bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of glial cells in neuroinflammation in the context of Alzheimer’s disease
Authors: Ferreira Rafaella de Lima Corrêa , Heimfarth Luana , Ferreira Sergio T , Ribeiro Felipe C 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) stands as the predominant form of dementia worldwide. The pathogenesis of AD encompasses elevated brain levels of amyloid‐β oligomers (AβOs), recognized as central neurotoxins linked to AD. The accumulation of AβOs is neurotoxic, resulting in detrimental effects such as synapse loss, mitochondrial dysfunction, and impairment of proteostasis mechanisms. Neuroinflammation, particularly the activation of microglia and astrocytes to pro‐inflammatory states, has been implicated in the pathogenesis of various neurodegenerative diseases. This study aimed to investigate the role of microglia and astrocytes within the framework of AD pathophysiology.MethodHere, we explored changes in morphology and function of glial cells in experimental models of AD, assessing (1) in vitro activation of microglia and astrocytes induced by AβOs, and (2) in vivo microglia and/or astrocytic activation in mice receiving an intracerebroventricular (icv) infusion of AβOs. Analysis of cytokine expression and glial markers was conducted using qPCR, ELISA, and fluorescence microscopy.ResultInitial results suggest an upregulation of glial activation markers, such as GFAP and F4/80, and complement immune system markers such as C1q, seven days post icv infusion of AβOs. No significant differences were observed in TNF‐α expression. Immunofluorescence analyses further indicate heightened nuclear translocation of NFkB in microglia cultures exposed to AβOs for 3 hours.ConclusionThe results align with a pivotal role of glial cells in AD pathogenesis, showcasing activated glial activity in both in vitro and in vivo models. In the context of chronic processes, these cells may persist in an activated state, releasing cytokines, complement components, and chemokines, potentially contributing to Aβ production and accumulation, thereby exacerbating pathology.
APOE genotype modifies benefits of calorie restriction against aging
Authors: Qiao Wenhui , Chen Yixing , Ren Yingxue , Ikezu Tadafumi C , Johnson Stephen , Li Fuyao , Chen Kai , Pan Meixia , Kashyap Sonu , Bueser Katrina Rae , Wetmore Allison , Kurti Aishe I. , Meneses Axel D. , Owens Jada A. , Chini Eduardo N. , Chen Jun , Han Xianlin , Bu Guojun , Zhao Na 
Published: January 2025

AbstractBackgroundThe efficacy of Calorie Restriction (CR) in enhancing cognition, promoting healthy aging, and extending lifespan is well‐established. Yet, it remains unclear whether the apolipoprotein E (APOE) genotype, a known modifier for aging and age‐related disorders, influences the beneficial effects of CR in countering aging.MethodsTo investigate this question, we utilized humanized APOE mouse models, which express APOE2, APOE3, or APOE4 alleles systematically (refer to as E2, E3, and E4 mice). These mice were subjected to either ad libitum (AL) feeding or 30% CR feeding, starting from 12 months and continuing up to 20 months of age (N = 11‐20/ genotype /group, mixed sex). We monitored energy expenditure using the Comprehensive Laboratory Animal Monitoring System (CLAMS). Additionally, we evaluated anxiety levels and memory capabilities through various behavioral tests. Finally, we collected brain, blood, and feces samples for transcriptomic, lipidomic, and microbiomic analyses.ResultsCLAMS measurements showed that CR significantly decreased the metabolic rate in E3 and E4 mice, but not E2 mice, during the non‐feeding period of the CR group, compared to the AL group. Furthermore, CR reduced anxiety and enhanced associative memory in E3 and E4 mice relative to the AL group. Brain transcriptomics revealed that CR upregulated the cholesterol synthesis pathway, potentially improving myelination‐related pathways in E3 and E4 mice. This finding was further validated by the increased staining intensity of myelin basic protein (MBP) observed in E3 and E4 mice from an independent cohort. In contrast, these effects were not pronounced in E2 mice. Additionally, while CR’s impact on the brain lipid profile was minor across all APOE genotypes, it significantly altered blood lipid profile of E2 mice, with minimal changes observed in E3 and E4 mice. Finally, in microbiomics, CR led to notable changes in the abundance of Bifidobacterium species in E3 and E4 mice and Lactobacillus species in E2 mice.ConclusionsOur study highlights the role of APOE genotypes in modulating the diverse effects of CR on cognition, brain transcriptomics, lipid metabolism, and the microbiome, providing a crucial foundation for considering APOE genotypes in developing prevention strategies for aging and age‐related disorders.
TDP‐43 regulates the ubiquitination degradation of BMAL1, cellular glucoseutilization and energy absorption
Authors: Gu Jianlan , Zhang Liti , Yan Ruolan , Chu Dandan , Liu Fei 
Published: January 2025

AbstractBackgroundCircadian rhythm disorder is not only a characteristic of neurodegenerative diseases but may participate in driving the pathological development in early stages of these diseases. Transactive response DNA‐binding protein of 43 kDa (TDP‐43) knockdown and its pathological aggregation are associated with severe neurodegenerative diseases such as amyotrophic lateral sclerosis.MethodsC57BL/6 mice were sleep deprived and sarcrificed at ZT0, ZT6, ZT12, and ZT18 and detected by Western blots. M17 cells infected with Lenti/TDP‐43KO and then performed to RNA sequencing, and detected by qPCR to verify the RNA‐seq results. Mice were intracerebroventricular injected with AAV/shTDP‐43 and detected by Western blots and qPCR. HEK‐293T cells were transfected with TDP‐43, TDP‐43KO or treated with MG132 or cycoheximide and performed to immunoprecipitation and detected by Western blots.ResultsHerein we found that TDP‐43 expression exhibited rhythmic patterns and regulated the expression of multiple circadian genes such as BMAL1, CLOCK, CRY1, and PER2, particularly affecting the mRNA and protein levels of BMAL1; knockdown of TDP‐43 in mice brain also changed the autonomous circadian wheel behavior, cognitive and balance ability of the animal. Further, we discovered that TDP‐43 could at least regulate the expression and alternative splicing of USP13, thereby affecting the protein level of USP13 and the ubiquitin‐mediated degradation of BMAL1 and regulated the AMPK signaling pathway, resulted in changing the cellular glucose uptake and ATP production.ConclusionOur findings would expand the understanding of the role of TDP‐43 dysfunction in circadian rhythm disruption in neurodegenerative diseases and provide new mechanistic evidences supporting the interaction between circadian rhythm disruption and neurodegeneration.
Neuroprotective Effect of Inosine Against Rotenone Induced Motor deficit & Biochemical Abnormalities in Wistar Rats
Authors: Singhal Manmohan , Agrawal Mohit , Chaudhary Hema 
Published: January 2025

AbstractBackgroundParkinson’s disease is a hypokinetic disorder characterized by selective loss of dopaminergic in substantia nigra pars compacta (SNPc) region of mid‐brain. Dopaminergic degeneration of neurons is considered to be due to oxidative stress, neuroinflammation, neurons mitochondrial dysfunction and glutamate excitotoxicity etc. Inosine a purine nucleoside has been reported to produce anti‐oxidant, anti‐inflammatory and neuromodulatory actions in previous studies. In the current study we have investigated the role of Inosine against rotenone induced motor deficit and biochemical abnormalities in Wistar ratsMethodRats were treated with 1.5mg/kg rotenone subcutaneously for 35 days. Inosine (50,100 and 200 mg/kg i.p.) was administered after 30 minutes of rotenone administration from day 7th to 35th day. Rotenone caused significant reduction in motor functions and body weight and produced elevation in striatal oxidative burden. The biochemical analysis revealed that there is reduction in the level of anti‐oxidants (GSH, Catalase, SOD) in the animals following rotenone administration. Whereas inosine treated rats were stable and regained their body weight.ResultIn addition inosine significantly attenuated rotenone induced motor deficit and striatal oxidative stress. Outcomes of the current study suggest neuroprotective potential of inosine and its ability to correct movement disability and thus could prone to be useful candidate molecule in the management of motor disorders.ConclusionOutcomes of the current study suggest neuroprotective potential of Inosine and its ability to correct movement disability and thus could prove to be useful candidate molecule in the management of motor disorders.
Exploring the neuroprotective role of ubiquinone by attenuation of oxidative stress and mitochondrial dysfunction in an experimental model of myalgic encephalomyelitis/chronic fatigue stress
Authors: Vashishth Anushka 
Published: January 2025

AbstractBackgroundMyalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is categorized as a complicated disorder of extreme fatigue lasting for at least six months without any underlying medical problem and currently has no concrete treatment regimen. This is associated with neurological complications like brain fog, insomnia, psychiatric disturbances and above all neuroinflammation. A chronic forced swim test model of CFS has been established since more than a decade at our laboratory. An important biomarker in CFS is reduced levels of ubiquinone that leads to oxidative stress in neurons, thus impairing neurodevelopment, and ultimately learning and memory.MethodA 15‐day chronic forced swim daily for 6 minutes induce CFS symptoms in mice. The neurobehavioral studies consist of assessment of locomotor activity, anxiety, motor coordination, cognitive dysfunction in addition to biochemical parameters of catalase, acetylcholinesterase, reduced glutathione, superoxide dismutase, lipid peroxidation and nitrite levels in cortex & hippocampus of mice brain. Histopathological analysis of differences between control and treatment groups was also conducted. Mitochondrial enzyme complex (1‐1V) was done to evaluate mitochondrial dysfunction. An additional in vitro study was conducted using PC12 cell lines to study ROS generation and DNA damage following cell viability in an H202 induced oxidative stress model.ResultTreatment with ubiquinone showed a positive impact by significantly improving the behavioral, biochemical, and cellular parameters of stress after reversing the imbalance between free radicals and anti‐oxidants which is attributed to its anti‐oxidant nature. Histopathological analysis showed significant neuronal loss in diseased group (darkly stained neurons with fragmented or no nucleus and few of the cells were shrunken or sickle shaped and with altered morphology) as compared to naïve group that showed improvement on drug treatment. Results of in vitro were consistent with above findings.ConclusionAs per available literature, this study successfully adds to the potential of ubiquinone as a treatment strategy for neurodegeneration. In an experimental model of CFS for evaluation of neurobehavioral, biochemical, and cellular changes to mitigate neuroinflammation, ubiquinone exhibits its role to be used further in research for severe neurodegenerative disorders like AD and PD. With more research this could lead to a safer and cost‐effective drug target.
Genotyping transposable element insertions and their novel application in gene mapping strategies for Alzheimer’s disease (AD) endophenotypes
Authors: Sargurupremraj Muralidharan , Yang Qiong , Jian Xueqiu , Himali Jayandra J. , Seshadri Sudha 
Published: January 2025

AbstractBackgroundConsortium‐wide studies of volumetric brain imaging measures with single‐nucleotide polymorphisms (SNPs) have revealed numerous disease‐risk SNPs and emphasized the significance of brain imaging phenotypes as preclinical markers (endophenotypes) for Alzheimer’s disease (AD). Nevertheless, the bulk of these risk variants are in genomic regions that govern multiple genes, posing major challenges in fine‐mapping strategies. Evolutionarily conserved transposable elements are master regulators of gene expression, and by studying these endogenous gene regulatory units in relation to AD endophenotypes, we aimed to better identify the disease‐causal gene.MethodWithin the Trans‐Omics for Precision Medicine Program (TOPMed) initiative, whole‐genome sequencing data (WGS) of the Framingham Heart Study individuals were used for genotyping polymorphic transposable element insertions (pTEIs). Fitting a whole‐genome regression model, we tested the association of the genotyped pTEIs with brain‐imaging measures (N = 2,472) (white matter hyperintensity, WMH; hippocampal volume, HV; total‐brain volume, TBV) and general cognitive function, GCF (N = 2,765). We performed i) single‐variant analyses (minor allele frequency ≥ 1%) and ii) region‐based burden tests per gene collapsing rare pTEIs overlapping with canonical transcripts and regulatory marks. We examined the colocalization evidence between the pTEIs and SNPs identified in genome‐wide association studies (GWAS) for our traits of interest, thus enhancing the fine‐mapping of disease‐risk SNPs.ResultBy studying the polymorphic nature of TE insertions in relation to brain‐imaging and cognitive traits, we identify evidence for multiple putative disease‐causal genes, albeit suggestive. Notably, this includes genes (BACH2, SPATA5) implicated in autoimmune and neurodevelopmental disorders, now showing pTEI‐based predisposition to cognitive decline and hippocampal atrophy. WMH and TBV risk SNPs exhibit colocalization evidence with pTEIs involved in the feature elongation of ECHDC3 and CRHR1, respectively, potentially leading to loss of gene function. Interestingly, the inclusion of ECHDC3 gene loss‐of‐function variants in burden test analysis (UK Biobank) shows association with brain maturation and ageing markers.ConclusionOur pragmatic approach using existing WGS data to genotype endogenous regulatory units for studying genetic underpinnings of preclinical AD markers identifies putatively novel disease‐causal genes with clear biological function. As a proof of concept, our approach highlights the scope of extending to other cohorts and AD related neurodegenerative disorders.
Selective Vulnerability of hippocampi for inducible nitric oxide synthase and 3‐nitrotyrosine in Alzheimer’s disease: A Postmortem Study
Authors: Justo Alberto Fernando Oliveira , Toscano Eliana Cristina de Brito , Paes Vitor Ribeiro , Leite Renata Elaine Paraizo , Pasqualucci Carlos Augusto , Jacob‐Filho Wilson , Nitrini Ricardo , Grinberg Lea T. , Suemoto Claudia Kimie 
Published: January 2025

AbstractBackgroundNitric oxide (NO) is involved in synaptic transmission and cerebral plasticity, playing a role in the memory process. However, in states of brain inflammation, hypoxia, or ischemia, there is induction of inducible nitric oxide synthase (iNOS) expression by astrocytes and pyramidal cells in the brain. Under conditions of chronic activation, there is a decoupling of iNOS dimers, leading to a massive generation of superoxide anion and peroxynitrite, O2.‐ and ONNO‐ respectively, with a significant neurotoxic role by oxidative stress. We aimed to quantify the expression of iNOS and 3‐nitrotyrosine (3‐NT, an oxidative marker of ONNO‐) in the hippocampus of individuals with AD neuropathological changes (ADNC)compared to individuals without AD pathology and investigate the association of iNOS and 3‐NT expression with cognition abilities and AD pathology.MethodWe evaluated the expression of the enzymes iNOS and 3‐NT using immunohistochemistry in the cornu ammonis (CA) and dentate gyrus from hippocampi from subjects with ADNC and the sex‐matched controls. Cognitive abilities were evaluated using the Clinical Dementia Rating (CDR) and AD pathology using Braak staging for neurofibrillary tangles and the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) for neuritic plaque. We used linear regression to examine the association of iNOS and 3‐NT with cognition and AD pathology.ResultSociodemographic and clinical variables were similar between the control and ADNC groups (Table 1). In individuals with ADNC, iNOS was overexpressed in the CA1 (p = 0.029) and CA3 (p = 0.030). Similarly, 3‐NT was overexpressed in CA3 (p = 0.039), shown in Figure 1. No expression was seen in the dentate gyrus for iNOS and 3‐NT. Increased levels of iNOS in CA3 were associated with AD pathology reported in CERAD score (β = 12.44, IC95% = 0.88;24;00, p = 0.036) and Braak staging (β = 25.48, IC95% = 6.12;44.84, p = 0.012), and with cognitive abilities (β = 73.05, IC95% = 29.25;149.90, p = 0.025). Increased 3‐NT levels in CA3 were associated only with cognitive abilities (β = 1.48, IC95% = 0.08;2.87, p = 0.038) (Table 2).ConclusionCA3 neurons shows a particular susceptibility to accumulate iNOS and 3‐NT during AD progression. The association between iNOS and functional cognition underscore the role of oxidative stress in AD pathogenesis. Of note, CA2 sector, a resistant region to AD showed no signs of oxidative stress in AD.
The signaling function of CHI3L1/YKL‐40 in neuroinflammation and Alzheimer’s disease
Authors: Huang Yu‐Wen Alvin 
Published: January 2025

AbstractBackgroundChitinase‐3‐like protein 1 (CHI3L1, or YKL‐40) is an important regulator of immunity and, in the brain, is primarily secreted by activated astrocytes and heralds a neurotoxic inflammatory state. While it has been well known as a high‐profile biomarker for Alzheimer’s disease (AD) and inflammatory brain conditions (e.g., aging, trauma and autoimmune disorders), the biological role of CHI3L1 in neuroinflammation and AD pathogenesis remains to be elucidated.MethodWe used a combination of in‐vitro and in‐vivo tools to recapitulate and manipulate CHI3L1 secretion in neuroinflammation, including i) cultures of primary mouse astrocytes and iPSC‐derived human neurons and neural stem cells (NSCs), and ii) established mouse models of astrocyte‐specific Chi3l1/Chil1 conditional knockout, Alzheimer’s disease (5xFAD) and the autoimmune‐mediated, primary astrocytopathy (neuromyelitis optica, NMO) hallmarked by CHI3L1 induction.ResultWe first confirmed the induction of CHI3L1 and neuroinflammatory features in cultured astrocytes activated by well‐characterized pro‐inflammatory stimuli, including the cytokine IL‐1b, amyloid‐b peptides (Ab42) and the autoantibody targeting astroglial protein aquaporin 4 (AQP4 IgG, as in NMO). Strikingly, astrocyte‐secreted CHI3L1 inhibited proliferation and neuronal differentiation of NSCs, and enhanced Ab production, tau phosphorylation and apoptosis in differentiated neurons in vitro. In vivo, we analyzed brain tissues from mice overexpressing CHI3L1 or receiving stereotaxic transfer of AQP4 IgG, and observed a significant reduction in adult hippocampal neurogenesis and defective learning behaviors as in 5XFAD mice; such in‐vivo defects, of note, can be rescued by CHI3L1 depletion in astrocytes, as demonstrated in our compound AD transgenic mice of astrocyte‐specific CHI3L1 knockout. We further characterized the molecular mechanism of CHI3L1 by identifying the receptor and downstream pathway in NSCs. Mechanistically, CHI3L1 engages the CRTH2 receptor and dampens β‐catenin signaling, which is critical for neurogenesis. Finally, we showed that this CHI3L1/CRTH2/β‐catenin cascade can be targeted to restore neurogenesis and ameliorate cognitive deficits resulting from neuroinflammation.ConclusionOur findings provide the pioneering evidence for the biological role of CHI3L1 in the brain, departing from its long‐regarded role as merely a biomarker. The discoveries we made here would be highly advantageous for the development of much‐needed therapeutics to prevent neuroinflammatory toxicity in AD and relevant brain disorders.
Microglial Activation Alters Chromatin Accessibility of AD‐Associated Transcription Factors
Authors: Chatila Zena K , Mares Jason , Vardarajan Badri N. , Elyaman Wassim , Menon Vilas , Bradshaw Elizabeth M 
Published: January 2025

AbstractBackgroundWhile dysregulated local innate immunity and microglial dysfunction are thought to play a pathogenic role in Alzheimer’s disease (AD), the underlying mechanisms remain unclear. Importantly, activation of immune and metabolic pathways in myeloid cells can lead to a functional reprogramming process, termed innate immune memory (IIM), in which the response to an initial stimulus shapes long‐lasting epigenetic modifications that alter the response to future inflammatory stimuli. This epigenetic imprinting process has been minimally studied in microglia. We posit that immune activation may result in epigenetic reprogramming which contributes to sustained microglial dysfunction as a pathogenic mechanism in AD.MethodWe treated an in vitro primary monocyte‐derived microglial model with a range of activators of specific innate immune receptors, disease‐associated stimuli, and pathogens. We investigated whether any of these stimuli induce epigenetic remodeling using single nucleus RNA‐and ATAC‐sequencing after a washout and seven‐day rest period, and probed for alterations in AD‐associated molecular pathways. We compared the rewired epigenetic signatures we observed to ATAC‐sequencing data from human microglia from post‐mortem AD brain tissue.ResultWe found that three stimuli in particular resulted in unique remodeled chromatin signatures: E. coli LPS (TLR4 activator), CpG ODNs (TLR9 activator), and HSV‐1 infection. Motif enrichment identified binding sites of AD‐associated transcription factors within the differential chromatin peaks remodeled by these stimuli. For example, TLR9 activation with CpG ODNs altered chromatin accessibility of MEF2A and MEF2C binding sites, transcription factors that have been genetically associated with AD. We identified that features of the unique chromatin signatures associated with these stimuli overlap with post‐mortem microglial chromatin configuration from human AD brain tissues. Lastly, we identified the functional consequences of microglial IIM induced by these three primary stimuli upon delayed secondary stimulation, including altered cytokine response.ConclusionMicroglial activation by specific inflammatory stimuli causes epigenetic rewiring, resulting in differential accessibility of AD‐associated transcription factors and altered response to future stimuli. In this way, microglial activation and IIM may later contribute to microglial dysfunction in AD pathogenesis.