Therapeutic Effects of Natural Compounds and Small Molecule Inhibitors Targeting Endoplasmic Reticulum Stress in Alzheimer’s Disease

Gao, Xun; Xu, Yuanyuan

doi:10.3389/fcell.2021.745011

Cited by 12 publications

(9 citation statements)

References 76 publications

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“…The downregulation of this peroxiporin in our analysis suggests the presence of ER stress in PS2APP GFAP-positive astrocytes. Additionally, as APP is synthesized in the ER, alterations in MAMs and ER stress are emerging as important pathological mechanisms of AD and interesting therapeutic targets to modify protein misfolding and synaptic failure (27–29). Furthermore, the upregulation of ubiquitin-related genes (Uba52, Ubc) may indicate compensatory attempts to mitigate the results of ER stress.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies

Bastiani

Bellaver

Brum

et al. 2022

Preprint

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Introduction: In Alzheimer's disease clinical research, glial fibrillary acidic protein (GFAP) released in the cerebrospinal fluid and blood is widely measured and perceived as a biomarker of reactive astrogliosis. However, it was recently demonstrated that plasma GFAP levels are associated with amyloid-beta (Abeta) but not tau pathology. The molecular underpinnings behind this specificity are unexplored. Here we investigated biomarker and transcriptomic associations of GFAP-positive astrocytes with Abeta and tau pathologies in humans and mouse models. Methods: We studied 90 individuals with plasma GFAP, Abeta- and Tau-PET to investigate the association between biomarkers. Then, transcriptomic analysis in hippocampal GFAP-positive astrocytes isolated from mouse models presenting Abeta (PS2APP) or tau (P301S) pathologies was applied to explore differentially expressed genes (DEGs), Gene Ontology processes, and protein-protein interaction networks associated with each phenotype. Findings: In humans, we found that plasma GFAP associates with Abeta but not tau pathology. Supporting these results, mouse transcriptomics showed scarce overlap of DEGs between the Abeta and tau mouse models, revealing the unique nature of GFAP-positive astrocytic responses to Abeta or tau pathology. While Abeta GFAP-positive astrocytes were overrepresented with genes associated with proteostasis and exocytosis-related processes, tau hippocampal GFAP-positive astrocytes presented greater abnormalities in functions related to DNA/RNA processing and cytoskeleton dynamics. Interpretation: Our results offer insights into Abeta and tau-driven specific signatures in GFAP-positive astrocytes. Characterizing how different underlying pathologies distinctly influence astrocyte responses is critical for the biological interpretation of astrocyte-related biomarker and suggests the need to develop context-specific astrocyte targets to study AD.

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Section: Discussionmentioning

confidence: 99%

Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies

Bastiani

Bellaver

Brum

et al. 2022

Preprint

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“…Several studies have demonstrated that certain plant-derived compounds alleviate ER stress and inflammation in neurodegenerative diseases [ 22 , 23 ]. Curcumin, a polyphenolic compound found in the plant Curcuma longa L. ( C. longa L.) [ 24 ], has been extensively studied for its role in regulating ER stress and for its anti-inflammatory, anti-cancer, and neuroprotective effects, which include antioxidant, immunomodulatory, anti-angiogenic, hepatoprotective, anti-atherosclerotic, and anti-diabetic effects [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Curcumae radix Reduces Endoplasmic Reticulum Stress in Mice with Chronic Neuroinflammation

Yang

Lee

et al. 2023

Biomedicines

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Endoplasmic reticulum (ER) stress is a condition in which the ER protein-folding machinery is impaired, leading to the accumulation of improperly folded proteins and triggering an unfolded-protein response. Excessive ER stress causes cell death and contributes to the development of chronic diseases. Interestingly, there is a bidirectional relationship between ER stress and the nuclear factor-kappa B (NF-κB) pathway. Curcumin, a natural polyphenolic compound found in Curcumae radix, exerts its neuroprotective effects by regulating ER stress and inflammation. Therefore, investigating the potential protective and regulatory effects of curcumin on ER stress, inflammation, and neurodegeneration under chronic neuroinflammatory conditions is of great interest. Mice were pretreated with Curcumae radix extract (CRE) for 19 days and then treated with CRE plus lipopolysaccharide for 1 week. We monitored pro-inflammatory cytokine levels in the serum and ER stress-, inflammation-, and neurodegeneration-related markers in the mouse cerebrum and hippocampus using Western blotting and qRT-PCR. CRE reduced Interleukin-1 beta levels in the blood and brain of mice with lipopolysaccharide-induced chronic inflammation. CRE also suppressed the expression of markers related to the ER stress and NF-κB signaling pathways. The expression of neurodegeneration-related markers was reduced in the mouse cerebrum and hippocampus. CRE exerts neuroprotective effects under chronic inflammatory conditions via multifaceted anti-inflammatory and ER stress-pathway regulatory mechanisms.

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“…Not only are Aβ generation from amyloidogenic processing of the APP, impairments in Aβ clearance or enzyme-mediated Aβ degradation considered to cause the accumulation and aggregation of Aβ [ 7 ]. The aggregated Aβ interferes with several cellular processes and results in the endoplasmic reticulum (ER) stress triggering a complex multistep cascade, leading to neuronal death and dementia [ 8 ]. Due to shared pathologies between AD and diabetes, the drugs used to treat diabetes may be a suitable therapeutic option for AD [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Diosmetin Targeted at Peroxisome Proliferator-Activated Receptor Gamma Alleviates Advanced Glycation End Products Induced Neuronal Injury

et al. 2022

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The present study aimed to evaluate the role of diosmetin in alleviating advanced glycation end products (AGEs)-induced Alzheimer’s disease (AD)-like pathology and to clarify the action mechanisms. Before stimulation with AGEs (200 μg/mL), SH-SY5Y cells were treated with diosmetin (10 μmol/L), increasing cell viability. The induction of AGEs on the reactive oxygen species overproduction and downregulation of antioxidant enzyme activities, including superoxide dismutase, glutathione peroxidase, and catalase, were ameliorated by diosmetin. Amyloid precursor protein upregulation, accompanied by increased production of amyloid-β, caused by AGEs, was reversed by diosmetin. In the presence of diosmetin, not only β-site amyloid precursor protein cleaving enzyme1 expression was lowered, but the protein levels of insulin-degrading enzyme and neprilysin were elevated. Diosmetin protects SH-SY5Y cells from endoplasmic reticulum (ER) stress response to AGEs by suppressing ER stress-induced glucose regulated protein 78, thereby downregulating protein kinase R-like endoplasmic reticulum kinase, eukaryotic initiation factor 2 α, activating transcription factor 4, and C/EBP homologous protein. Diosmetin-pretreated cells had a lower degree of apoptotic DNA fragmentation; this effect may be associated with B-cell lymphoma (Bcl) 2 protein upregulation, Bcl-2-associated X protein downregulation, and decreased activities of caspase-12/-9/-3. The reversion of diosmetin on the AGEs-induced harmful effects was similar to that produced by pioglitazone. The peroxisome proliferator-activated receptor (PPAR)γ antagonist T0070907 (5 μmol/L) abolished the beneficial effects of diosmetin on AGEs-treated SH-SY5Y cells, indicating the involvement of PPARγ. We conclude that diosmetin protects neuroblastoma cells against AGEs-induced ER injury via multiple mechanisms and may be a potential option for AD.

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Therapeutic Effects of Natural Compounds and Small Molecule Inhibitors Targeting Endoplasmic Reticulum Stress in Alzheimer’s Disease

Cited by 12 publications

References 76 publications

Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies

Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies

Curcumae radix Reduces Endoplasmic Reticulum Stress in Mice with Chronic Neuroinflammation

Diosmetin Targeted at Peroxisome Proliferator-Activated Receptor Gamma Alleviates Advanced Glycation End Products Induced Neuronal Injury

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