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

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

Author information

1
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Ch. Côte Ste-Catherine, Montreal, QC, H3T 1E2, Canada.
2
Department of Neurology and Neurosurgery, McGill University, 845 Sherbrooke St West, Montreal, QC, H3A 0G4, Canada.
3
Department of Anatomy and Cell Biology, McGill University, 845 Sherbrooke St West, Montreal, QC, H3A 0G4, Canada.
4
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Ch. Côte Ste-Catherine, Montreal, QC, H3T 1E2, Canada. andrea.leblanc@mcgill.ca.
5
Department of Neurology and Neurosurgery, McGill University, 845 Sherbrooke St West, Montreal, QC, H3A 0G4, Canada. andrea.leblanc@mcgill.ca.
6
Department of Anatomy and Cell Biology, McGill University, 845 Sherbrooke St West, Montreal, QC, H3A 0G4, Canada. andrea.leblanc@mcgill.ca.

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.

PMID:
30254377
PMCID:
PMC6156230
DOI:
10.1038/s41467-018-06449-x
[Indexed for MEDLINE]
Free PMC Article

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