Abstract
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 (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.
Highlights
Therapeutic interventions are essential to prevent Alzheimer Disease (AD)
Kg−1, VX-765 and VRT-043198 concentrations were measured by LC-MS/MS in the plasma, whole brain, and cerebrospinal fluid (CSF) at 0.25, 0.5, 1, 3, 6, 8 and 24 h after a single intraperitoneal injection (Fig. 1)
The discrepancy between the western blot and immunostaining data at 4- and 20-week WO is possibly due to differences in the regions of interest analysed, or the dilution of glial fibrillary acidic protein (GFAP) with other cell proteins during extraction. These results suggest that VX-765 pre-treatment delays GFAP astrogliosis for 3 months in J20 mice
Summary
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. Episodic memory scores correlate negatively with microglial activation These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD. Inhibition of the inflammasome Nod-like receptor protein 1 (Nlrp1)[18], Nlrp[315], Casp[115,19] or the inflammasome activator purinergic P2X7 receptor[20], reduces inflammation, improves synaptic pathology, reduces Aβ accumulation and reverses cognitive deficits in AD mouse models. Knockout or immunotherapy against the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase activated and recruitment domain (ASC), decreases Aβ deposition and improve cognitive behaviour in the amyloid precursor protein/presenilin 1 mutant (APP/PS1) AD mouse model[17].
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