A3 receptor as a target for the treatment of Alzheimer’s disease

Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disease with clinical features including memory loss, cognitive impairment and dementia that affects over six million Americans. Current treatments for AD have limited efficacy due, in part, to the poorly understood multifactorial nature of the mechanisms driving AD. Our data suggests that alteration of adenosine kinase‐dependent adenosine metabolism and inadequate A 3 adenosine receptor ( A 3 AR ) signaling in the central nervous system (CNS) are key to these processes. The SAMP8 mouse are a mouse model of sporadic AD exhibiting many key characteristics of AD including age‐associated impairment in learning and memory, which corresponds to age‐related increase in beta amyloid, phosphorylated tau, oxidative stress, neuroinflammation, impaired efflux across the blood‐brain barrier and increased regulatory T‐cells in the brain. Method We first measured expressions of ADK and A3AR in the hippocampus of 12 month old. SAMP8 mice. We then treated 11 month old SAMP8 mice with MRS5980 an A3AR receptor agonist MLN5980 every other day for 6 weeks. At the end of the 4 th week of treatment, behavior tests were conducted for two weeks. Mice were tested in T‐maze, Novel Object Recognition (NORPT), elevated plus maze and open field. Result 12 month old SAMP8 mice treated with the A3AR agonist MRS5980 had improved learning and memory in the T‐maze and NORPT compared to the vehicle treated control mice. There was no difference between the young vehicle treated SAMP8 mice and the MRS5980 treated mice. MRS5980 did not affect activity or anxiety in the open field or elevated plus mazes indicating these factors did nor contribute to improvement in learning and memory. Conclusion Here we identify A 3 AR in key cognitive centers of the brain and its expression increases with cognitive impairment in the SAMP8 AD mouse model. Moreover, adenosine kinase, an enzyme that reduces extracellular adenosine, also increased. We discovered that supplemental A 3 AR signaling with highly selective, orally bioavailable, CNS‐penetrant A 3 AR agonists reversed cognitive impairment without any confounding influence on locomotor activity or anxiety. Our results indicate that A3AR is a useful pathway to give additional insight into changes in the brain with AD potential novel therapies.