New mechanism of nerve injury in Alzheimer’s disease: β‐amyloid‐induced neuronal pyroptosis

Abstract

The present study was designed to investigate the role of β‐amyloid (Aβ 1‐42 ) in inducing neuronal pyroptosis and its mechanism. Mice cortical neurons (MCNs) were used in this study, LPS + Nigericin was used to induce pyroptosis in MCNs (positive control group), and Aβ 1‐42 was used to interfere with MCNs. In addition, propidium iodide (PI) staining was used to examine cell permeability, lactate dehydrogenase (LDH) release assay was employed to detect cytotoxicity, immunofluorescence (IF) staining was used to investigate the expression level of the key protein GSDMD, Western blot was performed to detect the expression levels of key proteins, and enzyme‐linked immunosorbent assay (ELISA) was utilized to determine the expression levels of inflammatory factors in culture medium, including IL‐1β, IL‐18 and TNF‐α. Small interfering RNA (siRNA) was used to silence the mRNA expression of caspase‐1 and GSDMD, and Aβ 1‐42 was used to induce pyroptosis, followed by investigation of the role of caspase‐1‐mediated GSDMD cleavage in pyroptosis. In addition, necrosulfonamide (NSA), an inhibitor of GSDMD oligomerization, was used for pre‐treatment, and Aβ 1‐42 was subsequently used to observe the pyroptosis in MCNs. Finally, AAV9‐siRNA‐caspase‐1 was injected into the tail vein of APP/PS1 double transgenic mice (Alzheimer's disease mice) for caspase‐1 mRNA inhibition, followed by observation of behavioural changes in mice and measurement of the expression of inflammatory factors and pyroptosis‐related protein. As results, Aβ 1‐42 could induce pyroptosis in MCNs, increase cell permeability and enhance LDH release, which were similar to the LPS + Nigericin‐induced pyroptosis. Meanwhile, the expression levels of cellular GSDMD and p30‐GSDMD were up‐regulated, the levels of NLRP3 inflammasome and GSDMD‐cleaved protein caspase‐1 were up‐regulated, and the levels of inflammatory factors in the medium were also up‐regulated. siRNA intervention in caspase‐1 or GSDMD inhibited Aβ 1‐42 ‐induced pyroptosis, and NSA pre‐treatment also caused the similar inhibitory effects. The behavioural ability of Alzheimer's disease (AD) mice was relieved after the injection of AAV9‐siRNA‐caspase‐1, and the expression of pyroptosis‐related protein in the cortex and hippocampus was down‐regulated. In conclusion, Aβ 1‐42 could induce pyroptosis by GSDMD protein, and NLRP3‐caspase‐1 signalling was an important signal to mediate GSDMD cleavage, which plays an important role in Aβ 1‐42 ‐induced pyroptosis in neurons. Therefore, GSDMD is expected to be a novel therapeutic target for AD.

ADMSC Exo‐MicroRNA‐22 improve neurological function and neuroinflammation in mice with Alzheimer's disease

“…The deposition of β‐amyloid protein in AD can cause local inflammation, which can simultaneously cause oxidative stress injury and excitatory injury. Our previous studies have found that β‐amyloid protein can cause pyroptosis in nerve cells by activating Caspase‐1‐GSDMD 20 . microRNAs are a type of RNAs with 18‐22nt in length.…”

NF-κB-Induced Upregulation of miR-146a-5p Promoted Hippocampal Neuronal Oxidative Stress and Pyroptosis via TIGAR in a Model of Alzheimer’s Disease

“…Pyroptosis is a recently discovered type of programmed cell death that depends on the activation of caspase-1 and the release of a large number of proinflammatory factors (Shi et al, 2017). Increasing evidence has indicated that the pyroptosis of neuronal cells is closely related to the progression of AD (Fricker et al, 2018;Han et al, 2020).…”

Phagocytic clearance of apoptotic, necrotic, necroptotic and pyroptotic cells

“…Similar to necroptotic cell clearance, the molecular mechanisms underpinning the removal of pyroptotic cells are still being defined (Figure 2). The clearance of pyroptotic cells is of significant interest as pyroptosis is widely implicated in inflammatory pathologies including Alzheimer's disease [92][93][94], liver fibrosis [95,96] and Salmonella infection [97,98]. Similar to the cleavage of PANX1 by caspase 3/7 during apoptosis, PANX1 is also activated by caspase 1/11 during pyroptosis and aids the release of ATP 'find-me' signals to mediate phagocytic recruitment [64,[99][100][101].…”