vx-765 and Alzheimer-Disease

Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APP

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Cognitive Dysfunction; Cytokines; Dipeptides; Disease Models, Animal; Encephalitis; Female; Humans; Inflammation; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; para-Aminobenzoates; Serpins; Spatial Memory; Viral Proteins

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.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Caspase 1; Caspase Inhibitors; Cognition; Cognition Disorders; Dipeptides; Disease Models, Animal; Humans; Memory; Memory Disorders; Mice, Knockout; para-Aminobenzoates