plays a role in cognitive dysfunction by impairing synaptic plasticity

Area of Science:

• Neuroscience
• Virology
• Molecular Biology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is linked to persistent neurological issues, including cognitive decline.
• The precise molecular mechanisms driving these long-term neurological symptoms remain largely unknown.

Purpose of the Study:

• To investigate the role of SARS-CoV-2 non-structural proteins (Nsps) in cognitive dysfunction.
• To elucidate the specific mechanisms by which SARS-CoV-2 impacts synaptic plasticity and neuronal function.

Main Methods:

• Assessed synaptic protein levels in SARS-CoV-2 infected SH-SY5Y neurons.
• Screened SARS-CoV-2 Nsps for their effect on synapsin-1.
• Overexpressed Nsp7 in neuronal cell cultures and primary mouse neurons.
• Injected AAV-GFP-Nsp7 into the hippocampus of C57BL/6 mice.
• Investigated mitochondrial function, reactive oxygen species (ROS) production, and ATP levels.
• Utilized the ROS inhibitor N-acetylcysteine (NAC).

Main Results:

• SARS-CoV-2 infection reduced synaptic protein levels in neurons.
• Nsp7 was identified as a key Nsp that decreases synapsin-1 levels.
• Nsp7 overexpression impaired synaptic protein levels without affecting neuronal viability.
• Mice receiving Nsp7 injections showed memory deficits, reduced dendritic spine density, and lower synaptic protein levels.
• Nsp7 induced mitochondrial damage, leading to increased ROS and decreased ATP, which suppressed synaptic protein expression.

Conclusions:

• SARS-CoV-2 Nsp7 plays a critical role in cognitive dysfunction.
• Nsp7 impairs synaptic plasticity through mitochondrial damage and ROS production.
• These findings provide insight into the pathogenesis of central nervous system symptoms associated with SARS-CoV-2 infection.