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

• Published in: Nature communications Vol. 11; no. 1; p. 4571
• Main Authors: Flores, Joseph, Noël, Anastasia, Foveau, Bénédicte, Beauchet, Olivier, LeBlanc, Andréa C
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 11.09.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Activation; Aging; Aging - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid precursor protein; Animal models; Animals; Behavior, Animal; Caspase-1; Clinical trials; Cognitive ability; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - metabolism; Correlation analysis; Cytokines - metabolism; Dipeptides - blood; Dipeptides - pharmacology; Disease Models, Animal; Encephalitis - metabolism; Encephalitis - pathology; Female; Genetic markers; Humans; Inflammation; Inflammation - metabolism; Inhibitors; Male; Medical treatment; Memory; Memory Disorders - metabolism; Memory tasks; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurodegenerative diseases; para-Aminobenzoates - blood; para-Aminobenzoates - pharmacology; Pathophysiology; Serpins - blood; Serpins - metabolism; Serpins - pharmacology; Spatial analysis; Spatial memory; Spatial Memory - physiology; Therapeutic applications; Therapeutic targets; Viral Proteins - blood; Viral Proteins - metabolism; Viral Proteins - pharmacology; β-Amyloid
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18405-9

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 (APP ) J20 and wild-type mice with VX-765 delays both APP - 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.