Authors: Adam H. Dyer, Isabella Batten, Conor Woods, James Gibney, Nollaig Bourke, Sean Kennelly
Published: 2020-12-07
DOI: 10.1002/alz.042147
Source: Full article
AbstractBackgroundMidlife Type 2 Diabetes Mellitus (T2DM) is a potent risk factor for later development of dementia. However, putative mechanisms mediating this risk are poorly understood. The NLRP3 inflammasome receptor, which drives strong pro‐inflammatory responses, has been implicated in both T2DM and Alzheimer’s disease (AD) pathogenesis, and can be activated by Amyloid β1‐42 (Aβ42).MethodPeripheral Blood Mononuclear Cells (PBMCs) were isolated from participants with T2DM (N = 39; 52.04 ± 8.01 years) and matched controls (N = 21; 52.16 ± 7.82 years) without any evidence of cognitive impairment. PBMCs were incubated for 18 hours under the following conditions: (i) Lipopolysaccharide (LPS), (ii) Aβ42, (iii) LPS & Aβ42 and (iv) LPS & Nigericin (potent NLRP3 activator). Cytokine production was measured using ELISA and gene expression using qPCR. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Gait speed was measured under normal and dual‐task conditions (reciting alternate letters of the alphabet). Wilcoxon rank‐sum tests were used for univariate analysis and Poisson and linear regression models used for multivariate analyses, adjusting for important covariates.ResultsTreatment of PBMCs under all four conditions resulted in a significant production of the pro‐inflammatory cytokines IL‐1β and IL‐6, which did not differ between T2DM and healthy controls. Greater IL‐1β production (an NLRP3‐dependent cytokine) under both Aβ‐42 (ii) and LPS & Nigericin (iv) conditions was associated with greater likelihood of error on the MoCA (aIRR 1.01, p = 0.010; aIRR 1.01, p = 0.004). Further, greater IL‐1β production under both LPS & Aβ42 (iii) and LPS & Nigericin (iv) conditions was associated with a greater slowing effect (cost) on the dual‐task (adjusted: β = 0.31, 0.04‐0.58, p = 0.023; 0.029, 0.05 – 0.54, p = 0.019). Effects were seen in the cohort overall, regardless of T2DM status, but were stronger in those with T2DM.ConclusionsGreater activation of the NLRP3 inflamamsome by Aβ42 was associated with poorer cognitive and gait performance in midlife T2DM. Further work will follow this cohort longitudinally and assess the ability of innate immune NLRP3 activity to predict later cognitive trajectories in those with midlife T2DM.