Q134R: Small Chemical Compound with NFAT Inhibitory Properties Improves Behavioral Performance and Synapse Function in Mouse Models of Amyloid Pathology

Authors

Pradoldej Sompol, University of KentuckyFollow
Jenna L. Gollihue, University of KentuckyFollow
Susan D. Kraner, University of KentuckyFollow
Irina A. Artiushin, University of KentuckyFollow
Ryan A. Cloyd, University of KentuckyFollow
Emad Chishti, University of KentuckyFollow
Shon A. Koren, University of Kentucky
Grant K. Nation, University of KentuckyFollow
Jose F. Abisambra, University of Florida
Orsolya Huzian, Avidin Ltd, Hungary
Lajos I. Nagy, Avidin Ltd, Hungary
Miklos Santha, ELKH Biological Research Centre, Hungary
Laszlo Hackler Jr., Avidin Ltd, Hungary
Laszlo G. Puskas, Avidin Ltd, Hungary
Christopher M. Norris, University of KentuckyFollow

Abstract

Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging-related Alzheimer's disease (AD)-like pathology. However, concerns over adverse effects have slowed the transition of common CN-inhibiting drugs to the clinic for the 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. However, small chemical inhibitors of NFATs have only rarely been described. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that suppresses NFAT signaling, without inhibiting CN activity. Q134R partially inhibited NFAT activity in primary rat astrocytes, but did not prevent CN-mediated dephosphorylation of a non-NFAT target, either in vivo, or in vitro. Acute (≤1 week) oral delivery of Q134R to APP/PS1 (12 months old) or wild-type mice (3–4 months old) infused with oligomeric Aβ peptides led to improved Y maze performance. Chronic (≥3 months) oral delivery of Q134R appeared to be safe, and, in fact, promoted survival in wild-type (WT) mice when given for many months beyond middle age. Finally, chronic delivery of Q134R to APP/PS1 mice during the early stages of amyloid pathology (i.e., between 6 and 9 months) tended to reduce signs of glial reactivity, prevented the upregulation of astrocytic NFAT4, and ameliorated deficits in synaptic strength and plasticity, without noticeably altering parenchymal Aβ plaque pathology. The results suggest that Q134R is a promising drug for treating AD and aging-related disorders.

Document Type

Article

Publication Date

6-12-2021

Notes/Citation Information

Published in Aging Cell, e13416.

© 2021 The Authors

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Digital Object Identifier (DOI)

https://doi.org/10.1111/acel.13416

Funding Information

This work was supported by National Institutes of Health Grants (RF1AG027297, R21AG051945, T32AG057461), a UK CCTS/UL1TR001998 grant, an Alzheimer’s Drug Discovery Foundation grant, The Sylvia Mansbach Research Fund, and The Hazel Embry Research Trust.

Related Content

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Repository Citation

Sompol, Pradoldej; Gollihue, Jenna L.; Kraner, Susan D.; Artiushin, Irina A.; Cloyd, Ryan A.; Chishti, Emad; Koren, Shon A.; Nation, Grant K.; Abisambra, Jose F.; Huzian, Orsolya; Nagy, Lajos I.; Santha, Miklos; Hackler, Laszlo Jr.; Puskas, Laszlo G.; and Norris, Christopher M., "Q134R: Small Chemical Compound with NFAT Inhibitory Properties Improves Behavioral Performance and Synapse Function in Mouse Models of Amyloid Pathology" (2021). Sanders-Brown Center on Aging Faculty Publications. 174.
https://uknowledge.uky.edu/sbcoa_facpub/174