Adiponectin ameliorates hypoperfusive cognitive deficits by boosting a neuroprotective microglial response

Area of Science:

• Neuroscience
• Endocrinology
• Pathology

Background:

• Vascular cognitive impairment and dementia (VaD) stems from chronic reduced blood flow to the brain.
• Adiponectin's role in VaD pathogenesis is unclear, despite its involvement in central nervous system (CNS) conditions.
• Transcriptomic data reveal decreased adiponectin/PPAR signaling and increased inflammation in VaD brains.

Purpose of the Study:

• To investigate the function of the adiponectin/PPARγ axis in chronic hypoperfusion-induced cognitive deficits.
• To explore the therapeutic potential of adiponectin receptor agonists in VaD.

Main Methods:

• Utilized the murine asymmetric common carotid artery stenosis (ACAS) model for chronic hypoperfusion.
• Analyzed transcriptomic data from human VaD brain tissues.
• Assessed cognitive function, neuroinflammation, microglial activation, and neuronal loss in vivo and in vitro.
• Administered adipoRon, an adiponectin receptor agonist, and studied PPARγ knockout models.

Main Results:

• Adiponectin/PPARγ axis is vital for mitigating cognitive deficits and neuroinflammation in the ACAS model.
• Adiponectin levels fluctuate in VaD: initially high in plasma, later low in cerebrospinal fluid.
• Adiponectin deficiency exacerbates cognitive decline, neuroinflammation, and neuronal loss.
• AdipoRon treatment rescued cognitive and histological deficits by enhancing PPARγ and reducing microglial inflammation.
• PPARγ in microglia/macrophages is essential for adipoRon's neuroprotective effects.

Conclusions:

• The adiponectin/PPARγ pathway is critical for preserving cognitive function against chronic hypoperfusion.
• Modulating microglial function via adiponectin/PPARγ signaling offers a promising therapeutic strategy for VaD.
• AdipoRon demonstrates potential as a novel therapeutic agent for vascular dementia.