Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice

Area of Science:

• Neuroscience
• Pharmacology
• Pathology

Background:

• Neuronal adenosine A2A receptors (A2ARs) are implicated in Alzheimer's disease (AD) pathogenesis, potentially causing synaptic and memory deficits.
• Mechanisms linking A2AR upregulation to AD-related cognitive decline remain poorly understood.

Purpose of the Study:

• To investigate the functional consequences of early neuronal A2AR upregulation in an Alzheimer's disease mouse model.
• To elucidate the cellular and molecular mechanisms underlying A2AR-mediated exacerbation of cognitive impairment.

Main Methods:

• APP/PS1 transgenic mice, modeling amyloid pathology, were used to induce neuronal A2AR upregulation in the hippocampus.
• Behavioral tests assessed memory function.
• Proteomic, transcriptomic, and immunofluorescence analyses evaluated amyloid and tau pathology, neuroinflammation, synaptic integrity, and mitochondrial function.

Main Results:

• Early A2AR upregulation exacerbated memory impairments in APP/PS1 mice without significantly altering amyloid plaque load.
• Increased phosphorylated tau at neuritic plaques correlated with memory deficits.
• Neuronal A2AR upregulation induced neuroinflammation, loss of excitatory synapses, and impaired mitochondrial function.

Conclusions:

• Neuronal A2AR dysfunction contributes to Alzheimer's disease pathogenesis and cognitive decline.
• A2AR antagonism represents a potential therapeutic strategy for mitigating memory impairments in AD.