Abstract
The pathogenesis of Alzheimer’s disease (AD) involves activation of many NLRP3 inflammatory bodies, which may be related to amyloid β 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 Aβ25–35 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-1α, IL-1β, IL-6, IL-12, and TNF-α, were increased and microglia were activated in the brains of both AD animal models. Endogenous overexpression of the APPswe gene and exogenous addition of Aβ25–35 increased the expression of NLRP3 inflammasome-related proteins, while exogenous Aβ25–35 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.
Highlights
Alzheimer’s disease (AD), the most common type of dementia, is a neurodegenerative disease with cognitive impairment as the primary clinical manifestation (Ahmed et al, 2017; Teimouri et al, 2020)
We found that overexpression of the transcription factor EB (TFEB) protein could increase the lysosomal-associated membrane protein lysosomal-associated membrane protein 1 (Lamp1) and reduce the immune-inflammatory response in an AD cell model
The results showed that the number of platform crossings in the Swedish mutant form of APP/PSEN1dE9 transgenic mice (APP/PS1) group and the amyloid-β 25–35 (Aβ25–35) group was lower than that in the WT group (p < 0.05; Figure 1G)
Summary
Alzheimer’s disease (AD), the most common type of dementia, is a neurodegenerative disease with cognitive impairment as the primary clinical manifestation (Ahmed et al, 2017; Teimouri et al, 2020). The inflammatory response, with the NLRP3 inflammasome as the core, is an important part of the neuroimmune response (You et al, 2017; La Rosa et al, 2019). Studies have found that high levels of toxic Aβ aggregation may induce the activation of the NLRP3 inflammasome, mediate harmful chronic inflammatory reactions, and promote the progression of AD (François et al, 2014). Autophagy, considered the main regulator of inflammatory bodies (Sun et al, 2017), is an important mechanism to inhibit the Aβ-induced neuroinflammatory response (Zhang et al, 2016). Autophagy plays multiple roles in regulating inflammatory cell activation and controlling the production, processing, and secretion of IL-1 family cytokines (Harris et al, 2017). Autophagy prevents tissue inflammation by scavenging apoptotic bodies (BostancıKlıoglu, 2019)
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