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

Joseph Flores, Anastasia Noël, Bénédicte Foveau, Jeffrey Lynham, Clotilde Lecrux and Andréa C. LeBlanc ()
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Joseph Flores: Jewish General Hospital
Anastasia Noël: Jewish General Hospital
Bénédicte Foveau: Jewish General Hospital
Jeffrey Lynham: Jewish General Hospital
Clotilde Lecrux: McGill University
Andréa C. LeBlanc: Jewish General Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06449-x

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