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

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.

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

“…106 However, in the mouse model of Alzheimer's disease, VX-765 crossed the BBB and alleviated neuroinflammation and accumulation of Aβ plaques and memory and cognition impairment. 107 Glyburide does not alter the expression of NLRP3, and its molecular target has not yet been discovered. 108 A series of NLRP3 inflammasome inhibitors was first inspired by the discovery that glyburide, a type 2 diabetes drug that can stop the NLRP3-mediated production of IL-1β but not that of NLRC4 and NLRP1.…”

“…because of the chance of developing hepatotoxicity and immunosuppression . However, in the mouse model of Alzheimer's disease, VX‐765 crossed the BBB and alleviated neuroinflammation and accumulation of Aβ plaques and memory and cognition impairment …”

Inflammasomes in neuroinflammatory and neurodegenerative diseases

“…Indirect inhibition of NLRP3 inflammasome activation by clinically approved fenamate non‐steroidal anti‐inflammatory drugs that target cyclooxygenase enzymes and volume‐regulated anion channels (VRAC) also was shown to suppress microglia‐mediated neuroinflammation and memory loss in 3×TgAD mice (Daniels et al , ). Finally, pharmacological inhibition of caspase‐1 activity by VX‐765 reduced amyloid‐β accumulation, brain inflammation, and cognitive impairment (Flores et al , ). Collectively, these findings suggest that misfolded Aβ activates the microglial NLRP3 inflammasome, which triggers the release of pro‐inflammatory factors that perpetrate a chronic neuroinflammatory environment and promote AD pathology.…”

Inflammasome and Cognitive Symptoms in Human Diseases: Biological Evidence from Experimental Research

“…The caspase-1 inhibitor VX-765 suppressed both neuroinflammation and accumulation of Aβ in a J20 APP Sw/Ind transgenic mouse model of AD. Also, VX-765 attenuated learning and memory impairment in this AD model [114].…”

“…In addition, MCC950 and VX-765 have shown protective effects in AD models [113,114]. MCC950 improved disrupted synaptic plasticity and LTP in transgenic rat overexpressing APP [113].…”