Formulated Chinese medicine Shaoyao Gancao Tang reduces NLRP1 and NLRP3 in Alzheimer’s disease cell and mouse models for neuroprotection and cognitive improvement

Chiu, Ya Jen; Lin, Chin‐Feng; Lee, Ming Chung; Hsieh-Li, Hsiu Mei; Chen, Chiung Mei; Wu, Yih Ru; Chang, Kuo Hsuan; Lee-Chen, Guey Jen

doi:10.18632/aging.203125

Cited by 35 publications

(14 citation statements)

References 77 publications

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“…A study by Daniels et al (2016) demonstrated that Fenamate NSAIDs improved the microglia-mediated neuroinflammation and memory loss in 3×TgAD mice by indirectly inhibiting the activation of NLRP3 inflammasome. Then, Chiu et al (2021) found that SG-Tang could act as a neuroprotective agent against Aβ aggregation and neuroinflammation by regulating the NLRP1/NLRP3 pathway. Subsequently, Kuwar et al (2021) suggested that loaded Aβ can be reduced significantly, alleviate neuroinflammation, improve hippocampal neuronal activity, and relieve cognitive function in APP/PS1 mice via inhibiting NLRP3 inflammasome with JC124.…”

Section: Introductionmentioning

confidence: 99%

Salidroside Ameliorates Alzheimer's Disease by Targeting NLRP3 Inflammasome-Mediated Pyroptosis

Cai

Chai

et al. 2022

Front. Aging Neurosci.

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Amyloid β-protein (Aβ) is reported to activate NLRP3 inflammasomes and drive pyroptosis, which is subsequently involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). To date, the pathogenesis of AD is unfortunately insufficiently elucidated. Therefore, this study was conducted to explore whether Salidroside (Sal) treatment could benefit AD by improving pyroptosis. Firstly, two animal models of AD, induced, respectively, by Aβ1-42 and D-galactose (D-gal)/AlCl3, have been created to assist our appreciation of AD pathophysiology. We then confirmed that pyroptosis is related to the pathogenesis of AD, and Sal can slow the progression of AD by inhibiting pyroptosis. Subsequently, we established the D-gal and Nigericin-induced PC12 cells injury model in vitro to verify Sal blocks pyroptosis mainly by targeting the NLRP3 inflammasome. For in vivo studies, we observed that Aβ accumulation, Tau hyperphosphorylation, neurons of hippocampal damage, and cognitive dysfunction in AD mice, caused by bilateral injection of Aβ1-42 into the hippocampus and treatments with D-gal combine AlCl3. Besides, accumulated Aβ promotes NLRP3 inflammasome activation, which leads to the activation and release of a pro-inflammatory cytokine, interleukin-1 beta (IL-1β). Notably, both Aβ accumulation and hyperphosphorylation of Tau decreased and inhibited pyroptosis by downregulating the expression of IL-1β and IL-18, which can be attributed to the treatment of Sal. We further found that Sal can reverse the increased protein expression of TLR4, MyD88, NF-κB, P-NF-κB, NLRP3, ASC, cleaved Caspase-1, cleaved GSDMD, IL-1β, and IL-18 in vitro. The underlying mechanism may be through inhibiting TLR4/NF-κB/NLRP3/Caspase-1 signaling pathway. Our study highlights the importance of NLRP3 inflammasome-mediated pyroptosis in AD, and how the administration of pharmacological doses of Sal can inhibit NLRP3 inflammasome-mediated pyroptosis and ameliorate AD. Thus, we conclude that NLRP3 inflammasome-mediated pyroptosis plays a significant role in AD and Sal could be a therapeutic drug for AD.

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Section: Introductionmentioning

confidence: 99%

Salidroside Ameliorates Alzheimer's Disease by Targeting NLRP3 Inflammasome-Mediated Pyroptosis

Cai

Chai

et al. 2022

Front. Aging Neurosci.

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“…These include membrane glycoprotein CD200, fractalkine ligand CX3CL1, as well as various neurotrophins and other molecules. The investigation of the NLRP1 inflammasome gains even more importance when knowing that NLRP1 gene variants are associated with AD [ 28 ], whereas its silencing improves cognitive abilities and has a protective effect on neurons in animal models of AD [ 30 , 39 , 40 , 41 , 42 ]. In this study, we focused on the NLRP1 inflammasome, which had not been thoroughly analyzed before in AD, and to further assess the possible role of the inflammasome in AD.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the expression of the NLRP1 increases upon the addition of Aβ in neuronal cell cultures and is increasingly expressed in several animal models of AD [ 30 ]. Likewise, silencing the NLRP1 gene improves cognitive abilities and has a protective effect on neurons in animal models of AD [ 30 , 39 , 40 , 41 , 42 ].…”

Section: Introductionmentioning

confidence: 99%

NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer’s Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss

Španić

Horvat

Ilić

et al. 2022

Cells

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Neuroinflammation is one of the core pathological features of Alzheimer’s disease (AD) as both amyloid β (Aβ) and tau monomers and oligomers can trigger the long-term pro-inflammatory phenotype of microglial cells with consequent overactivation of the inflammasomes. To investigate the NLRP1 inflammasome activation in AD, we analyzed the expression of NLRP1, ASC, cleaved gasdermin (cGSDMD), and active caspase-6 (CASP-6) proteins in each hippocampal subdivision (hilar part of CA3, CA2/3, CA1, subiculum) of postmortem tissue of 9 cognitively healthy controls (HC) and 11 AD patients whose disease duration varied from 3 to 7 years after the clinical diagnosis. The total number of neurons, along with the total number of neurofibrillary tangles (NFTs), were estimated in Nissl- and adjacent modified Bielschowsky-stained sections, respectively, using the optical disector method. The same 9 HC and 11 AD cases were additionally semiquantitatively analyzed for expression of IBA1, HLA-DR, and CD68 microglial markers. Our results show that the expression of NLRP1, ASC, and CASP-6 is present in a significantly greater number of hippocampal formation neurons in AD brains compared to controls, suggesting that the NLRP1 inflammasome is more active in the AD brain. None of the investigated inflammasome and microglial markers were found to correlate with the age of the subjects or the duration of AD. However, besides positive correlations with microglial IBA1 expression in the subiculum and with microglial CD68 expression in the CA1 field and subiculum in the AD group, the overall NLRP1 expression in the hippocampal formation was positively correlated with the number of NFTs, thus providing a causal link between neuroinflammation and neurofibrillary degeneration. The accumulation of AT8-immunoreactive phosphorylated tau proteins that we observed at nuclear pores of large pyramidal neurons of the Ammon’s horn further supports their role in the extent of neuronal dysfunction and degeneration in AD. This is important because unlike fibrillar amyloid-β deposits that are not related to dementia severity, total NFTs and neuron numbers in the hippocampal formation, especially in the CA1 field, are the best correlates of cognitive deterioration in both human brain aging and AD. Our findings also support the notion that the CA2 field vulnerability is strongly linked to specific susceptibilities to different tauopathies, including primary age-related tauopathy. Altogether, these findings contrast with reports of nonsignificant microglial activation in aged nonhuman primates and indicate that susceptibility to inflammasome activation may render the human brain comparatively more vulnerable to neurodegenerative changes and AD. In conclusion, our results confirm a key role of NLRP1 inflammasome in AD pathogenesis and suggest NLRP1 as a potential diagnostic marker and therapeutic target to slow or prevent AD progression.

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“…In vivo , pre-administration of ABPPk inhibits the activation of microglia in the CA3 region of the hippocampus, promotes the polarization of the microglia M2 phenotype, and reduces the expression of NLRP3, cleaved caspase-1 and ASC in the brain, thereby significantly improving the cognitive impairment of mice ( Ge et al, 2021 ). In addition, there are other Chinese herbal medicines, including Dl-3-n-butylphthalide (Dl-NBP) ( Wang et al, 2019 ), Shaoyao Gancao Tang (SG-Tang) ( Chiu et al, 2021 ), and Liquiritigenin (LG) ( Du et al, 2021 ), which can play a neuroprotective role in AD by inhibiting the NLRP3 inflammasome pathway. Therefore, these Chinese herbal medicines and extracts that can inhibit the activation of NLRP3 may be a promising and safe treatment for AD.…”

Section: Nlrp3 Inflammasome Inhibitors As a Potential Target For The ...mentioning

confidence: 99%

The Role of NLRP3 Inflammasome in Alzheimer’s Disease and Potential Therapeutic Targets

Liang

Zhang

et al. 2022

Front. Pharmacol.

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Alzheimer’s disease (AD) is a common age-related neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. The typical pathological characteristics of AD are extracellular senile plaques composed of amyloid ß (Aβ) protein, intracellular neurofibrillary tangles formed by the hyperphosphorylation of the microtubule-associated protein tau, and neuron loss. In the past hundred years, although human beings have invested a lot of manpower, material and financial resources, there is no widely recognized drug for the effective prevention and clinical cure of AD in the world so far. Therefore, evaluating and exploring new drug targets for AD treatment is an important topic. At present, researchers have not stopped exploring the pathogenesis of AD, and the views on the pathogenic factors of AD are constantly changing. Multiple evidence have confirmed that chronic neuroinflammation plays a crucial role in the pathogenesis of AD. In the field of neuroinflammation, the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a key molecular link in the AD neuroinflammatory pathway. Under the stimulation of Aβ oligomers and tau aggregates, it can lead to the assembly and activation of NLRP3 inflammasome in microglia and astrocytes in the brain, thereby causing caspase-1 activation and the secretion of IL-1β and IL-18, which ultimately triggers the pathophysiological changes and cognitive decline of AD. In this review, we summarize current literatures on the activation of NLRP3 inflammasome and activation-related regulation mechanisms, and discuss its possible roles in the pathogenesis of AD. Moreover, focusing on the NLRP3 inflammasome and combining with the upstream and downstream signaling pathway-related molecules of NLRP3 inflammasome as targets, we review the pharmacologically related targets and various methods to alleviate neuroinflammation by regulating the activation of NLRP3 inflammasome, which provides new ideas for the treatment of AD.

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Formulated Chinese medicine Shaoyao Gancao Tang reduces NLRP1 and NLRP3 in Alzheimer’s disease cell and mouse models for neuroprotection and cognitive improvement

Cited by 35 publications

References 77 publications

Salidroside Ameliorates Alzheimer's Disease by Targeting NLRP3 Inflammasome-Mediated Pyroptosis

Salidroside Ameliorates Alzheimer's Disease by Targeting NLRP3 Inflammasome-Mediated Pyroptosis

NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer’s Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss

The Role of NLRP3 Inflammasome in Alzheimer’s Disease and Potential Therapeutic Targets

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