Adenosine A2A receptor antagonist SCH58261 improves the cognitive function in Alzheimer's disease model mice through activation of Nrf2 via an autophagy-dependent pathway

Aims: Adenosine, an important endogenous neuromodulator, contributes to a broad set of several neurodegenerative diseases. The adenosine A2A receptor (A2AR) is the most involved in neuropathological effects and plays an important role in the pathogenesis of Alzheimer's disease (AD). However, the effect of A2AR antagonist and the underlying mechanism in AD model mice remains unclear.

Results: The amyloid beta (Aβ)_1-42-induced mice AD models were used in this study. Several behavioral experiments were performed to evaluate the improvement of AD mice treat with A2AR receptor antagonist. For mechanism analysis, autophagy-related proteins, Kelch-like ECH-associated protein1(Keap1)- nuclear factor erythroid-derived factor 2-related factor (Nrf2) pathway activation and synaptic function were studied by using western blot, immunofluorescence (IF), immunohistochemistry (IHC), transmission electron microscope (TEM), real-time quantitative (PCR) and patch clamp. Pharmacological blockade of adenosine A2AR by SCH58261 (SCH) ameliorated cognitive deficits and decreased expression levels of several AD biomarkers, including Aβ and hyperphosphorylation of Tau. Moreover, SCH activated the Nrf2 pathway through Autophagy mediated Keap1 degradation, resulting in the improvement of neurons Autophagy dysfunction, synaptic plasticity, and synaptic transmission.

Innovation: Our data clarified that the SCH58261 (an antagonist of adenosine A2A receptor) could increase the level of Autophagy, promote the ability of anti-oxidative stress by the activation of Keap1-Nrf2 pathway, and improve the synaptic function in Aβ_1-42-induced Alzheimer's disease mice or cell model, which provided a potential therapeutic strategy for AD.

Conclusion: A2AR antagonism represents a promising strategy for the anti-AD agents development through autophagy-dependent pathway.