Mitochondrial PKA Is Neuroprotective in a Cell Culture Model of Alzheimer’s Disease

Banerjee, Tania Das; Reihl, Kelly; Swain, Maryann; Torres, Mariana; Dagda, Ruben K.

doi:10.1007/s12035-021-02333-w

Cited by 13 publications

(11 citation statements)

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“…Activation of the PKA/SIRT1 signaling pathway by photobiomodulation therapy decreases A β levels in AD [ 58 ]. Caspase-3 is a key mediator of neuronal programmed cell death in many chronic neurodegenerative diseases [ 59 ] and is involved in the regulation of multi-neuro-degenerative disorders, including AD [ 60 ]. Moreover, PI3K-AKT signaling was identified as the most important pathway involved in ginseng against AD.…”

Section: Discussionmentioning

confidence: 99%

The Effective Components, Core Targets, and Key Pathways of Ginseng against Alzheimer’s Disease

Wang

Liu

2023

Evidence-Based Complementary and Alternative Medicine

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Background. Panax ginseng C. A. Mey (ginseng) is a traditional Chinese medicinal herb used for the treatment of nervous system disorders, such as Alzheimer’s disease (AD). However, the pharmacological mechanisms of ginseng involved in AD have not been systematically investigated. Here, a network pharmacology approach was adopted to explore the effective components, core targets, and key pathways of ginseng against AD. Methods. TCMSP database was used to screen the active ingredients of ginseng. Prediction of the targets of ginseng and AD-related genes was performed using online public databases. “Compound-Target,” “Compound-Target-Disease,” “Protein-Protein Interaction (PPI),” “Compound-Target-Pathway,” and “Compound-Target-GO–Pathway” networks were constructed with Cytoscape 3.7.2 software. Gene Ontology (GO) function annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed by using the DAVID database. Results. A total of 22 bioactive compounds were identified from ginseng, and 481 targets of ginseng and 763 AD-related targets were obtained from public databases. The PPI network screened out 19 hub genes of ginseng against AD. According to GO function enrichment, ginseng influenced cell proliferation, death, the nitric oxide biosynthetic process, hypoxia response, and synaptic transmission. Neuroactive ligand-receptor interaction, serotonergic synapse, calcium signaling, cAMP signaling, FoxO signaling, Ras signaling, and PI3K-AKT signaling were among the most key regulatory pathways. The compound-target-GO-route network found EGFR, MAPK1, MAPK14, AKT1, CASP3, and PRKACA as key genes, with PI3K-AKT signaling being the most important pathway for ginseng’s anti-AD activity. Conclusion. Ginseng exerts neuroprotective effects in AD patients through multicomponent, multitarget, and multipathway modes, providing novel insight into the pharmacological and experimental research on ginseng against AD.

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Section: Discussionmentioning

confidence: 99%

The Effective Components, Core Targets, and Key Pathways of Ginseng against Alzheimer’s Disease

Wang

Liu

2023

Evidence-Based Complementary and Alternative Medicine

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“…Imaging NO in Cellular AD Model. A cellular AD model can be established by incubating the cells with Aβ, 31,32 in which Golgi fragmentation may be connected with the Golgi stress. Using Golgi-NO, here we have explored the variation of the NO level in the Aβ-induced Alzheimer's disease model.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…To establish the Alzheimer’s disease model, Aβ42 (10 μM) was incubated with SH-SY5Y cells for 24 h according to the previous work. , …”

Section: Methodsmentioning

confidence: 99%

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Golgi-Targeted Fluorescent Probe for Imaging NO in Alzheimer’s Disease

Liu

et al. 2022

Anal. Chem.

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Nitric oxide (NO) is a crucial neurotransmitter participating in many biological processes via nitrosylation reaction. NO produced in diverse subcellular regions also regulates the function of cells in different manners. A Golgi apparatus is rich in nitric oxide synthase and may serve as a potential therapeutic target for Alzheimer's disease (AD). However, due to the lack of an effective tool, it is difficult to reveal the relationship between Golgi-NO and AD. Herein, we report Golgi-NO as the first Golgitargeted fluorescent probe for sensing and imaging NO in the Golgi apparatus. The probe is designed and synthesized by incorporating 4-sulfamoylphenylamide as a Golgi-targeted moiety to 6-carboxyrhodamine B, generating a fluorophore of Golgi-RhB with modifiable carboxyl, which is then combined with the NO recognition moiety of o-diaminobenzene. The probe shows superior analytical performance including accurate Golgi-targeted ability and high selectivity for NO. Moreover, using the probe, we disclose a significant increase of NO in Golgi apparatus in the AD model. This study provides a competent tool for studying the function and nitrosylation of NO in the Golgi apparatus in related diseases.

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“…Using phosphorylation prediction programs, NetPhos (http://www.cbs.dtu.dk/services/ NetPhos, accessed 18 October 2019) and GPS (http://gps.biocuckoo.org/online.php, accessed 18 October 2019), we predicted the upstream kinases for each putative GFAP target residue (Supplementary Table S1 and Figure 3a). All of the implicated kinases (AKT2, ROCK1, BARK/GRK, and PKA), predicted to phosphorylate GFAP at the modified sites, had been previously implicated in AD pathogenesis or progression [45][46][47][48][49][50][51][52][53]. We therefore tested the effects of individual kinase knockdowns on protein aggregation in human neuroblastoma cells (SH-SY5Y-APP Sw ; Figure 3b,c) and human glioblastoma cells (T98G; Figure 3d,e), with or without siRNA-mediated knockdown.…”

Section: Identification Of Potential Kinases Mediating Gfap Phosphory...mentioning

confidence: 99%

Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer’s Disease

et al. 2022

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Glial fibrillary acidic protein (GFAP) is an intermediate filament structural protein involved in cytoskeleton assembly and integrity, expressed in high abundance in activated glial cells. GFAP is neuroprotective, as knockout mice are hypersensitive to traumatic brain injury. GFAP in cerebrospinal fluid is a biomarker of Alzheimer’s disease (AD), dementia with Lewy bodies, and frontotemporal dementia (FTD). Here, we present novel evidence that GFAP is markedly overexpressed and differentially phosphorylated in AD hippocampus, especially in AD with the apolipoprotein E [ε4, ε4] genotype, relative to age-matched controls (AMCs). Kinases that phosphorylate GFAP are upregulated in AD relative to AMC. A knockdown of these kinases in SH-SY5Y-APPSw human neuroblastoma cells reduced amyloid accrual and lowered protein aggregation and associated behavioral traits in C. elegans models of polyglutamine aggregation (as observed in Huntington’s disease) and of Alzheimer’s-like amyloid formation. In silico screening of the ChemBridge structural library identified a small molecule, MSR1, with stable and specific binding to GFAP. Both MSR1 exposure and GF AP-specific RNAi knockdown reduce aggregation with remarkably high concordance of aggregate proteins depleted. These data imply that GFAP and its phosphorylation play key roles in neuropathic aggregate accrual and provide valuable new biomarkers, as well as novel therapeutic targets to alleviate, delay, or prevent AD.

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Mitochondrial PKA Is Neuroprotective in a Cell Culture Model of Alzheimer’s Disease

Cited by 13 publications

References 46 publications

The Effective Components, Core Targets, and Key Pathways of Ginseng against Alzheimer’s Disease

The Effective Components, Core Targets, and Key Pathways of Ginseng against Alzheimer’s Disease

Golgi-Targeted Fluorescent Probe for Imaging NO in Alzheimer’s Disease

Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer’s Disease

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