ADAM17 Inhibition Protects Cognition in Intermittent Hypoxia: The Role of TREM2

Area of Science:

• Neuroscience
• Immunology
• Sleep Medicine

Background:

• Obstructive sleep apnea (OSA) is linked to cognitive impairment.
• Intermittent hypoxia (IH) is a key feature of OSA.
• The role of TREM2 in OSA-related cognitive dysfunction is not well understood.

Purpose of the Study:

• To investigate the effect of TREM2 on cognitive impairment in OSA.
• To elucidate the regulatory mechanism of TREM2 in OSA-related cognitive impairment.

Main Methods:

• Established IH animal and BV2 cell models.
• Utilized lentivirus for TREM2 knockdown and overexpression.
• Inhibited ADAM17 activity with TAPI-1.
• Assessed cognitive function using Morris water maze and molecular mechanisms via PCR, Western blotting, and ELISA.

Main Results:

• IH decreased TREM2 levels and promoted neuroinflammation (IL-1β, TNF-α, CD86) and neuronal injury (p-Tau).
• TREM2 overexpression mitigated IH-induced damage, while knockdown exacerbated it.
• IH increased ADAM17 activity and TREM2 shedding; TAPI-1 treatment reversed these effects.
• ADAM17 inhibition improved cognitive function and reduced neuroinflammation.

Conclusions:

• TREM2 protects against IH-induced neuroinflammation and neuronal injury by promoting M2 microglia polarization.
• IH enhances ADAM17 activity, leading to TREM2 degradation.
• Inhibiting ADAM17 to restore TREM2 is a promising therapeutic approach for OSA-related cognitive impairment.