Q134R: Small chemical compound with NFAT inhibitory properties improves behavioral performance and synapse function in mouse models of amyloid pathology
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.
This study conducted both in primary cell cultures and in intact mice demonstrated that the novel hydroxyquinoline compound Q134R exhibits NFAT inhibitory properties in the absence of CN modulation. In an intact mouse model of AD-like amyloid pathology, Q134R reduced the expression of the NFAT4 isoform, which is typically upregulated in reactive astrocytes. Similar to peptide-based inhibitors of NFAT (i.e., VIVIT), Q134R improved cognitive and synaptic function, and generally promoted survival beyond mid-age. Recently, Q134R was proven safe and well-tolerated in a Phase 1A clinical trial (EudraCT Number: 2016-000368-40).
Together with the present findings, these results suggest that Q134R is a promising drug candidate to treat and/or prevent dementia in patients with AD or AD-related disorders.
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Chronic Q134R treatment improves hippocampal synaptic function and plasticity in APP/PS1 mice. Chronic Q134R treatment improves hippocampal synaptic function and plasticity in APP/PS1 mice Six-month-old WT and APP/PS1 mice were oral gavaged 2×/day with vehicle (Veh) or Q134R (4 mg/kg) for 3 months as described in Figures 4,5. In situ brain slices were prepared for electrophysiological analyses in hippocampal CA1 stratum radiatum. (a-c) representative waveforms illustrating the synaptic parameters measured. EPSP slope to FV ratio (a) was measured to derive synaptic strength. Calibration bars: vertical = 0.5 mV, horizontal =5 ms. Twin stimulus pulses delivered 50 ms apart were used to elicit two successive field EPSPs (b). PPF was obtained by dividing the EPSP slope of pulse 2 (s2) by the EPSP slope of pulse 1 (s1) and multiplying by 100. The EPSP slope value measured at the first appearance of a PS in the ascending arm of the EPSP was used to assess PS Threshold (c). D-G, Synaptic strength curves and LTP time plots for WT mice (d, e) and APP/PS1 mice (f, g), respectively. For synaptic strength curves (d, f), mean ± SEM EPSP slope amplitudes (vertical error bars) are plotted against corresponding mean ± SEM presynaptic FV amplitudes (horizontal error bars). For LTP plots (e, g), mean ± SEM EPSP slope values (% of baseline) are plotted during the 20 min prior to (baseline) and 60 min after the delivery of two 100 Hz (1-s duration) stimulus trains (separated by 10 s). Calibration bars: vertical = 0.5 mV, horizontal = 5 ms. Treatment with Q134R shifted the synaptic strength curve to the left and enhanced LTP levels in APP/PS1 mice (f, g), but had little effect in WT mice. (h-k) Mean ±SEM values for the EPSP/FV ratio (h), PS threshold (i), PPF (j), and LTP (k) at 60 min post 100 Hz stimulation. Q134R significantly increased the EPSP/FV ratio and enhanced LTP levels in APP/PS1 mice, but had little effect in WT mice. n = 8–14 mice per genotype/drug group