Enhanced Autolysosomal Function Ameliorates the Inflammatory Response Mediated by the NLRP3 Inflammasome in Alzheimer's Disease

The pathogenesis of Alzheimer's disease (AD) involves activation of many NLRP3 inflammatory bodies, which may be related to amyloid beta peptide and aggregation of misfolded proteins. Autophagy is an important regulator of inflammatory bodies. However, autophagy shows dynamic changes in the development of AD, and its role in inflammation remains controversial. In this study, the key link between autophagic disorders and the NLRP3 inflammasome in AD was investigated. APP/PS1 double transgenic mice and C57 mice with A beta(25-35) injected into the lateral ventricle were used as two animal models of AD. Immunofluorescence staining and Western blot analysis showed that NLRP3 inflammasome-related proteins and inflammatory cytokines, such as IL-1 alpha, IL-1 beta, IL-6, IL-12, and TNF-alpha, were increased and microglia were activated in the brains of both AD animal models. Endogenous overexpression of the APPswe gene and exogenous addition of A beta(25-35) increased the expression of NLRP3 inflammasome-related proteins, while exogenous A beta(25-35) intervention more significantly activated inflammation. Furthermore, LC3 was increased in the AD animal and cell models, and the level of Lamp1 decreased. After overexpression of the primary regulator of lysosomal biogenesis, TFEB, the lysosome protein Lamp1 was increased, and LC3 and inflammatory protein expression were decreased. These results suggest that the NLRP3 inflammasome-mediated inflammatory response is activated in AD animal and cell models, which may be related to the decline in autolysosome function. Overexpression of the TFEB protein can reduce the inflammatory response by improving autolysosome function in AD model cells.

Automated summary

This study investigated the key link between autophagic disorders and the NLRP3 inflammasome in Alzheimer's disease (AD) and found that the NLRP3 inflammasome-mediated inflammatory response is activated in AD animal and cell models, possibly related to the decline in autolysosome function. Overexpression of the TFEB protein can reduce the inflammatory response by improving autolysosome function in AD model cells.