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  • Q134R: Small chemical compound with NFAT inhibitory properties improves behavioral performance and synapse function in mouse models of amyloid pathology.

Q134R: Small chemical compound with NFAT inhibitory properties improves behavioral performance and synapse function in mouse models of amyloid pathology.

Aging cell (2021-06-13)
Pradoldej Sompol, Jenna L Gollihue, Susan D Kraner, Irina A Artiushin, Ryan A Cloyd, Emad A Chishti, Shon A Koren, Grant K Nation, Jose F Abisambra, Orsolya Huzian, Lajos I Nagy, Miklos Santha, Laszlo Hackler, Laszlo G Puskas, Christopher M Norris
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.

MATERIALS
Product Number
Brand
Product Description

Millipore
Phosphatase Inhibitor Cocktail Set II, A cocktail of five phosphatase inhibitors for the inhibition of acid and alkaline phosphatases as well as protein tyrosine phosphatases (PTPs). Suitable for use with cell lysates and tissue extracts.
Sigma-Aldrich
Anti-MAP2 Antibody, clone AP20, clone AP20, Chemicon®, from mouse
Sigma-Aldrich
Calpain Inhibitor Set, The Calpain Inhibitor Set controls the biological activity of Calpain. This small molecule/inhibitor is primarily used for Protease Inhibitors applications.
Millipore
Protease Inhibitor Cocktail Set III, EDTA-Free, Protease inhibitor cocktail III, EDTA-free for inhibiting aspartic, cysteine, and serine proteases as well as aminopeptidases in mammalian cells and tissues.