NF-κB-Induced Upregulation of miR-146a-5p Promoted Hippocampal Neuronal Oxidative Stress and Pyroptosis via TIGAR in a Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is a common neurodegenerative disorder that places a heavy burden on patients and society. Hippocampal neuronal loss is a hallmark of AD progression. Therefore, understanding the mechanism underlying hippocampal neuronal death would be of great importance for the diagnosis and treatment of AD. This study aimed to explore the molecular mechanism via which nuclear factor kappa β (NF-κB) promotes hippocampal neuronal oxidative stress and pyroptosis in AD. We collected serum samples from 101 healthy elderly people and 112 patients with AD at the Affiliated Hospital of Kunming University of Science and Technology between January 2017 and January 2020. Commercially available human hippocampal neurons (HHNs) were used to establish an AD model (AD-HHN) following Aβ25–35 treatment. The mRNA expression levels of NF-κB and pyroptosis markers [NLR family pyrin domain-containing 3, caspase-1, interleukin (IL)-1β, and interleukin-18] mRNA and the expression level of miR-146a-5p in the serum samples of patients with AD and AD-HHNs were determined by quantitative reverse transcription polymerase chain reaction. Oxidative stress indices (reactive oxygen species, malondialdehyde, nicotinamide adenine dinucleotide phosphate, superoxide dismutase, glutathione, and catalase) were measured by Enzyme-Linked Immunosorbent Assay (ELISA). The expression of proteins [NF-κB, TP53-induced glycolysis and apoptosis regulator (TIGAR), and pyroptosis markers] was tested by western blotting. The relationship between miR-146a-5p and TIGAR was investigated using a dual luciferase reporter gene assay. We found that NF-κB and miR-146a-5p were highly expressed, while TIGAR was low expressed in patients with AD and AD-HHNs. In addition, there was a significant positive correlation between the expression levels of NF-κB and miR-146a-5p, but a negative correlation between NF-κB mRNA and TIGAR mRNA in patients with AD, as well as miR-146a-5p and TIGAR mRNA in patients with AD. In AD-HNNs, miR-146a-5p targeted and downregulated the expression of TIGAR. Knockdown of NF-κB or overexpression of TIGAR markedly attenuated oxidative stress and pyroptosis in AD-HHNs, while concurrent overexpression of miR-146a-5p inhibited these effects. In conclusion, NF-κB-induced upregulation of miR-146a-5p promoted oxidative stress and pyroptosis in AD-HNNs by targeting TIGAR.

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BRUCE silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in Alzheimer’s disease

Translational Psychiatry ◽

10.1038/s41398-021-01427-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lu Zhang ◽

Yu Fang ◽

Xinyu Zhao ◽

Yake Zheng ◽

Yunqing Ma ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nuclear Translocation ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Axon Growth ◽

Luciferase Reporter ◽

Axonal Dystrophy ◽

Luciferase Reporter Gene ◽

Ht22 Cells ◽

Gene Assay

AbstractAxonal dystrophy is a swollen and tortuous neuronal process that contributes to synaptic alterations occurring in Alzheimer’s disease (AD). Previous study identified that brain-derived neurotrophic factor (BDNF) binds to tropomyosin-related kinase B (TrkB) at the axon terminal and then the signal is propagated along the axon to the cell body and affects neuronal function through retrograde transport. Therefore, this study was designed to identify a microRNA (miRNA) that alters related components of the transport machinery to affect BDNF retrograde signaling deficits in AD. Hippocampus tissues were isolated from APP/PS1 transgenic (AD-model) mice and C57BL/6J wild-type mice and subject to nicotinamide adenine dinucleotide phosphate and immunohistochemical staining. Autophagosome-lysosome fusion and nuclear translocation of BDNF was detected using immunofluorescence in HT22 cells. The interaction among miR-204, BIR repeat containing ubiquitin-conjugating enzyme (BRUCE) and Syntaxin 17 (STX17) was investigated using dual luciferase reporter gene assay and co-immunoprecipitation assay. The expression of relevant genes and proteins were determined by RT-qPCR and Western blot analysis. Knockdown of STX17 or BRUCE inhibited autophagosome–lysosome fusion and impacted axon growth in HT22 cells. STX17 immunoprecipitating with BRUCE and co-localization of them demonstrated BRUCE interacted with STX17. BRUCE was the target of miR-204, and partial loss of miR-204 by inhibitor promoted autophagosome–lysosome fusion to prevent axon dystrophy and accumulated BDNF nuclear translocation to rescue BDNF/TrkB signaling deficits in HT22 cells. The overall results demonstrated that inhibition of miR-204 prevents axonal dystrophy by blocking BRUCE interaction with STX17, which unraveled potential novel therapeutic targets for delaying AD.

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Autophagy and mitophagy biomarkers are reduced in sera of patients with Alzheimer’s disease and mild cognitive impairment

Scientific Reports ◽

10.1038/s41598-019-56614-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 11

Author(s):

Massimiliano Castellazzi ◽

Simone Patergnani ◽

Mariapina Donadio ◽

Carlotta Giorgi ◽

Massimo Bonora ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Late Onset ◽

Memory Loss ◽

Serum Levels ◽

Enzyme Linked Immunosorbent Assay ◽

Serum Samples ◽

Cellular Processes

AbstractDementia is a neurocognitive disorder characterized by a progressive memory loss and impairment in cognitive and functional abilities. Autophagy and mitophagy are two important cellular processes by which the damaged intracellular components are degraded by lysosomes. To investigate the contribution of autophagy and mitophagy in degenerative diseases, we investigated the serum levels of specific autophagic markers (ATG5 protein) and mitophagic markers (Parkin protein) in a population of older patients by enzyme-linked immunosorbent assay. Two hundred elderly (≥65 years) outpatients were included in the study: 40 (20 F and 20 M) with mild-moderate late onset Alzheimer’s disease (AD); 40 (20 F and 20 M) affected by vascular dementia (VAD); 40 with mild cognitive impairment (MCI); 40 (20 F and 20 M) with “mixed” dementia (MD); 40 subjects without signs of cognitive impairment were included as sex-matched controls. Our data indicated that, in serum samples, ATG5 and Parkin were both elevated in controls, and that VAD compared with AD, MCI and MD (all p < 0.01). Patients affected by AD, MD, and MCI showed significantly reduced circulating levels of both ATG5 and Parkin compared to healthy controls and VAD individuals, reflecting a significant down-regulation of autophagy and mitophagy pathways in these groups of patients. The measurement of serum levels of ATG5 and Parkin may represent an easily accessible diagnostic tool for the early monitoring of patients with cognitive decline.

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Oxidative Stress Targeting Amyloid Beta Accumulation and Clearance in Alzheimer’s Disease: Insight into Pathological Mechanisms and Therapeutic Strategies

Current Psychopharmacologye ◽

10.2174/2211556009666191231155927 ◽

2020 ◽

Vol 9 (1) ◽

pp. 22-42

Author(s):

Sunpreet Kaur ◽

Puneet Kumar ◽

Shamsher Singh

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Beta ◽

Neurodegenerative Disorder ◽

Acetylcholinesterase Inhibitors ◽

The Elderly ◽

Biochemical Alterations ◽

App Trafficking ◽

Copper Aluminum

Background: Alzheimer’s disease is the most common neurodegenerative disorder affecting the elderly population and emerges as a leading challenge for the scientific research community. The wide pathological aspects of AD made it a multifactorial disorder and even after long time it’s difficult to treat due to unexplored etiological factors. Methods: The etiogenesis of AD includes mitochondrial failure, gut dysbiosis, biochemical alterations but deposition of amyloid-beta plaques and neurofibrillary tangles are implicated as major hallmarks of neurodegeneration in AD. The aggregates of these proteins disrupt neuronal signaling, enhance oxidative stress and reduce activity of various cellular enzymes which lead to neurodegeneration in the cerebral cortex, neocortex and hippocampus. The metals like copper, aluminum are involved in APP trafficking and promote amyloidbeta aggregation. Similarly, disturbed ubiquitin proteasomal system, autophagy and amyloid- beta clearance mechanisms exert toxic insult in the brain. Result and conclusion : The current review explored the role of oxidative stress in disruption of amyloid homeostasis which further leads to amyloid-beta plaque formation and subsequent neurodegeneration in AD. Presently, management of AD relies on the use of acetylcholinesterase inhibitors, antioxidants and metal chelators but they are not specific measures. Therefore, in this review, we have widely cited the various pathological mechanisms of AD as well as possible therapeutic targets.

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The Triggering Receptor Expressed on Myeloid Cells 2: “TREM-ming” the Inflammatory Component Associated with Alzheimer's Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/860959 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 19

Author(s):

Troy T. Rohn

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurofibrillary Tangles ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Senile Plaques ◽

Myeloid Cells ◽

Disease Process ◽

Age Related

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by a progressive loss of memory and cognitive skills. Although much attention has been devoted concerning the contribution of the microscopic lesions, senile plaques, and neurofibrillary tangles to the disease process, inflammation has long been suspected to play a major role in the etiology of AD. Recently, a novel variant in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has been identified that has refocused the spotlight back onto inflammation as a major contributing factor in AD. Variants in TREM2 triple one's risk of developing late-onset AD. TREM2 is expressed on microglial cells, the resident macrophages in the CNS, and functions to stimulate phagocytosis on one hand and to suppress cytokine production and inflammation on the other hand. The purpose of this paper is to discuss these recent developments including the potential role that TREM2 normally plays and how loss of function may contribute to AD pathogenesis by enhancing oxidative stress and inflammation within the CNS. In this context, an overview of the pathways linking beta-amyloid, neurofibrillary tangles (NFTs), oxidative stress, and inflammation will be discussed.

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Ceramides in Alzheimer’s Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and AβAccumulation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/346783 ◽

2015 ◽

Vol 2015 ◽

pp. 1-17 ◽

Cited By ~ 76

Author(s):

Maja Jazvinšćak Jembrek ◽

Patrick R. Hof ◽

Goran Šimić

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuronal Apoptosis ◽

Neurodegenerative Disorder ◽

Neuronal Degeneration ◽

Sphingolipid Metabolism ◽

Cytochrome C Release ◽

Biochemical Alterations

Alzheimer’s disease (AD), the most common chronic and progressive neurodegenerative disorder, is characterized by extracellular deposits of amyloidβ-peptides (Aβ) and intracellular deposits of hyperphosphorylated tau (phospho-tau) protein. Ceramides, the major molecules of sphingolipid metabolism and lipid second messengers, have been associated with AD progression and pathology via Aβgeneration. Enhanced levels of ceramides directly increase Aβthrough stabilization ofβ-secretase, the key enzyme in the amyloidogenic processing of Aβprecursor protein (APP). As a positive feedback loop, the generated oligomeric and fibrillar Aβinduces a further increase in ceramide levels by activating sphingomyelinases that catalyze the catabolic breakdown of sphingomyelin to ceramide. Evidence also supports important role of ceramides in neuronal apoptosis. Ceramides may initiate a cascade of biochemical alterations, which ultimately leads to neuronal death by diverse mechanisms, including depolarization and permeabilization of mitochondria, increased production of reactive oxygen species (ROS), cytochrome c release, Bcl-2 depletion, and caspase-3 activation, mainly by modulating intracellular signalling, particularly along the pathways related to Akt/PKB kinase and mitogen-activated protein kinases (MAPKs). This review summarizes recent findings related to the role of ceramides in oxidative stress-driven neuronal apoptosis and interplay with Aβin the cascade of events ending in neuronal degeneration.

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Probiotics: An Adjuvant therapy for D-Galactose induced Alzheimer's disease

Journal of Medical Research and Innovation ◽

10.15419/jmri.15 ◽

2017 ◽

Vol 1 (1) ◽

pp. 30-33 ◽

Cited By ~ 4

Author(s):

Varshil Mehta ◽

Kavya Bhatt ◽

Nimit Desai ◽

Mansi Naik

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Brain Regions ◽

Health Concern ◽

Major Health ◽

Acetyl Choline ◽

Glycation End Products ◽

Anti Oxidant

Alzheimer’s disease (AD) is a chronic and slowly progressing neurodegenerative disorder which has become a major health concern worldwide. The literature has shown that oxidative stress is one of the most important risk factors behind the cause of AD. Oxidative stress often leads to the production of Reactive Oxygen Species (ROS). D-Galactose, a physiological nutrient and reducing sugar, non-enzymatically reacts with amines of amino acids in proteins and peptides to form Advanced Glycation End products which activate its receptors coupled to Biochemical pathways that stimulate free radical production and induces mitochondrial dysfunction which damages the neuron intracellularly. High dosage of D-Galactose also suppresses the expression of nerve growth factors and its associated protein which results in the degeneration of nerve cells and reduction of acetylcholine levels in brain regions. This article put forwards the advantages of using Lactic Acid Bacteria (Probiotics) possessing anti-oxidant properties and which produces Acetyl Choline against D-Galactose induced Alzheimer’s disease.

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Angiotensin-converting enzyme 2 (ACE2) is upregulated in Alzheimer’s disease brain

10.1101/2020.10.08.331157 ◽

2020 ◽

Cited By ~ 2

Author(s):

Qiyue Ding ◽

Nataliia V. Shults ◽

Brent T. Harris ◽

Yuichiro J. Suzuki

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Angiotensin Converting Enzyme ◽

Protein Expression ◽

Neurodegenerative Disorder ◽

Host Cells ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

The Brain

AbstractAlzheimer’s disease is a chronic neurodegenerative disorder and represents the main cause of dementia. Currently, the world is suffering from the pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of Alzheimer’s disease patients. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimer’s disease and the ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimer’s disease, and Alzheimer’s disease brains examined in this study also exhibited higher carbonylated proteins as well as increased thiol oxidation state of peroxiredoxin 6 (Prx6). The positive correlation was found between the increased ACE2 protein expression and oxidative stress in Alzheimer’s disease brain. Thus, the present study reveals the relationships between Alzheimer’s disease and ACE2, the receptor for SARS-CoV-2. These results warrant monitoring Alzheimer’s disease patients with COVID-19 carefully for the possible higher viral load in the brain and long-term adverse neurological consequences.

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Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

10.1101/735449 ◽

2019 ◽

Author(s):

Viviana Soto-Mercado ◽

Miguel Mendivil-Perez ◽

Carlos Velez-Pardo ◽

Francisco Lopera ◽

Marlene Jimenez-Del-Rio

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Memory Loss ◽

Cholinergic Neurons ◽

Tau Phosphorylation ◽

Cellular Mechanisms ◽

Limited Effectiveness ◽

Aβ42 Peptide

AbstractAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive disturbance as a consequence of the loss of cholinergic neurons in the brain, neuritic plaques and hyperphosphorylation of TAU protein. Although the underlying mechanisms leading to these events are unclear, mutations in presenilin 1 (PSEN1), e.g., E280A (PSEN1 E280A), are causative factors for autosomal dominant early-onset familial AD (FAD). Despite advances in the understanding of the physiopathology of AD, there are no efficient therapies to date. Limitations in culturing brain-derived live neurons might explain the limited effectiveness of AD research. Here, we show that mesenchymal stromal (stem) cells (MSCs) can be used to model FAD, providing novel opportunities to study cellular mechanisms and to establish therapeutic strategies. Indeed, we cultured MSCs with the FAD mutation PSEN1 E280A and wild-type (WT) PSEN1 from umbilical cords and characterized the transdifferentiation of these cells into cholinergic-like neurons (ChLNs). PSEN1 E280A ChLNs but not WT PSEN1 ChLNs exhibited increased intra- and extracellular Aβ42 peptide and TAU phosphorylation (at residues Ser202/Thr205), recapitulating the molecular pathogenesis of FAD caused by mutant PSEN1. Furthermore, PSEN1 E280A ChLNs presented oxidative stress (OS) as evidenced by the oxidation of DJ-1Cys106-SH into DJ-1Cys106-SO3 and the detection of DCF-positive cells and apoptosis markers such as activated pro-apoptosis proteins p53, c-JUN, PUMA and CASPASE-3 and the concomitant loss of the mitochondrial membrane potential and DNA fragmentation. Additionally, mutant ChLNs displayed Ca2+ flux dysregulation and deficient acetylcholinesterase (AChE) activity compared to control ChLNs. Interestingly, the inhibitor JNK SP600125 almost completely blocked TAU phosphorylation. Our findings demonstrate that FAD MSC-derived cholinergic neurons with the PSEN1 E280A mutation are a valid model of AD and provide important clues for the identification of targetable pathological molecules.

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Brain Dicer1 is down-regulated in a mouse model of Alzheimer’s disease via Aβ42-induced repression of nuclear factor erythroid 2-related factor 2

10.21203/rs.3.rs-25902/v1 ◽

2020 ◽

Author(s):

Yan Wang ◽

Meiling Lian ◽

Jing Zhou ◽

shengzhou wu

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Luciferase Reporter ◽

Cultured Neurons ◽

Related Factor ◽

Mrna Levels ◽

Nuclear Factor ◽

Dicer1 Expression

Abstract Background Oxidative stress critically underlies the neurodegenerative pathogenesis of Alzheimer's disease (AD). Depletion of Dicer1, an endoribonuclease central to microRNA maturation, also leads to neurodegeneration. We therefore hypothesized that altered Dicer1 expression may play a role in AD. Results Using immunoblotting and quantitative real-time PCR, we found that Dicer1 protein and mRNA levels were reduced in the hippocampi of animals of the AD mouse model APPswe/PSEN1dE9 compared with littermate controls. SiRNA-meditated Dicer1 knockdown induced oxidative stress, reduced mitochondrial intermembrane potential, and increased apoptosis in cultured neurons. Aβ42 exposure decreased Dicer1 and also down-regulated the oxidative stress–induced transcriptional regulator nuclear factor erythroid 2-related factor 2 (Nrf2). Conversely, Nrf2 overexpression increased Dicer1 mRNA and protein levels and reverted the Aβ42-induced Dicer1 reduction. To further investigate Dicer1 regulation, we cloned Dicer1 promoter variants harboring the Nrf2-binding site, the antioxidant response elements (ARE), into a luciferase reporter and found that simultaneous transfection of Nrf2-expressing plasmid increased luciferase expression from these promoter constructs. ChIP assays indicated that Nrf2 directly interacted with the ARE motifs in the Dicer1 promoter. Furthermore, Dicer1 overexpression in cultured neurons reverted Aβ42-induced neurite deficits. Of note, injection of Dicer1-expressing adenovirus into the hippocampus of the AD mice significantly improved spatial learning. Conclusions These findings indicate that Dicer1 expression is reduced in the AD brain and that chronic Aβ exposure decreases Dicer1 levels in neurons via Nrf2–ARE signaling. Our results uncover a significant role for Dicer1 in AD and highlight that Dicer1 expression responds to oxidative stress in the brain.

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Differential Expression of miR-381-3p in Alzheimer’s Disease Patients and Its Role in Beta-Amyloid-Induced Neurotoxicity and Inflammation

NeuroImmunoModulation ◽

10.1159/000519780 ◽

2021 ◽

pp. 1-9

Author(s):

Meng Zhang ◽

Yonglei Liu ◽

Pingping Teng ◽

Qing Yang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Proliferation ◽

Inflammatory Cytokines ◽

Roc Curve ◽

Pearson Correlation ◽

Luciferase Reporter ◽

Cell Models ◽

Gene Assay ◽

Proliferation And Apoptosis

Introduction: This study aimed to explore the diagnostic value and effect of miR-381-3p on Alzheimer’s disease (AD). Methods: RT-qPCR was used for the measurement of miR-381-3p levels. Pearson correlation coefficient was used for the correlation analysis. Receiver operating characteristic (ROC) curve was constructed to assess the distinct ability of miR-381-3p for AD. SH-SY5Y cells were treated with Aβ25-35 to establish an AD cell model. The role of miR-381-3p on cell proliferation and apoptosis was detected. ELISA was applied to detect the protein levels of inﬂammatory cytokine expression. The target relationship of miR-381-3p with PTGS2 was verified by luciferase reporter gene assay. Results: Low expression of miR-381-3p was detected in the serum of AD patients and cell models. There was a negative association of serum miR-381-3p with the serum inflammatory cytokines. The ROC curve demonstrated the distinct ability of serum miR-381-3p for AD, with the AUC value of 0.898, with a sensitivity of 87.5%, and a specificity of 77.7%. Overexpression of miR-381-3p reversed the influence of Aβ25-35 on cell proliferation and apoptosis, but miR-381-3p downregulation exacerbated the influence. miR-381-3p overexpression inhibited the release of IL-6, IL-1β, and TNF-α induced by Aβ25-35 treatment, whereas miR-381-3p downregulation further promoted the release of inflammatory cytokines. PTGS2 was the target gene of miR-381-3p and was upregulated in AD cell models. Conclusion: miR-381-3p is less expressed in the serum of AD patients and has potential diagnostic values for AD. Overexpression of miR-381-3p may attenuate Aβ25-35-induced neurotoxicity and inflammatory responses via targeting PTGS2 in SH-SY5Y cells.

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