Evaluation of NLRP3 and NLRP1 inflammasome pathways in patients with Alzheimer’s disease: a clinicopathological study

Abstract

AbstractBackgroundA growing body of evidence has suggested a detrimental role of NLRP1 and NLRP3 inflammasome in experimental AD. However, the characterization of these pathways in AD human brains is still missing. We aimed to characterize the hippocampal expression of the NLRP1 and NLRP3 inflammasomes in individuals with AD neuropathological change (ADNC) compared to age‐ and sex‐matched controls. We also sought to investigate the association of the expression of these proteins with cognitive abilities and AD‐pathology.MethodThe expression of NLRP1, NLRP3, caspase‐1, ASC, and hyperphosphorylated tau (p‐tau) was evaluated in the cornu ammonis (CA), dentate gyrus (DG), and subiculum (SUB) of individuals with pure AD and controls (n = 28 per group), using immunohistochemistry. The percentage of the immunostained area (IA) and the optical density (OD) of the staining were quantified through semiautomatic morphometry. Cognitive abilities were evaluated using the Clinical Dementia Rating – sum of boxes (CDR‐SB) and the AD‐pathology was based on Braak staging and the Consortium to Establish a Registry for AD (CERAD) criteria. We applied the Mann‐Whitney test to compare control with ADNC hippocampi, linear regression to examine the association of inflammasome proteins with cognition and AD‐pathology, and Spearman coefficient to examine the correlation of these proteins with p‐tau.ResultSociodemographic and clinical variables were similar between the groups (Table 1). NLRP1 and caspase‐1 expression was predominant in neurons, while ASC was detected in glial cells. NLRP3 was expressed in neurons and glia. NLRP1 and NLRP3 deposits were observed in neuritic plaques. Except for NLRP1, all the inflammasome proteins were overexpressed in CA and SUB of individuals with ADNC compared to controls (p<0.05) (Figure 1). CDR‐SB and CERAD criteria were associated with increased IA for NLRP3, caspase‐1, and ASC; the Braak stage was associated with higher expression of caspase‐1 and ASC (p<0.05, Table 2). Interestingly, NLRP3 (r = ‐0.52, p = 0.009) and ASC expression (r = ‐0.43, p = 0.004) correlated negatively with OD of p‐tau immunostaining in the CA of individuals with ADNCConclusionNLRP3 inflammasome pathway is up‐regulated in the ADNC hippocampi and was associated with AD‐pathology. Our results suggest that NLRP3 inflammasome contributes to cognitive impairment in AD.