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

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.

• Authors: Joseph Flores, Anastasia Noël, Bénédicte Foveau, Olivier Beauchet, Andréa C LeBlanc
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 4571 (09 11 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32917871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Cytokines
• Dipeptides
• Serpins
• Viral Proteins
• para-Aminobenzoates
• belnacasan
• interleukin-1beta-converting enzyme inhibitor

Topics

• Aging (metabolism)
• Alzheimer Disease (drug therapy, metabolism)
• Amyloid beta-Peptides (metabolism)
• Animals
• Behavior, Animal
• Cognitive Dysfunction (drug therapy, metabolism)
• Cytokines (metabolism)
• Dipeptides (blood, pharmacology)
• Disease Models, Animal
• Encephalitis (metabolism, pathology)
• Female
• Humans
• Inflammation (metabolism)
• Male
• Memory Disorders (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Serpins (blood, metabolism, pharmacology)
• Spatial Memory (physiology)
• Viral Proteins (blood, metabolism, pharmacology)
• para-Aminobenzoates (blood, pharmacology)