Journal of Neurochemistry最新文献

{"title":"Prenatal Valproic Acid Induces Autistic-Like Behaviors in Rats via Dopaminergic Modulation in Nigrostriatal and Mesocorticolimbic Pathways","authors":"Luana C. Cezar,&nbsp;Caio Cesar N. da Fonseca,&nbsp;Marianne O. Klein,&nbsp;Thiago B. Kirsten,&nbsp;Luciano F. Felicio","doi":"10.1111/jnc.16282","DOIUrl":"10.1111/jnc.16282","url":null,"abstract":"<div>\u0000 \u0000 <p>Autism spectrum disorder (ASD) is a complex developmental disorder characterized by several behavioral impairments, especially in socialization, communication, and the occurrence of stereotyped behaviors. In rats, prenatal exposure to valproic acid (VPA) induces autistic-like behaviors. Previous studies by our group have suggested that the autistic-like phenotype is possibly related to dopaminergic system modulation because tyrosine hydroxylase (TH) expression was affected. The objective of the present study was to understand the dopaminergic role in autism. Wistar rats on gestational day 12.5 received VPA (400 mg/kg) and behaviors related to rat models of ASD were evaluated in juvenile offspring. Neurochemical and genetic dopaminergic components were studied in different brain areas of both juvenile and adult rats. Prenatal VPA-induced autistic-like behaviors in comparison to a control group: decreased maternal solicitations by ultrasonic vocalizations, cognitive inflexibility and stereotyped behavior in the T-maze test, decreased social interaction and play behavior, as well as motor hyperactivity. Prenatal VPA also decreased dopamine synthesis and activity in the striatum and prefrontal cortex, as well as dopamine transporter, D1 and D2 receptors, and TH expressions. Moreover, prenatal VPA increased TH+ immunoreactive neurons of the ventral tegmental area–substantia nigra complex. In conclusion, the dopaminergic hypoactivity associated with the behavioral impairments exhibited by the rats that received prenatal VPA suggests the important role of this system in the establishment of the characteristic symptoms of ASD in juvenile and adult males. Dopamine was demonstrated to be an important biomarker and a potential pharmacological target for ASD.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of Dendrite and Dendritic Spine Formation by TCF20","authors":"Ersilia Vinci,&nbsp;Stefania Beretta,&nbsp;Veronica Colombo,&nbsp;Antonio Zippo,&nbsp;Alberto Catanese,&nbsp;Christoph Wiegreffe,&nbsp;Stefan Britsch,&nbsp;Tobias Boeckers,&nbsp;Chiara Verpelli,&nbsp;Carlo Sala","doi":"10.1111/jnc.16297","DOIUrl":"10.1111/jnc.16297","url":null,"abstract":"<p>Mutations in the Transcription Factor 20 (TCF20) have been identified in patients with autism spectrum disorders (ASDs), intellectual disabilities (IDs), and other neurological issues. Recently, a new syndrome called TCF20-associated neurodevelopmental disorders (TAND) has been described, with specific clinical features. While TCF20's role in the neurogenesis of mouse embryos has been reported, little is known about its molecular function in neurons. In this study, we demonstrate that TCF20 is expressed in all analyzed brain regions in mice, and its expression increases during brain development but decreases in muscle tissue. Our findings suggest that TCF20 plays a central role in dendritic arborization and dendritic spine formation processes. RNA sequencing analysis revealed a downregulation of pre- and postsynaptic pathways in TCF20 knockdown neurons. We also found decreased levels of GABRA1, BDNF, PSD-95, and c-Fos in total homogenates and in synaptosomal preparations of knockdown TCF20 rat cortical cultures. Furthermore, synaptosomal preparations of knockdown TCF20 rat cortical cultures showed significant downregulation of GluN2B and GABRA5, while GluA2 was significantly upregulated. Overall, our data suggest that TCF20 plays an essential role in neuronal development and function by modulating the expression of proteins involved in dendrite and synapse formation and function.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AENK ameliorates cognitive impairment and prevents Tau hyperphosphorylation through inhibiting AEP-mediated cleavage of SET in rats with ischemic stroke","authors":"Yi Liu,&nbsp;Wei Liu,&nbsp;Cuiping Guo,&nbsp;Jian Bao,&nbsp;Huiliang Zhang,&nbsp;Wensheng Li,&nbsp;Youwei Li,&nbsp;Yurang Gui,&nbsp;Yi Zeng,&nbsp;Xiaochuan Wang,&nbsp;Caixia Peng,&nbsp;Xiji Shu,&nbsp;Rong Liu","doi":"10.1111/jnc.16283","DOIUrl":"10.1111/jnc.16283","url":null,"abstract":"<p>Brain damage induced by ischemia promotes the development of cognitive dysfunction, thus increasing the risk of dementia such as Alzheimer's disease (AD). Studies indicate that cellular acidification-triggered activation of asparagine endopeptidase (AEP) plays a key role in ischemic brain injury, through multiple molecular pathways, including cleavage of its substrates such as SET (inhibitor 2 of PP2A, I₂^PP2A) and Tau. However, whether direct targeting AEP can effectively prevent post-stroke cognitive impairment (PSCI) remains unanswered. Here, we explored the therapeutic effect and underlying mechanism of the AEP inhibitor AENK on cognitive impairment of the rats with middle cerebral artery occlusion (MCAO) and on neuronal damage in cultured primary neurons exposed to oxygen and glucose deprivation (OGD). We found that the administration of AENK significantly reduces activated AEP levels in ischemic rat brains, attenuates cognitive deficits, and rescues synaptic dysfunction. For the mechanism, with AEP inhibition, cleavage of SET, inhibition of protein phosphatase 2A (PP2A), and Tau hyperphosphorylation resulted from PP2A inhibition, were all completely or partially reversed. In primary neurons, AENK effectively prevents AEP activation, SET cleavage and cytoplasmic retention, tau hyperphosphorylation and synaptic damage induced by OGD. We conclude that AENK ameliorates cognitive impairment and prevents tau hyperphosphorylation, through inhibiting AEP-mediated cleavage of SET in ischemic brain injury, and direct inhibition of AEP might be a potential therapeutic strategy for preventing synaptic damage and cognitive impairment after stroke.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuronal TRPV1-CGRP axis regulates peripheral nerve regeneration through ERK/HIF-1 signaling pathway","authors":"Huiling Che,&nbsp;Yu Du,&nbsp;Yixuan Jiang,&nbsp;Zhanfeng Zhu,&nbsp;Mingxuan Bai,&nbsp;Jianan Zheng,&nbsp;Mao Yang,&nbsp;Lin Xiang,&nbsp;Ping Gong","doi":"10.1111/jnc.16281","DOIUrl":"10.1111/jnc.16281","url":null,"abstract":"<p>Severe trauma frequently leads to nerve damage. Peripheral nerves possess a degree of regenerative ability, and actively promoting their recovery can help restore the sensory and functional capacities of tissues. The neuropeptide calcitonin gene-related peptide (CGRP) is believed to regulate the repair of injured peripheral nerves, with neuronal transient receptor potential vanilloid type 1 (TRPV1) potentially serving as a crucial upstream factor. In this study, we established a mouse model of sciatic nerve (SN) crush injury and found that intrathecal injection of capsaicin (Cap) activated the neuronal TRPV1-CGRP axis, thereby promoting SN repair. Conversely, the application of capsazepine (Cpz), which inhibits the neuronal TRPV1-CGRP axis, delayed SN repair. Local restoration of CGRP expression at the injury site enhanced the repair process. In vitro experiments, we employed the rat Schwann cell (SC) line RSC96 to establish an indirect co-culture model of neurons and SCs. We observed that the proliferation, migration, expression of myelination-associated proteins, and neurotrophic secretion functions of RSC96 cells are positively correlated with the degree of activation of neuronal TRPV1. Inhibition of neuronal TRPV1, followed by the restoration of CGRP levels, improved these functions in RSC96 cells. Furthermore, activation of the neuronal TRPV1-CGRP axis resulted in an upregulation of extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation levels and an increase in hypoxia-inducible factor 1α (HIF-1α) accumulation in RSC96 cells, thereby promoting their proliferation and migration. In summary, this study demonstrates that neuronal TRPV1-CGRP axis can regulate biological behavior of SCs and axon regeneration by activating the ERK/HIF-1 signaling pathway following peripheral nerve injury. This finding clarifies the role of CGRP in neuroregulatory networks and provides a novel reference point for the development of drugs and biomaterials for treating nerve damage.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetically Confirmed Optimal Causal Association of Cerebrospinal Fluid Metabolites With Hemorrhagic Stroke","authors":"Yingjie Shen,&nbsp;Yaolou Wang,&nbsp;Yongze Shen,&nbsp;Xi Zhang,&nbsp;Zhao Yu,&nbsp;Hangjia Xu,&nbsp;Tie Lin,&nbsp;Yiwei Rong,&nbsp;Chunmei Guo,&nbsp;Aili Gao,&nbsp;Hongsheng Liang","doi":"10.1111/jnc.16293","DOIUrl":"10.1111/jnc.16293","url":null,"abstract":"<div>\u0000 \u0000 <p>Hemorrhagic stroke (HS) mainly includes intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), both of which seriously affect the patient's prognosis. Cerebrospinal fluid (CSF) metabolites and HS showed a link in observational studies. However, the causal association between them is not clear. We aimed to establish the optimal causality of CSF metabolites with HS. Mendelian randomization (MR) was employed to identify associations between CSF metabolites and different sources of HS. Univariable MR and false discovery rates (FDR) were used to identify initial causal associations. Linkage disequilibrium score regression determined genetic correlations. Multiple sensitive analyses ensured the reliability of the results. Multivariable MR and MR Bayesian Model Averaging were used to identify the optimal causal associations. The combined effects of metabolites and HS were assessed by meta-analyses. Pathway analyses were performed to identify potential pathways of action. Reverse MR was also conducted to identify reverse causal associations. Finally, Corresponding blood metabolites were used to explore the multiple roles of metabolites. We identified 20 CSF metabolites and six metabolic pathways associated with ICH; 15 CSF metabolites and three metabolic pathways associated with SAH. Nineteen and seven metabolites were causally associated with deep and lobar ICH, respectively. CSF levels of mannose (OR 0.63; 95% CI 0.45–0.88; <i>P</i>_combined = 0.0059) and <i>N</i>-acetyltaurine (OR 0.68; 95% CI 0.47–0.98; <i>P</i>_combined = 0.0395) may serve as the optimal exposures for ICH and SAH, respectively. Additionally, CSF ascorbic acid 3-sulfate levels significantly decrease the risk of deep ICH (OR 0.79; 95% CI 0.66–0.94; <i>p</i> = 0.0065; <i>P</i>_FDR = 0.091). Supplemental analysis of blood metabolites suggested multiple roles for CSF and blood <i>N</i>-formylanthranilic acid and hippurate. There are significant causal associations between CSF metabolites and HS, which provides a further rationale for the prevention and monitoring of ICH and SAH.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Dietary Ketosis and Nicotinamide Riboside on Hippocampal Krebs Cycle Intermediates and Mitochondrial Energetics in a DNA Repair-Deficient 3xTg/POLβ+/− Alzheimer Disease Mouse Model","authors":"Robert Pawlosky,&nbsp;Tyler G. Demarest,&nbsp;M. Todd King,&nbsp;Darlene Estrada,&nbsp;Richard L. Veech,&nbsp;Vilhelm A. Bohr","doi":"10.1111/jnc.16295","DOIUrl":"10.1111/jnc.16295","url":null,"abstract":"&lt;p&gt;Alzheimer disease is a neurodegenerative pathology-modifying mitochondrial metabolism with energy impairments where the effects of biological sex and DNA repair deficiencies are unclear. We investigated the therapeutic potential of dietary ketosis alone or with supplemental nicotinamide riboside (NR) on hippocampal intermediary metabolism and mitochondrial bioenergetics in older male and female wild-type (Wt) and 3xTgAD-DNA polymerase-β-deficient (3xTg/POLβ&lt;sup&gt;+/−&lt;/sup&gt;) (AD) mice. DNA polymerase-β is a key enzyme in DNA base excision repair (BER) of oxidative damage that may also contribute to mitochondrial DNA repair. Metabolic alterations imparted by ketosis and/or NR were assessed in 16 male and female groups, 4 Wt and 4 AD. At 73 weeks of age, mice were divided into: (A) carbohydrate diet (Carb); (B) Carb diet with NR (Carb-NR); (C) Ket diet (Ket); and (D) Ket diet with NR (Ket-NR) groups and remained on their respective treatments for 12 weeks. Mice were euthanized and hippocampi were rapidly removed and frozen. Glycolytic and TCA cycle intermediates were determined by quantitative GC–MS and the ratios of the mitochondrial free [NAD&lt;sub&gt;ox&lt;/sub&gt;]/[NADH&lt;sub&gt;red&lt;/sub&gt;] and coenzyme ubiquinone (CoQ/CoQH&lt;sub&gt;2&lt;/sub&gt;) couples and the Gibbs free energy of the Complex I–II system of the electron transport chain (ETC) (&lt;span&gt;&lt;/span&gt;&lt;math&gt;\u0000 &lt;semantics&gt;\u0000 &lt;mrow&gt;\u0000 &lt;msubsup&gt;\u0000 &lt;mrow&gt;\u0000 &lt;mo&gt;∆&lt;/mo&gt;\u0000 &lt;mi&gt;G&lt;/mi&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;mrow&gt;\u0000 &lt;mtext&gt;mitochondrial Complex&lt;/mtext&gt;\u0000 &lt;mspace&gt;&lt;/mspace&gt;\u0000 &lt;mi&gt;I&lt;/mi&gt;\u0000 &lt;mo&gt;−&lt;/mo&gt;\u0000 &lt;mi&gt;II&lt;/mi&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;mo&gt;′&lt;/mo&gt;\u0000 &lt;/msubsup&gt;\u0000 &lt;/mrow&gt;\u0000 &lt;annotation&gt;$$ Delta {G}_{mathrm{mitochondrial} mathrm{Complex} mathrm{I}-mathrm{II}}^{prime } $$&lt;/annotation&gt;\u0000 &lt;/semantics&gt;&lt;/math&gt;) were calculated from selected metabolites. Mice in Groups C and D had elevated blood ketones (1–2 mM). In most groupings, male mice had higher concentrations of TCA cycle intermediates than females. Moreover, higher concentrations of fumarate in Wt males were associated with elevations in the Δ&lt;i&gt;G&lt;/i&gt;′ of Complex I–II compared to females. In Wt males, NR treatments were associated with elevated concentrations of α-ketoglutarate and malate and linked to increased energy of Complex I–II. In AD males, both NR treatment and dietary ketosis restored the Δ&lt;i&gt;G&lt;/i&gt;′ of Complex I–II, where the ratio of the CoQ/CoQH&lt;sub&gt;2&lt;/sub&gt; couple was oxidized and the [NAD&lt;sub&gt;ox&lt;/sub&gt;]/[NADH&lt;sub&gt;red&lt;/sub&gt;] couple was reduced. In AD females, only mice in the Ket diet group had a sufficiently reduced [NAD&lt;sub&gt;ox&lt;/sub&gt;]/[NADH&lt;sub&gt;red&lt;/sub&gt;] couple to restore the free energy profi","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of neural stem cells by innervating neurons","authors":"Nicole Leanne Dittmann,&nbsp;Lauren Chen,&nbsp;Anastassia Voronova","doi":"10.1111/jnc.16287","DOIUrl":"10.1111/jnc.16287","url":null,"abstract":"<p>The adult central nervous system (CNS) hosts several niches, in which the neural stem and precursor cells (NPCs) reside. The subventricular zone (SVZ) lines the lateral brain ventricles and the subgranular zone (SGZ) is located in the dentate gyrus of the hippocampus. SVZ and SGZ NPCs replace neurons and glia in the homeostatic as well as diseased or injured states. Recently, NPCs have been found to express neurotransmitter receptors, respond to electrical stimulation and interact with neurons, suggesting that neuron-NPC communication is an emerging critical regulator of NPC biology. In this review, we discuss reports that demonstrate neuronal innervation and control of the neurogenic niches. We discuss the role of innervating neurons in regulating NPC fates, such as activation, proliferation, and differentiation. Our review focuses primarily on the innervation of the SVZ niche by the following neuronal types: glutamatergic, GABAergic projection and interneurons, cholinergic, dopaminergic, serotonergic, neuropeptidergic, nitrergic, and noradrenergic. We also discuss the origins of SVZ niche innervating neurons, such as striatum, cortex, basal ganglia, raphe nuclei, substantia nigra and ventral tegmental area, hypothalamus, and locus coeruleus. Our review highlights the various roles of innervating neurons in SVZ NPC fates in a spatiotemporal manner and emphasizes a need for future investigation into the impact of neuronal innervation on NPC gliogenesis.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tubulin-Binding Region Modulates Cholesterol-Triggered Aggregation of Tau Proteins","authors":"Abid Ali,&nbsp;Mikhail Matveyenka,&nbsp;Davis N. Pickett,&nbsp;Axell Rodriguez,&nbsp;Dmitry Kurouski","doi":"10.1111/jnc.16294","DOIUrl":"10.1111/jnc.16294","url":null,"abstract":"<div>\u0000 \u0000 <p>A hallmark of Alzheimer disease (AD) and tauopathies, severe neurodegenerative diseases, is the progressive aggregation of Tau, also known as microtubule-associated Tau protein. Full-length Tau_1-441, also known as 2N4R, contains two N-terminal inserts that bind to tubulin. This facilitates the self-assembly of tubulin simultaneously enhancing stability of cell microtubules. Other Tau isoforms have one (1N4R) or zero (0N4R) N-terminal inserts, which makes 2N4R Tau more and 0N4R less effective in promoting microtubule self-assembly. A growing body of evidence indicates that lipids can alter the aggregation rate of Tau isoforms. However, the role of N-terminal inserts in Tau-lipid interactions remains unclear. In this study, we utilized a set of biophysical methods to determine the extent to which N-terminal inserts alter interactions of Tau isoforms with cholesterol, one of the most important lipids in plasma membranes. Our results showed that 2 N insert prevents amyloid-driven aggregation of Tau at the physiological concentration of cholesterol, while the absence of this N-terminal repeat (1N4R and 0N4R Tau) resulted in the self-assembly of Tau into toxic amyloid fibrils. We also found that the presence of cholesterol in the lipid bilayers caused a significant increase in the cytotoxicity of 1N4R and 0N4R Tau to neurons. This effect was not observed for 2N4R Tau fibrils formed in the presence of lipid membranes with low, physiological, and elevated concentrations of cholesterol. Using molecular assays, we found that Tau aggregates primarily exert cytotoxicity by damaging cell endosomes, endoplasmic reticulum, and mitochondria.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indole and Coumarin Derivatives Targeting EEF2K in Aβ Folding Reporter Cells","authors":"Shun-Tzu Chi,&nbsp;Pei-Cih Wei,&nbsp;Ya-Jen Chiu,&nbsp;Te-Hsien Lin,&nbsp;Chih-Hsin Lin,&nbsp;Chiung-Mei Chen,&nbsp;Ching-Fa Yao,&nbsp;Wenwei Lin,&nbsp;Guey-Jen Lee-Chen,&nbsp;Kuo-Hsuan Chang","doi":"10.1111/jnc.16300","DOIUrl":"10.1111/jnc.16300","url":null,"abstract":"<div>\u0000 \u0000 <p>Misfolding and accumulation of amyloid-β (Aβ) in the brains of patients with Alzheimer's disease (AD) lead to neuronal loss through various mechanisms, including the downregulation of eukaryotic elongation factor 2 (EEF2) protein synthesis signaling. This study investigated the neuroprotective effects of indole and coumarin derivatives on Aβ folding and EEF2 signaling using SH-SY5Y cells expressing Aβ-green fluorescent protein (GFP) folding reporter. Among the tested compounds, two indole (NC009-1, -6) and two coumarin (LM-021, -036) derivatives effectively reduced Aβ misfolding and associated reactive oxygen species (ROS) production. Additionally, these compounds decreased acetylcholinesterase and caspase-3/-6 activities while promoting neurite outgrowth. NC009-1 increased active phosphorylation of extracellular-signal regulated kinase (ERK) (T202/Y204), leading to an increase in inactive eukaryotic elongation factor 2 kinase (EEF2K) phosphorylation (S366). LM-021 decreased the active phosphorylation of AMP-activated protein kinase (AMPK) (T172) and EEF2K (S398), while LM-036 exhibited dual effects, increasing inactive phosphorylation and decreasing active phosphorylation of EEF2K. These changes in EEF2K phosphorylation led to decreased EEF2K activity and a subsequent reduction in inactive phosphorylation of EEF2 (T56). This cascade further promoted the phosphorylation of transcription factor cAMP-response-element binding protein (CREB) (S133) and the expression of brain-derived neurotrophic factor (BDNF), and reduced BCL-2 associated X-protein (BAX)/B-cell lymphoma 2 (BCL2) ratio. Knockdown of EEF2 abolished the effects of NC009-1, LM-021, and LM-036 on CREB phosphorylation, BDNF expression, caspase-3 activity, and neurite outgrowth. These findings demonstrate that NC009-1, LM-021, and LM-036 exert their neuroprotective effects through modulation of EEF2K signaling, highlighting their potentials as therapeutic candidates for AD.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Glucocorticoid-Associated Stress-Like Conditions on Aquaporin-4 in Cultured Astrocytes and Its Modulation by Adenosine A2A Receptors","authors":"Liliana Dias,&nbsp;Ana Margarida Nabais,&nbsp;Vladimir P. P. Borges-Martins,&nbsp;Paula M. Canas,&nbsp;Rodrigo A. Cunha,&nbsp;Paula Agostinho","doi":"10.1111/jnc.16299","DOIUrl":"10.1111/jnc.16299","url":null,"abstract":"<div>\u0000 \u0000 <p>Astrocytes participate in brain clearance of extracellular proteins and metabolites, through the activity of the water channel aquaporin-4 (AQP4), which can be deregulated in stress-related disorders, impairing brain waste clearance. The present study investigates the impact of dexamethasone (Dexa), a synthetic glucocorticoid used as a simplified in vitro stress model, on astrocytic AQP4 and its modulation by adenosine A_2A receptors (A_2AR), which blockade reverses conditions related with maladaptive stress, such as anxiety and depression. The clearance of proteins in primary astrocytic cultures, assessed using 5 kDa FITC-dextran and 45 kDa TRITC-dextran uptake, was decreased by a 24 h exposure to 100 nM Dexa. The Dexa exposure decreased α-syntrophin density, a protein-targeting AQP4 to astrocytic processes, potentially affecting AQP4 location and, consequently, its activity. Accordingly, Dexa exposure decreased astrocytic water influx (assessed with calcein fluorescence), which paralleled the impairment of dextran clearance. The Dexa-induced decrease in extracellular protein uptake was prevented by the AQP4 activator TGN-073 and A_2AR antagonism with SCH58261, showing that the impairment of AQP4-mediated protein clearance was controlled by A_2AR in this Dexa-simplified <i>in vitro</i> stress model. Additionally, the effects of Dexa in AQP4 location and activity were prevented by SCH58261, confirming that A_2AR modulate AQP4 function. This conclusion was reinforced by the observed AQP4/A_2AR physical interaction in astrocytes. Overall, the data indicate that <i>in vitro</i> conditions related to stress affect the localisation of astrocytic AQP4 and its role in extracellular protein uptake, which was modulated by A_2AR. These findings unveil a novel therapeutic mechanism to prevent brain extracellular protein accumulation and associated neurological disorders by tinkering with AQP4 and A_2AR.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}