Tau Pathology Drives Disease-Associated Astrocyte Reactivity in Salt-Induced Neurodegeneration

Area of Science:

• Neuroscience
• Neuroinflammation
• Astrocytes

Background:

• High salt intake is a risk factor for cognitive decline and Alzheimer's disease (AD).
• Disease-associated astrocytes (DAA)-like astrocytes are linked to AD pathology.
• The role of these astrocytes in high-salt diet (HSD) models is unknown.

Purpose of the Study:

• To investigate the impact of HSD on DAA-like astrocyte reactivity.
• To elucidate the mechanisms underlying HSD-induced astrocyte reactivity and neuroinflammation.
• To explore potential therapeutic targets for HSD-related cognitive deficits.

Main Methods:

• Mice were fed a high-salt diet (HSD).
• Astrocyte reactivity was assessed in the hippocampus.
• Neuronal tau pathology, adenosine A1R signaling, Cers1 pathway, and Lcn2 expression were analyzed.
• Lcn2 knockout and receptor antagonist studies were performed.

Main Results:

• HSD significantly increased DAA-like astrocyte reactivity in the hippocampal CA3 region.
• Astrocyte reactivity was dependent on neuronal tau pathology and activated adenosine A1R signaling.
• Neurons released Proteins Associated with Promoting DAA-like Astrocyte Reactivity (PAPD), with Lcn2 being crucial.
• Lcn2 knockout or receptor blockade reduced HSD-induced astrocyte reactivity and neuroinflammation.

Conclusions:

• A vicious cycle exists between tau pathology and adenosine A1R signaling, driving DAA-like astrocyte reactivity.
• Targeting the Tau-A1R axis may be a therapeutic strategy for HSD-induced neuroinflammation and cognitive decline.