Hv1 inhibition rescues AD pathology by restoring microglial mitochondrial function and enhancing mitochondrial...

Area of Science:

• Neuroscience
• Immunology
• Mitochondrial Biology

Background:

• Alzheimer's disease (AD) is characterized by tau pathology and neuroinflammation, with microglia playing a key role.
• Microglial mitochondrial health is crucial for immune homeostasis and clearing pathological tau in AD.
• Mechanisms of microglial mitochondrial dysfunction in AD are not well understood, hindering therapeutic strategies.

Purpose of the Study:

• To investigate the role of Hydrogen voltage-gated channel 1 (Hv1) in microglial mitochondrial dysfunction in Alzheimer's disease.
• To explore the therapeutic potential of targeting Hv1 in AD.

Main Methods:

• Utilized AD mouse models to examine Hv1 expression in activated microglia.
• Assessed mitochondrial function, including electron transport chain activity, oxidative stress, ATP production, and mitophagy.
• Evaluated the effects of the Hv1-specific inhibitor YHV98-4 on microglial function, tau clearance, and cognitive performance.

Main Results:

• Hv1 is upregulated in activated microglia in AD mouse models.
• Hv1 inhibition by YHV98-4 reversed mitochondrial dysfunction, including oxidative stress and impaired ATP production.
• YHV98-4 treatment improved tau clearance and enhanced microglia-to-neuron mitochondrial transfer, rescuing neuronal damage and improving cognition.

Conclusions:

• Hv1 plays a critical role in mediating microglial mitochondrial dysfunction in Alzheimer's disease.
• Targeting Hv1 with YHV98-4 represents a promising therapeutic strategy for AD, by restoring mitochondrial function and enhancing neuroprotective mechanisms.