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

Author

Listed:
  • Joseph Flores

    (Jewish General Hospital
    McGill University)

  • Anastasia Noël

    (Jewish General Hospital
    McGill University)

  • Bénédicte Foveau

    (Jewish General Hospital)

  • Olivier Beauchet

    (Jewish General Hospital
    Sir Mortimer B. Davis - Jewish General Hospital
    Nanyang Technological University)

  • Andréa C. LeBlanc

    (Jewish General Hospital
    McGill University
    McGill University)

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.

Suggested Citation

  • Joseph Flores & Anastasia Noël & Bénédicte Foveau & Olivier Beauchet & Andréa C. LeBlanc, 2020. "Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18405-9
    DOI: 10.1038/s41467-020-18405-9
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