Novel Small Chemical Compound with NFAT Modulatory Properties Alleviates Synaptic Dysfunction and Improves Cognition in Mouse Models of Amyloid Pathology

AbstractBackgroundHyperactivity of the protein phosphatase calcineurin (CN) in brain directly corresponds to key neuropathological and clinical features of Alzheimer’s disease (AD). While inhibition of CN ameliorates pathophysiologic and cognitive changes in mice with AD‐like pathology, concerns over adverse effects have slowed the transition of common CN‐inhibiting drugs to the clinic for treatment of AD and AD‐related disorders. Targeting substrates of CN, like the nuclear factor of activated T‐cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that modulates NFAT signaling, without inhibiting CN activity.Method Cell culture studies — Rat cortical astrocyte cultures were treated with a variety of pathogenic factors in the presence of Q134R or the CN inhibitor, cyclosporine. NFAT‐dependent luciferase activity and dephosphorylation of non‐NFAT substrates were assessed. Intact mouse studies — Q134R was delivered (via oral gavage) to APP/PS1 mice at different ages, or to wild type (WT) mice infused with oligomeric amyloid‐beta peptides. Cognition was assessed on a Y maze along with several postmortem measures including NFAT4 activity, glial activation (GFAP and Iba‐1 expression), amyloid deposition, long‐term survival, and synaptic function and plasticity.ResultIn primary astrocytes, Q134R significantly inhibited NFAT activation in a concentration‐dependent manner, but did not inhibit the CN‐dependent dephosphorylation of non‐NFAT substrates in vivo or in vitro. Short‐term treatment of APP/PS1 mice with Q134R inhibited the nuclear translocation of NFAT4 in hippocampal astrocytes while causing a significant drop in GFAP volume, a mild reduction in Iba1, and no change in amyloid pathology. Short‐term treatment with Q134R also improved cognitive function in APP/PS1 mice and amyloid‐infused WT mice. Long‐term oral delivery of Q134R over many months promoted survival in WT mice and improved synaptic function and plasticity in APP/PS1 mice.ConclusionQ134R has novel CN‐independent, NFAT modulatory properties and improves key neurologic function parameters in mouse models of AD‐like pathology. The results suggest that Q134R is a promising drug for treating AD and AD‐related disorders.