Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model

Nat Commun. 2018 Sep 25;9(1):3916. doi: 10.1038/s41467-018-06449-x.

Abstract

Alzheimer's disease (AD) is an intractable progressive neurodegenerative disease characterized by cognitive decline and dementia. An inflammatory neurodegenerative pathway, involving Caspase-1 activation, is associated with human age-dependent cognitive impairment and several classical AD brain pathologies. Here, we show that the nontoxic and blood-brain barrier permeable small molecule Caspase-1 inhibitor VX-765 dose-dependently reverses episodic and spatial memory impairment, and hyperactivity in the J20 mouse model of AD. Cessation of VX-765 results in the reappearance of memory deficits in the mice after 1 month and recommencement of treatment re-establishes normal cognition. VX-765 prevents progressive amyloid beta peptide deposition, reverses brain inflammation, and normalizes synaptophysin protein levels in mouse hippocampus. Consistent with these findings, Caspase-1 null J20 mice are protected from episodic and spatial memory deficits, neuroinflammation and Aβ accumulation. These results provide in vivo proof of concept for Caspase-1 inhibition against AD cognitive deficits and pathologies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology
  • Alzheimer Disease / prevention & control*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / physiopathology
  • Caspase 1 / genetics
  • Caspase 1 / metabolism*
  • Caspase Inhibitors / pharmacology*
  • Cognition / drug effects
  • Cognition / physiology
  • Cognition Disorders / metabolism
  • Cognition Disorders / physiopathology
  • Cognition Disorders / prevention & control*
  • Dipeptides / pharmacology
  • Disease Models, Animal*
  • Humans
  • Memory / drug effects
  • Memory / physiology
  • Memory Disorders / metabolism
  • Memory Disorders / physiopathology
  • Memory Disorders / prevention & control*
  • Mice, Knockout
  • para-Aminobenzoates / pharmacology

Substances

  • Amyloid beta-Peptides
  • Caspase Inhibitors
  • Dipeptides
  • para-Aminobenzoates
  • belnacasan
  • Caspase 1