Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging

Joseph Flores, Anastasia Noël, Bénédicte Foveau, Olivier Beauchet and Andréa C. LeBlanc ()
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Joseph Flores: Jewish General Hospital
Anastasia Noël: Jewish General Hospital
Bénédicte Foveau: Jewish General Hospital
Olivier Beauchet: Jewish General Hospital
Andréa C. LeBlanc: Jewish General Hospital

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.

Date: 2020
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DOI: 10.1038/s41467-020-18405-9

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