NPD1 Enhances Autophagy and Reduces Hyperphosphorylated Tau and Amyloid-β42 by Inhibiting GSK3β Activation in N2a/APP695swe Cells

2021 ◽  
pp. 1-13
Author(s):  
Songyang Dai ◽  
Fanlin Zhou ◽  
Jieyun Sun ◽  
Yu Li
Keyword(s):  
Glycogen Synthase ◽  
Cell Model ◽  
Amyloid Β ◽  
Hyperphosphorylated Tau ◽  
Neuroprotective Effects ◽  
Transmission Electron ◽  
Associated Proteins ◽  
Gsk 3Β ◽  
Neuroprotective Function ◽  
Autophagy Activity

Background: The most prevalent kind of dementia, Alzheimer’s disease (AD), is a neurodegenerative disease. Previous research has shown that glycogen synthase kinase-3β (GSK-3β) is involved in the etiology and progression of AD, including amyloid-β (Aβ), phosphorylated tau, and mitochondrial dysfunction. NPD1 has been shown to serve a neuroprotective function in AD, although the mechanism is unclear. Objective: The effects of NPD1 on Aβ expression levels, tau protein phosphorylation, apoptosis ratio, autophagy activity, and GSK-3β activity in N2a/APP695swe cells (AD cell model) were studied, as well as the mechanism behind such effects. Methods: N2a/APP695swe cells were treated with NPD1, SB216763, or wortmannin as an AD cell model. The associated proteins of hyperphosphorylated tau and autophagy, as well as the activation of GSK3β, were detected using western blot and RT-PCR. Flow cytometry was utilized to analyze apoptosis and ELISA was employed to observe Aβ 42. Images of autophagy in cells are captured using transmission electron microscopy. Results: In N2a/APP695swe cells, NPD1 decreased Aβ 42 and hyperphosphorylated tau while suppressing cell death. NPD1 also promoted autophagy while suppressing GSK-3β activation in N2a/APP695swe cells. The outcome of inhibiting GSK-3β is comparable to that of NPD1 therapy. However, after activating GSK-3β, the opposite experimental results were achieved. Conclusion: NPD1 might minimize cell apoptosis, downregulate Aβ expression, control tau hyperphosphorylation, and enhance autophagy activity in AD cell models to promote neuronal survival. NPD1’s neuroprotective effects may be mediated via decreasing GSK-3β.

Effect of amyloid-β (Aβ) immunization on hyperphosphorylated tau: a potential role for glycogen synthase kinase (GSK)-3β

2015 ◽  
Vol 41 (4) ◽  
pp. 445-457 ◽  
Author(s):  
Jay Amin ◽  
Claire Paquet ◽  
Alex Baker ◽  
Ayodeji A. Asuni ◽  
Seth Love ◽  
...  
Keyword(s):  
Potential Role ◽  
Glycogen Synthase ◽  
Amyloid Β ◽  
Glycogen Synthase Kinase ◽  
Hyperphosphorylated Tau ◽  
Gsk 3Β

scholarly journals Design and Synthesis of New Benzo[d]oxazole-Based Derivatives and Their Neuroprotective Effects on β-Amyloid-Induced PC12 Cells

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5391
Author(s):  
Zheng Liu ◽  
Ming Bian ◽  
Qian-Qian Ma ◽  
Zhuo Zhang ◽  
Huan-Huan Du ◽  
...  
Keyword(s):  
Pc12 Cells ◽  
Glycogen Synthase ◽  
B Cell Lymphoma ◽  
Nuclear Factor Κb ◽  
In Vivo Studies ◽  
Neuroprotective Effects ◽  
Β Amyloid ◽  
Gsk 3Β

A series of novel synthetic substituted benzo[d]oxazole-based derivatives (5a–5v) exerted neuroprotective effects on β-amyloid (Aβ)-induced PC12 cells as a potential approach for the treatment of Alzheimer’s disease (AD). In vitro studies show that most of the synthesized compounds were potent in reducing the neurotoxicity of Aβ25-35-induced PC12 cells at 5 μg/mL. We found that compound 5c was non-neurotoxic at 30 μg/mL and significantly increased the viability of Aβ25-35-induced PC12 cells at 1.25, 2.5 and 5 μg/mL. Western blot analysis showed that compound 5c promoted the phosphorylation of Akt and glycogen synthase kinase (GSK-3β) and decreased the expression of nuclear factor-κB (NF-κB) in Aβ25-35-induced PC12 cells. In addition, our findings demonstrated that compound 5c protected PC12 cells from Aβ25-35-induced apoptosis and reduced the hyperphosphorylation of tau protein, and decreased the expression of receptor for AGE (RAGE), β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), inducible nitric oxide synthase (iNOS) and Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) via Akt/GSK-3β/NF-κB signaling pathway. In vivo studies suggest that compound 5c shows less toxicity than donepezil in the heart and nervous system of zebrafish.

scholarly journals GSK-3 Is Activated by the Tyrosine Kinase Pyk2 during LPA1-mediated Neurite Retraction

2006 ◽  
Vol 17 (4) ◽  
pp. 1834-1844 ◽  
Author(s):  
C. Laura Sayas ◽  
Aafke Ariaens ◽  
Bas Ponsioen ◽  
Wouter H. Moolenaar
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Glycogen Synthase ◽  
Serine Phosphorylation ◽  
Protein Signaling ◽  
Serine Threonine Kinase ◽  
Microtubule Associated Proteins ◽  
Neurite Retraction ◽  
Associated Proteins ◽  
Gsk 3Β

Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine kinase that is usually inactivated by serine phosphorylation in response to extracellular cues. However, GSK-3 can also be activated by tyrosine phosphorylation, but little is known about the upstream signaling events and tyrosine kinase(s) involved. Here we describe a G protein signaling pathway leading to GSK-3 activation during lysophosphatidic acid (LPA)-induced neurite retraction. Using neuronal cells expressing the LPA1 receptor, we show that LPA1 mediates tyrosine phosphorylation and activation of GSK-3 with subsequent phosphorylation of the microtubule-associated protein tau via the Gi-linked PIP2 hydrolysis-Ca2+ mobilization pathway. LPA concomitantly activates the Ca2+-dependent tyrosine kinase Pyk2, which is detected in a complex with GSK-3β. Inactivation or knockdown of Pyk2 inhibits LPA-induced (but not basal) tyrosine phosphorylation of GSK-3 and partially inhibits LPA-induced neurite retraction, similar to what is observed following GSK-3 inhibition. Thus, Pyk2 mediates LPA1-induced activation of GSK-3 and subsequent phosphorylation of microtubule-associated proteins. Pyk2-mediated GSK-3 activation is initiated by PIP2 hydrolysis and may serve to destabilize microtubules during actomyosin-driven neurite retraction.

scholarly journals The combination of β-asarone and icariin inhibits amyloid-β and reverses cognitive deficits by promoting mitophagy in models of Alzheimer’s disease

2021 ◽  
Author(s):  
Nanbu Wang ◽  
Haoyu Wang ◽  
Qi Pan ◽  
Jian Kang ◽  
Ziwen Liang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Pc12 Cell ◽  
Cell Model ◽  
Amyloid Β ◽  
Beclin 1 ◽  
Group Model ◽  
Cell Models ◽  
Age Related ◽  
Transmission Electron ◽  
Potential Strategy

Abstract Background: β-Asarone is the main constituent of Acorus tatarinowii Schott and exhibits important effects in diseases such as neurodegenerative and neurovascular diseases. Icariin (ICA) is a major active ingredient of Epimedium that has attracted increasing attention because of its unique pharmacological effects in degenerative disease. In this paper, we primarily explored the effects of the combination of β-asarone and ICA in clearing noxious proteins and reversing cognitive deficits. The accumulation of damaged mitochondria and mitophagy are characteristics of ageing and age-related neurodegeneration, including AD.Methods: APP/PS1 mice and in Aβ1-42-induced PC12 cell models were used. The groups were divided into five: normal group, model group (above animals and cells), icariin combined with β-asarone group, A3 and CSA group. Transmission electron microscopy was used to observe brain tissues (hippocampus and temporal lobe)/cell mitochondria, autophagosomes and other structures. IF and WB were used to detect the expression of Beclin-1, LC3, p62, Pink1, Parkin and p-Parkin. Dal-autophagy combined with LSCM was used to detect the occurrence of Autophagy. Mitophagy Detection Kit combined with LSCM was used to detect the occurrence of mitochondrial autophagy, and the effects of icariin combined with β-asarone on mitochondrial autophagy in AD animal and cell model were investigated.Results: We showed evidence that autophagy/mitophagy is damaged in the hippocampus of APP/PS1 mice and in Aβ1-42-induced PC12 cell models. Then, we found that the combination therapy can reduce the cytotoxicity caused by Aβ1-42, increase cell viability, inhibit the expression of Aβ, APP, PS1 and BACE1, and promote the expression of SYN. The efficacy of the combination is better than that of the single drug. What’s more, it also promoted the expression of Beclin-1, LC3 Ⅰ/ in, Pink1, Parkin and p-parkin while inhibited p62. Conclusion: These conclusions suggest that weakened removal of defective mitochondria is a pivotal event in AD pathogenesis and that combination treatment with mitophagy inducers represents a potential strategy for therapeutic intervention.

scholarly journals Hyperphosphorylation of tau by GSK-3β in Alzheimer’s disease: The interaction of Aβ and sphingolipid mediators as a therapeutic target

2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Maja Jembrek ◽  
Mirjana Babić ◽  
Nela Pivac ◽  
Patrick Hof ◽  
Goran Šimić
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mammalian Cells ◽  
Neurodegenerative Disorder ◽  
Glycogen Synthase ◽  
Proteolytic Processing ◽  
Microtubule Assembly ◽  
Hyperphosphorylated Tau ◽  
Adequate Treatment ◽  
Gsk 3Β

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the extracellular deposits of β amyloid peptides (Aβ) in senile plaques, and intracellular aggregates of hyperphosphorylated tau in neurofibrillary tangles (NFT). Although accumulation of Aβ has been long considered a leading hypothesis in the disease pathology, it is increasingly evident that the role hyperphosphorylation of tau in destabilization of microtubule assembly and disturbance of axonal transport is equally detrimental in the neurodegenerative process. The main kinase involved in phosphorylation of tau is glycogen-synthase kinase 3-beta (GSK-3β). Intracellular accumulation of Aβ also likely induces increase in hyperphosphorylated tau by a mechanism dependent on GSK-3β. In addition, Aβ affects production of ceramides, the major sphingolipids in mammalian cells, by acting on sphingomyelinases, enzymes responsible for the catabolic formation of ceramides from the sphingomyelin. Generated ceramides in turn increase production of Aβ by acting on β-secretase, a key enzyme in the proteolytic processing of the amyloid precursor protein (APP), altogether leading to a ceramide-Aβ-hyperphosphorylated tau cascade that ends in neuronal death. Modulators and inhibitors acting on members of this devastating cascade are considered as potential targets for AD therapy. There is still no adequate treatment for AD patients. Novel therapeutic strategies increasingly consider the combination of multiple targets and interactions among the key members of implicated molecular pathways. This review summarizes recent findings and therapeutic perspectives in the pathology and treatment of AD, with the emphasis on the interplay between hyperphosphorylated tau, amyloid β, and sphingolipid mediators.

scholarly journals The Isoquinoline Alkaloid Dauricine Targets Multiple Molecular Pathways to Ameliorate Alzheimer-Like Pathological Changes In Vitro

2018 ◽  
Vol 2018 ◽  
pp. 1-19 ◽  
Author(s):  
Pan Liu ◽  
Xiao Chen ◽  
Haizhe Zhou ◽  
Liqun Wang ◽  
Zaijun Zhang ◽  
...  
Keyword(s):  
Cell Model ◽  
Isoquinoline Alkaloid ◽  
Signaling Proteins ◽  
Tau Hyperphosphorylation ◽  
Neuroprotective Effects ◽  
App Processing ◽  
N2a Cells ◽  
Associated Proteins ◽  
Related Proteins

Alzheimer’s disease (AD), the most common neurodegenerative disease, has no effective treatment. Dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid isolated from the root of Menispermum dauricum DC, reportedly has neuroprotective effects in cerebral ischemia. Here, we investigated the effects of DAU on N2a cells stably transfected with Swedish mutant amyloid precursor protein (N2a/APP), an AD-like cell model. ELISA and Western blot analysis revealed that DAU inhibited APP processing and reduced Aβ accumulation. In addition, DAU ameliorated tau hyperphosphorylation via PP2A, p35/25, and CDK5 pathways in N2a/APP cells. The amelioration of tau hyperphosphorylation by DAU was also validated in HEK293/Tau cells, another cell line with tau hyperphosphorylation. Proteomic analysis revealed 85 differentially expressed proteins in the lysates between the wild-type N2a cells (N2a/WT) and the N2a/APP cells in the presence or absence of DAU; these were classified into 6 main categories according to their functions: endoplasmic reticulum (ER) stress-associated proteins, oxidative stress-associated proteins, cytoskeleton proteins, molecular chaperones, mitochondrial respiration and metabolism-related proteins, and signaling proteins. Taken together, we demonstrated that DAU treatment reduces AD-like pathology, thereby suggesting that DAU has potential therapeutic utility in AD.

scholarly journals Mechanical Stretching-Induced Traumatic Brain Injury Is Mediated by the Formation of GSK-3β-Tau Complex to Impair Insulin Signaling Transduction

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1650
Author(s):  
Pei-Wen Cheng ◽  
Yi-Chung Wu ◽  
Tzyy-Yue Wong ◽  
Gwo-Ching Sun ◽  
Ching-Jiunn Tseng
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Oxidative Dna Damage ◽  
Glycogen Synthase ◽  
Amyloid Β ◽  
Neuronal Injury ◽  
Mechanical Injury ◽  
Public Health Burden ◽  
Increased Risk ◽  
Gsk 3Β

Traumatic brain injury confers a significant and growing public health burden. It is a major environmental risk factor for dementia. Nonetheless, the mechanism by which primary mechanical injury leads to neurodegeneration and an increased risk of dementia-related diseases is unclear. Thus, we aimed to investigate the effect of stretching on SH-SY5Y neuroblastoma cells that proliferate in vitro. These cells retain the dopamine-β-hydroxylase activity, thus being suitable for neuromechanistic studies. SH-SY5Y cells were cultured on stretchable membranes. The culture conditions contained two groups, namely non-stretched (control) and stretched. They were subjected to cyclic stretching (6 and 24 h) and 25% elongation at 1 Hz. Following stretching at 25% and 1 Hz for 6 h, the mechanical injury changed the mitochondrial membrane potential and triggered oxidative DNA damage at 24 h. Stretching decreased the level of brain-derived neurotrophic factors and increased amyloid-β, thus indicating neuronal stress. Moreover, the mechanical injury downregulated the insulin pathway and upregulated glycogen synthase kinase 3β (GSK-3β)S9/p-Tau protein levels, which caused a neuronal injury. Following 6 and 24 h of stretching, GSK-3βS9 was directly bound to p-TauS396. In contrast, the neuronal injury was improved using GSK-3β inhibitor TWS119, which downregulated amyloid-β/p-Taus396 phosphorylation by enhancing ERK1/2T202/Y204 and AktS473 phosphorylation. Our findings imply that the neurons were under stress and that the inactivation of the GSK3β could alleviate this defect.

scholarly journals MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways

2018 ◽  
Author(s):  
Rachid El Fatimy ◽  
Shaomin Li ◽  
Zhicheng Chen ◽  
Tasnim Mushannen ◽  
Sree Gongala ◽  
...  
Keyword(s):  
Rna Binding ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Therapeutic Benefit ◽  
Glutamate Excitotoxicity ◽  
Amyloid Β Peptide ◽  
Neuroprotective Effects ◽  
Term Potentiation ◽  
Neuroprotective Function ◽  
Multiple Signaling

AbstractMicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here we describe a neuroprotective function of miR-132, the miRNA most significantly down-regulated in Alzheimer’s disease. miR-132 protects mouse and human wild-type neurons and more vulnerable Tau-mutant primary neurons against amyloid β-peptide (Aβ) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopathies, promotes neurite elongation and branching, and reduces neuronal death. Similarly, miR-132 attenuates PHF Tau pathology and neurodegeneration and enhances long-term potentiation in the P301S Tau transgenic mice. The neuroprotective effects are mediated by direct regulation of the Tau modifiers acetyltransferase EP300, kinase GSK3β, RNA-binding protein Rbfox1, and proteases Calpain 2 and Caspases 3/7. These data suggest miR-132 as a master regulator of neuronal health and indicate that miR-132 supplementation could be of therapeutic benefit for the treatment of Tau-associated neurodegenerative disorders.

scholarly journals Brain Region-Specific Neuroprotective Action and Signaling of Corticotropin-Releasing Hormone in Primary Neurons

Endocrinology ◽  
2003 ◽  
Vol 144 (9) ◽  
pp. 4051-4060 ◽  
Author(s):  
Nadhim Bayatti ◽  
Jürgen Zschocke ◽  
Christian Behl
Keyword(s):  
Brain Region ◽  
Cortical Neurons ◽  
Intracellular Signaling ◽  
Glycogen Synthase ◽  
Primary Cultures ◽  
Amyloid Β ◽  
Receptor Expression ◽  
Neuronal Cultures ◽  
Neuroprotective Effects ◽  
Hippocampal Cultures

Abstract CRH regulates the body’s response to stressful stimuli by modulating the activity of the hypothalamic pituitary axis. In primary cultures and cell lines, CRH also acts as a potent neuroprotective factor in response to a number of toxins. Using primary neuronal cultures from the cerebellum, cerebral cortex, and hippocampus, we demonstrate that CRH exerts a brain region-specific neuroprotective effect on amyloid β 25–35 toxicity. At low CRH concentrations (10−8m), neuroprotective effects can be observed only in cerebellar and hippocampal cultures, but a higher CRH concentration (10−7m) additionally led to the protection of cortical neurons. These neuroprotective effects were inhibited by H89, a specific protein kinase A inhibitor. Western blot analysis, carried out using phospho-specific antibodies directed against MAPK, cAMP response element-binding protein (CREB), and glycogen synthase kinase (GSK)3β also resulted in brain legion-specific differences regarding intracellular signaling. Correlating with cell survival, low CRH concentrations resulted in activation of the CREB pathway and inactivation of GSK3β in cerebellar and hippocampal cultures, but higher concentrations additionally resulted in activated CREB and inactivated GSK3β in cortical cultures. In contrast, MAPK activation occurred only in cortical neurons. Differences in signaling were found to be independent of receptor expression levels because RT-PCR analysis indicated no region-specific differences in CRHR1 mRNA expression.

scholarly journals Presenilin 1 associates with glycogen synthase kinase-3β and its substrate tau

1998 ◽  
Vol 95 (16) ◽  
pp. 9637-9641 ◽  
Author(s):  
Akihiko Takashima ◽  
Miyuki Murayama ◽  
Ohoshi Murayama ◽  
Toshiyuki Kohno ◽  
Toshiyuki Honda ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Amyloid Β ◽  
Glycogen Synthase Kinase ◽  
Presenilin 1 ◽  
Amyloid Β Protein ◽  
Glycogen Synthase Kinase 3Β ◽  
Β Protein ◽  
Gsk 3Β

Families bearing mutations in the presenilin 1 (PS1) gene develop Alzheimer’s disease. Previous studies have shown that the Alzheimer-associated mutations in PS1 increase production of amyloid β protein (Aβ1–42). We now show that PS1 also regulates phosphorylation of the microtubule-associated protein tau. PS1 directly binds tau and a tau kinase, glycogen synthase kinase 3β (GSK-3β). Deletion studies show that both tau and GSK-3β bind to the same region of PS1, residues 250–298, whereas the binding domain on tau is the microtubule-binding repeat region. The ability of PS1 to bring tau and GSK-3β into close proximity suggests that PS1 may regulate the interaction of tau with GSK-3β. Mutations in PS1 that cause Alzheimer’s disease increase the ability of PS1 to bind GSK-3β and, correspondingly, increase its tau-directed kinase activity. We propose that the increased association of GSK-3β with mutant PS1 leads to increased phosphorylation of tau.

Sign in / Sign up

Export Citation Format

Share Document