Research Progress of Pyroptosis in Alzheimer’s Disease

Xue, Weiyue; Cui, Di; Qiu, Ye

doi:10.3389/fnmol.2022.872471

Cited by 17 publications

(7 citation statements)

References 51 publications

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“…Further probing of pathways significantly altered by amyloid-positivity was conducted using the Reactome database ( Figure 6B ), which revealed pathways related to “DNA methylation” and “chromatin organization”. Additionally, a “defective pyroptosis” pathway was identified, possibly indicating processes linked to increased cell death (71). We probed this further using Gene Ontology enrichment analysis on the plasma proteins associated with amyloid-positivity and found consensus with altered biological processes related to chromatin organization and assembly ( Figure 6C ).…”

Section: Resultsmentioning

confidence: 99%

“…Plasma levels of SAA1 were found to be upregulated in amyloid-positive subjects, which was supported by pathway analysis and enrichment of gene ontology terms linked to inflammation. Pathway analysis on plasma proteins altered in amyloid-positive subjects highlighted changes in processes previously linked to AD pathogenesis, including the blood-brain barrier (85, 86), programmed cell death by pyroptosis (71), and altered epigenetic mechanisms related to DNA and chromatin manipulations (87). A study measuring plasma proteins in AD cases and controls highlighted some of these pathways (“regulation of apoptotic process” and “extracellular matrix organization”) but also distinct pathways (29), possibly due to the more advanced ages and/or pathology in their cohort.…”

Section: Discussionmentioning

confidence: 99%

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APOEgenotype or presence of brain amyloid alters the plasma proteome in cognitively normal, elderly subjects

Philippi

Kailash

Raj

et al. 2022

Preprint

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Background: Processes that drive Alzheimer's disease pathogenesis have long been considered to occur within the central nervous system, yet recent studies have bolstered the possibility that changes in the periphery may be relevant to the disease process. Accumulating evidence has suggested that proteins changing in the blood may be reliable indicators of disease within the brain. Recent advances in geroscience have identified potential mechanisms of blood-brain communication that modulate brain function in ways that could be harnessed for therapy. While blood-borne proteins associated with either youth or old age have been targeted to restore function to the aged brain, it remains unclear whether other dysfunctional systemic states can be exploited for similar benefits. Here we investigate whether APOE allelic variation or presence of brain amyloid are associated with distinct proteomic changes within the systemic environment and what molecular processes are associated with these changes. Methods: Using the SOMAscan assay, we measured 1,305 plasma proteins from 53 homozygous APOE3 and APOE4 subjects (mean age = 68 years; minimum = 54 years) who exhibited no cognitive impairment, some of whom can be categorized as harboring cerebral amyloid based on cerebrospinal fluid Aβ42 measurements. Using the Dream R package for linear mixed effects modeling, we investigated possible contributions of either the APOE-ϵ4 allele or amyloid positivity to changes in the plasma proteome. Ontology-based pathway and module trait correlation analyses were performed to understand disrupted pathways that vary based on APOE genotype or amyloid positivity. Results: We found that expression of the APOE-ϵ4 allele produced distinct changes in the composition of the plasma proteome. Using both pathway enrichment analysis and weighted gene co-expression network analysis, we found that plasma proteins associated with APOE4 expression were linked to pathways related to atherosclerosis, lipid transport, the extracellular matrix, and synaptogenesis signaling. Independent of APOE4, we found that cognitively normal, amyloid-positive subjects exhibit distinct plasma proteome signatures associated with pathways previously linked to AD pathology, relative to amyloid-negative controls. Harboring brain amyloid was associated with plasma proteomic changes linked to dysfunction in blood-brain barrier and other neural cell types. Our results indicate that changes in the plasma proteome are related to possession of AD risk alleles, as well as the presence of amyloid pathology in subjects prior to the onset of symptoms. This work highlights the possibility that pathways in the systemic environment in certain risk contexts may be plausible targets to explore for modulating disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

APOEgenotype or presence of brain amyloid alters the plasma proteome in cognitively normal, elderly subjects

Philippi

Kailash

Raj

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Recent studies have suggested that pyroptosis is closely related to the pathogenesis of AD [19], and recently, Cell reported [12] that inhibiting the pyroptosis pathway may constitute a breakthrough in the molecular mechanism of AD treatment. Moreover, the expression level of Caspase-1 in the brains of APP/PS1 transgenic mice increased.…”

Section: Discussionmentioning

confidence: 99%

Dipeptidyl Peptidase 4 mediated Caspase-8 Affects Cognitive Impairment in Mice with Alzheimer's Disease

Wang,

Chen,

Wang

et al. 2024

Preprint

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To investigate the effect of dipeptidyl peptidase 4 (DPP4) on cognitive impairment in Alzheimer's disease (AD), the present study used seven-week-old male C57BL/6J and DPP4 knockout mice. The AD model was induced by microinjection of Aβ25−35 into the lateral ventricle. Morris water maze test showed that DPP4 knockout significantly improved the spatial learning and memory abilitoes of AD mice. Western blot results showed that DPP4 knockout increased the expression levels of BDNF, CREB and Bcl-2 in the hippocampus of AD mice while the expression levels of Caspase-8, pyroptosis-related proteins NLRP3, Caspase-1, GSDMD, 1L-18, 1L-1β and apoptosis-related proteins Caspase-3 and Bax were decreased. Similar results were observed after HT22 neurons were treated with Aβ25−35 and DPP4 inhibitor sitagliptin (Sit). Moreover, the treatment with Caspase-8 inhibitor (Z-LETD-FMK) showed that the inhibition of Caspase-8 inhibited the expression of NLRP3 and Caspase-1 in the AD model cells, but had no further inhibitory effect under the treatment of Sit. Our results suggests that DPP4 knockout may ameliorate learning and memory dysfunction in AD model mice by regulating pyroptosis and apoptosis pathways through Caspase-8.

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“…Pyroptosis can cause inflammation that is activated by extracellular or intracellular stimuli [ 52 ] and is associated with various diseases, such as cardiovascular disease [ 53 ], Alzheimer’s disease [ 54 ], atherosclerosis [ 55 ], and muscle atrophy [ 56 ]. A recent study showed that pyroptosis occurs during dexamethasone-induced muscle atrophy [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

The Inhibition of Autophagy and Pyroptosis by an Ethanol Extract of Nelumbo nucifera Leaf Contributes to the Amelioration of Dexamethasone-Induced Muscle Atrophy

et al. 2023

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Muscle atrophy is characterized by a decline in muscle mass and function. Excessive glucocorticoids in the body due to aging or drug treatment can promote muscle wasting. In this study, we investigated the preventive effect of Nelumbo nucifera leaf (NNL) ethanolic extract on muscle atrophy induced by dexamethasone (DEX), a synthetic glucocorticoid, in mice and its underlying mechanisms. The administration of NNL extract increased weight, cross-sectional area, and grip strength of quadriceps (QD) and gastrocnemius (GA) muscles in DEX-induced muscle atrophy in mice. The NNL extract administration decreased the expression of muscle atrophic factors, such as muscle RING-finger protein-1 and atrogin-1, and autophagy factors, such as Beclin-1, microtubule-associated protein 1A/1B-light chain 3 (LC3-I/II), and sequestosome 1 (p62/SQSTM1) in DEX-injected mice. DEX injection increased the protein expression levels of NOD-like receptor pyrin domain-containing protein 3 (NLRP3), cleaved-caspase-1, interleukin-1beta (IL-1β), and cleaved-gasdermin D (GSDMD), which were significantly reduced by NNL extract administration (500 mg/kg/day). In vitro studies using C2C12 myotubes also revealed that NNL extract treatment inhibited the DEX-induced increase in autophagy factors, pyroptosis-related factors, and NF-κB. Overall, the NNL extract prevented DEX-induced muscle atrophy by downregulating the ubiquitin–proteasome system, autophagy pathway, and GSDMD-mediated pyroptosis pathway, which are involved in muscle degradation.

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Research Progress of Pyroptosis in Alzheimer’s Disease

Cited by 17 publications

References 51 publications

APOEgenotype or presence of brain amyloid alters the plasma proteome in cognitively normal, elderly subjects

APOEgenotype or presence of brain amyloid alters the plasma proteome in cognitively normal, elderly subjects

Dipeptidyl Peptidase 4 mediated Caspase-8 Affects Cognitive Impairment in Mice with Alzheimer's Disease

The Inhibition of Autophagy and Pyroptosis by an Ethanol Extract of Nelumbo nucifera Leaf Contributes to the Amelioration of Dexamethasone-Induced Muscle Atrophy

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