Journal Article

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

Beauchet, Olivier, Foveau, Bénédicte, Flores, Joseph, Noël, Anastasia, LeBlanc, Andréa C.

2020

Overview

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 Sw/Ind ) J20 and wild-type mice with VX-765 delays both APP Sw/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. Previous work showed that the caspase 1 inhibitor VX-765 rescued cognitive deficits in the J20 mouse model of Alzheimer’s disease, and this may occur via reduced inflammation. Here the authors show that administration of the drug prior to onset of cognitive deficits and pathology in mice delays the onset of deficits.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/51 / 14/63 / 42 / 45 / 45/90 / 631/378/1689/1283 / 631/378/2612 / 64/60 / 82/1 / 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 / Episodic memory / Female / Genetic markers / Humanities and Social Sciences / Humans / Inflammation / Inflammation - metabolism / Inhibitors / Male / Medical treatment / Memory / Memory Disorders - metabolism / Memory tasks / Mice / Mice, Inbred C57BL / Mice, Transgenic / multidisciplinary / Neurodegenerative diseases / para-Aminobenzoates - blood / para-Aminobenzoates - pharmacology / Pathophysiology / Science / Science (multidisciplinary) / 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