Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer\u2019s disease mouse model

Joseph Flores,Bénédicte Foveau,Clotilde Lecrux,Anastasia Noël,Andréa C Leblanc,Jeffrey Lynham

doi:10.1038/s41467-018-06449-x

Joseph Flores, Bénédicte Foveau + Show 4 more

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https://doi.org/10.1038/s41467-018-06449-x

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Journal: Nature Communications	Publication Date: Sep 25, 2018
Citations: 197	License type: open-access

Affiliation: McGill University, Jewish General Hospital

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.

Highlights

Alzheimer's disease (AD) is an intractable progressive neurodegenerative disease characterized by cognitive decline and dementia
We identified a human neurodegenerative pathway, mediated by neuronal Nlrp[1] inflammasome activation of Casp[1], which activates Caspase-6 (Casp6), in stressed CNS human primary neuron cultures and AD brains[11]
J20 and littermate WT mice showed normal motivation behaviour determined by % time moving and did not exhibit thigmotaxis indicative of anxiety, but J20 mice showed a strong deficit in the novel object recognition (NOR) episodic memory discrimination index (Fig. 1b)

Summary

Introduction

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. 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. 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. The early manifestation of these symptoms and pathologies allows rapid analyses of the VX-765 effects

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Results

Conclusion