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