Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disorder and the leading cause of dementia. Presently, there is no cure for AD. Recent treatment strategies, involving the removal of amyloid protein deposits from the brain, have failed in clinical trials to impart significant protection from cognitive decline, suggesting that the pursuit of other molecular mechanisms and/or novel therapeutic approaches would be prudent. In this project, we propose to use a novel compound kinolol (Q134) developed by Avidin Ltd to target an alternative mechanism for AD pathophysiology i.e. the Nuclear Factor of Activated T cells (NFAT). NFATs are factors that directly regulate gene expression. They are activated by a signaling enzyme called calcineurin. Together, calcineurin and NFATs orchestrate critical cellular responses, like adaptive immunity. However, hyperactivation of calcineurin/NFATs can lead to cellular dysfunction. Mounting evidence suggests that calcineurin/NFATs are hyperactivated in the brain at early stages of AD, leading to neuroinflammation and neurodegeneration. Suppression of the calcineurin/NFAT pathway with FDA-approved calcineurin inhibitors is generally very protective in experimental models of AD, suggesting that these drugs would be a promising alternative/complimentary approach to existing AD therapies. However, calcineurin inhibitors also show many adverse effects that dampen enthusiasm for their use in the clinic. In this proposal, we will test a novel compound, Q134, that inhibits NFAT activity, but does not inhibit calcineurin, per se. The lack of calcineurin-inhibiting properties is expected to make Q134 a safer drug than currently available calcineurin inhibitors. We will investigate the NFAT inhibiting properties of Q134 in neural cells and will determine if Q134 ameliorates AD-like symptoms (e.g. memory dysfunction, and amyloid pathology) in an intact preclinical mouse model of AD.