Caffeine and adenosine A2a receptor antagonists prevent β-amyloid (25–35)-induced cognitive deficits in mice

Consumption of caffeine, an adenosine receptor antagonist, was found to be inversely associated with the incidence of Alzheimer's disease. Moreover, caffeine protects cultured neurons against β-amyloid-induced toxicity, an effect mimicked by adenosine A2A but not A1 receptor antagonists. We now tested if caffeine administration would prevent β-amyloid-induced cognitive impairment in mice and if this was mimicked by A2A receptor blockade. One week after icv administration of the 25–35 fragment of β-amyloid (Aβ, 3 nmol), mice displayed impaired performance in both inhibitory avoidance and spontaneous alternation tests. Prolonged treatment with caffeine (1 mg/ml) had no effect alone but prevented the Aβ-induced cognitive impairment in both tasks when associated with acute caffeine (30 mg/kg) 30 min treatment before Aβ administration. The same protective effect was observed after subchronic (4 days) treatment with daily injections of either caffeine (30 mg/kg) or the selective adenosine A2A receptor antagonist SCH58261 (0.5 mg/kg). This provides the first direct in vivo evidence that caffeine and A2A receptor antagonists afford a protection against Aβ-induced amnesia, which prompts their interest for managing Alzheimer's disease.