bluuebunny/crossref_metadata_2025_split huggingface dataset:
3‐O Sulfated Heparan Sulfate as an Emerging Drug Target and Biomarker for Alzheimer’s Disease
Authors: Wang Chunyu , Liu Jian , Wang Lianchun , Mah Dylan , Zhang Fuming 
Published: January 2025

AbstractBackgroundHeparan sulfate (HS) interacts with many important proteins. These interactions are primarily driven by electrostatics, with specificity determined by sulfation patterns. Although 3‐O‐sulfation is a rare modification in HS, several genome‐wide association studies (GWAS) revealed that the Hs3st1 gene, encoding HS‐3‐O‐sulfotransferase‐1, is significantly linked to late onset AD risk.MethodNMR, SPR, glycan array were used to study HS‐protein interactions. A novel LC‐MS/MS method was developed to quantify the low abundance 3‐O‐sulfated HS from human brain, with 13C labeled calibrants. Alexa‐488 labeled Tau and ApoE was used to assess tau cell surface binding and uptake in HS3ST‐1 knockout cellular lines.ResultWe have demonstrated that tau, the major component of neurofibrillary tangles, specifically recognizes the 3‐O‐sulfation (3‐OS). In addition, ApoE, whose isoform ApoE4 is the most significant genetic risk factor for late onset AD, also interacts with 3‐OS. In addition, the affinity between ApoE isoform and heparin correlates with AD risk, with ApoE4 having the highest affinity to heparin, while the protective ApoE2 and Christchurch having significantly lower affinity. With a novel LC‐MS/MS method for quantifying 3‐O‐sulfation, our recent studies have further demonstrated a marked increase in 3‐O‐sulfated HS in AD brains.ConclusionTaken together, our findings underscore the importance of 3‐OS in AD pathogenesis, suggesting its potential as a novel drug target and biomarker in Alzheimer’s disease.
Impaired mechanisms of context encoding in APP/PS1 mice are rescued by increasing cerebral blood flow
Authors: Berkowitz Laura E , Todorova Ralitsa , Cabus Dana I , Letendre Jack T , Tehrani Natalie , Shimizu Jean‐Luc , Dong Xuelai , Oliva Azahara , Fernandez‐Ruiz Antonio , Nishimura Nozomi , Schaffer Chris B 
Published: January 2025

AbstractBackgroundSpatial disorientation is an early symptom of Alzheimer’s disease (AD). The hippocampus creates a cognitive map, wherein cells form firing fields in specific locations within an environment, termed place cells. Critically, place cells remain stable across visits to an environment, but change their firing rate or field location in a different environment. In rodent models of AD‐like pathology, place cells exhibit broadened tuning and altered responses to environmental changes. Additionally, events known as sharp wave ripples (SWRs), coordinate the firing of hippocampal neurons, including place cells, and are disrupted in mouse models of AD. Our lab found that increasing cerebral blood flow (CBF) with anti‐Ly6G antibody treatment improved performance on spatial memory tasks. Here, we investigate the effect of increased CBF on neural mechanisms associated with cognitive map stability across contexts.MethodWe investigated the association between CBF and cognitive map stability in 7‐9‐month‐old APP/PS1 mice and wild‐type controls by recording neural activity in hippocampus area CA1 using 64‐channel silicon probes. Mice were recorded as they explored open field arenas with differing environmental contexts, A and B. Place cells were identified as neurons with significant spatial information in their firing rate maps. Local field potential recordings from pyramidal and stratum radiatum layers of CA1 were used to detect awake‐SWRs (aSWRs).ResultPlace cells from APP/PS1 mice did not exhibit higher place field correlations within contexts (AA' or BB'), as compared to between (AB) contexts, suggesting these different contexts are not differentially encoded (Figure 1). In contrast, wild‐type control mice showed higher within context correlation (Figure 1). APP/PS1 mice also had a reduced rate and duration of aSWR compared to controls (Figure 2). Following treatment with anti‐Ly6G antibodies, both context discrimination by place cells and duration of aSWR increased in APP/PS1 mice (Figure 2).ConclusionThese results highlight the association between place cell stability and subsequent aSWR dynamics as a potential mechanism contributing to an impaired cognitive map in AD. Importantly, the rescue of behavioral features and aSWR physiological properties following anti‐Ly6G antibody treatment suggests that increasing CBF may be a candidate therapy to mitigate spatial memory impairments in AD.
The P301L tau mutation alters extracellular vesicle biogenesis in astrocyte and contributes to astrocyte‐mediated tau pathology in a human iPSC‐derived model of tauopathies
Authors: You Yang , Mann Sean D , Lu Wenyan , Poon Wayne W. , Ikezu Seiko , Kanekiyo Takahisa , Dickson Dennis W. , Sławek Jarosaw , Wszolek Zbigniew , Ikezu Tsuneya 
Published: January 2025

AbstractBackgroundTauopathies are a group of neurodegenerative disorders which are characterized by the accumulation of abnormal tau protein in the brain. However, the mechanistic understanding of pathogenic tau formation and spread within the brain remains elusive. Astrocytes are major immune reactive cells in the brain and have been implicated in exacerbating tau pathology by releasing extracellular vesicles (AEVs) containing pro‐inflammatory cytokines and chemokines upon activation. Our prior investigation revealed a significant association between AEVs and tau pathology development, as well as cognitive function, by analyzing brain‐derived EV proteins from AD patients. In this study, we explore the potential roles of AEVs in tau pathogenesis using a human induced pluripotent stem cell (iPSC) model.MethodWe obtained two male P301L tau mutant iPSC lines from a Polish family with frontotemporal dementia. By including two male control lines, these iPSCs were differentiated into astrocytes (iAs) and characterized by immunocytochemistry and subjected for bulk RNAseq. Bioinformatics analysis was conducted to compare the transcriptome profile between wild‐type (WT) and P301L iAs. EVs from WT and P301L iAs were isolated by ultracentrifugation combined with size exclusion chromatography. Characterization of WT and P301L iAEVs involved nanoparticle tracking analysis, nano‐flow cytometry and super‐resolution microscopy.ResultWe successfully differentiated WT and P301L mutant iPSC lines into astrocytes with >99% purity. P301L iAs displayed distinctive astrocyte reactivity compared to WT cells, with elevated levels of pan‐reactive astrocyte genes (e.g., GFAP, CD44) and decreased expression of neuroprotective A2 astrocyte‐specific genes (e.g., TM4SF1, PTGS2). Additionally, gene enrichment set analysis of RNAseq data revealed dysregulation in the endo‐lysosomal pathway and extracellular matrix in P301L iAs compared to WT iAs. The count of intraluminal vesicles marked by CD9+ were reduced in P301L iAs compared to WT cells. Moreover, we observed a significant increase in the internalization of Tau by P301L iAs compared to WT iAs following incubation with preformed Tau fibrils, resulting in an augmented release of tau‐containing EVs from P301L iAs.ConclusionOur findings suggest a potential alteration in EV biogenesis in P301L iAs, potentially contributing to astrocyte‐mediated tau pathology. Future investigations will focus on understanding how AEVs contribute to tau propagation and accumulation.
Neuropsychological test performance in mild cognitive impairment with Lewy bodies: a meta‐analysis
Authors: Wyman‐Chick Kathryn A , Bayram Ece , Gravett Stephanie , D'Antonio Fabrizia , Kane Joseph PM , Rodriguez‐Porcel Federico , Olson‐Bullis Barbara A , Bonanni Laura , Ferreira Daniel 
Published: January 2025

AbstractBackgroundProdromal dementia with Lewy bodies (DLB) research criteria were recently published and further work is needed to characterize the neuropsychological profile and refine clinical criteria. We performed a meta‐analysis to compare the cognitive performance of mild cognitive impairment with Lewy bodies (MCI‐LB) groups to controls, MCI due to Alzheimer’s disease (MCI‐AD), and DLB.MethodFollowing PRISMA guidelines, we searched the literature for 1) English‐language studies on MCI‐LB; 2) published January 1990‐March 2023, 3) with ≥1 standardized cognitive measure; and 4) comparison data from controls, MCI‐AD, and/or DLB. Pooled means with 95% confidence intervals were calculated for demographics. Effect sizes were calculated for group comparisons on cognitive domains. Random effects meta‐analysis models were used for group comparisons.ResultThere were 3440 participants from 27 studies across 10 countries. Mean age did not differ between groups. The percentage of female subjects was lower in the MCI‐LB group than the MCI‐AD group. Mean years of education for the MCI‐LB group was lower than the controls, but similar to MCI‐AD and DLB groups (Table 1). Compared to controls, the MCI‐LB group had lower scores for the global screening, executive function, visuospatial, language, learning, and memory domains. Compared to MCI‐AD, MCI‐LB performed better on learning and delayed recall, but similarly across other domains. Compared to DLB, MCI‐LB had better scores for global screening, executive function, language, and delayed recall (Table 2). Recognition for MCI‐LB vs. MCI‐AD; visuospatial, learning, and recognition for MCI‐LB vs. DLB could not be assessed, as fewer than 3 studies reported this data.ConclusionCognitive measures can help differentiate MCI‐LB from controls and DLB. Neuropsychological measures of learning and memory may be required to discriminate MCI‐LB from MCI‐AD in clinical practice but global screening measure scores appear insufficient in this regard. High heterogeneity across MCI‐LB studies highlights the need for harmonized neuropsychological research protocols.
Extracellular‐Vesicle mediated pyroptosis leads to gut‐brain axis after stroke in a mouse model of Alzheimer’s Disease
Authors: Kerr Nadine A , Higueras Alfredo Fernandez , Sanchez‐Molano Juliana , Walters Winston , Vaccari Juan Pablo de Rivero , Keane Robert W , Bramlett Helen M , Dietrich W Dalton 
Published: January 2025

AbstractBackgroundStroke and AD patients with gut complications often present worsened neurological outcomes. The goal of this study was to examine the role of extracellular vesicle (EV)‐mediated pyroptosis in the bi‐directional gut‐brain axis after photothrombotic stroke (PTS) in aged 3xTg mice and wildtype (WT) controls.MethodTwelve‐month 3xTg and WT male and female mice underwent PTS using a YAG laser. Lesion volume analysis was performed at 1‐month post‐PTS. At 24 hours after PTS, intestinal and cortical tissue was collected for Western Blot analysis for the following inflammasome proteins: caspase‐1, apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC), interleukin‐1b, and Gasdermin‐D (GSDMD). Additionally, brain and intestines were sectioned for immunohistochemical analysis of GSDMD and Amyloid‐Beta (Ab). In order to show changes in gut function, gut permeability was measured 72 hours post PTS using a FITC‐dextran assay. Moreover, we performed an adoptive transfer in which stool‐derived EVs collected from 3xTg‐ PTS and WT‐PTS mice were injected into naïve 3xTg and WT mice. Cortical lysates were examined for expression of inflammasome proteins, GSDMD, and Ab using Western Blot analysis.Results3xTg mice presented increased infarct volume compared to WT‐PTS mice one month after PTS. Based on Western blot analysis, we found that inflammasome proteins, GSDMD, and Ab were significantly increased in both intestinal and cortical tissue in 3xTg‐ PTS mice compared to WT‐ PTS mice at 24 hours post‐stroke. Results from the FITC‐Dextran assay showed that gut permeability was significantly increased in the aged 3xTg‐PTS mice compared to WT‐ PTS mice 72 hours post‐PTS. Additionally, our immunohistochemical analysis in both WT and 3xTg PTS mice presented evidence of activated/ameboid microglial morphology as well as the presence of GSDMD and Ab in the brain and intestines 72 hours after stroke. Lastly, we demonstrated increased levels of inflammasome proteins, GSDMD, and Ab after adoptive transfer.ConclusionTaken together these results indicate an important role for EV signaling and pyroptosis in disruption of the bidirectional gut‐brain axis after stroke in aged 3xTg mice in an animal model of stroke.
Intermittent cold exposure reversed high‐fat diet‐induced metabolic and cognitive dysfunctions in mice
Authors: Barros Wellinghton de Medeiros , Bellozi Paula Maria , Bezerra Maria Luiza Soccio , Domingues Daniel , Garcia Pereira Louise Tavares , Goulart Jair Trapé , Amato Angélica Amorim , de Bem Andreza Fabro ,   Laboratory of Bioenergetics and Metabolism – Department of Physiological Sciences, University of Brasília – Brasília/DF, Brazil
Published: January 2025

AbstractBackgroundRecent research has demonstrated that the consumption of high fat diet (HFD) can lead to metabolic dysfunctions and cognitive impairments in both mice models and humans. Given the potential negative effects of HFD, it is crucial to explore non‐pharmacological alternatives that can serve as a potential treatment for both metabolic dysfunctions and behavioral effects induced by HFD. Therefore, the aim of this study is to assess the impact of chronic and intermittent exposure to cold temperature on the metabolic and cognitive changes associated with HFD consumption.MethodsMale and female C57Bl/6 adult mice were divided into 8 groups exposed to different diets and temperature conditions (HFD or control diet (CD) and, cold (4oC) or room temperature (RT) (22oC) exposure for 10 weeks). The ∆ of body mass, brown adipose tissue (BAT) temperature and oxygen consumption as well as behavior were evaluated after the experimental period.ResultsHFD increased the body mass in females (CD+RT x HFD+Cold p = 0.02) and males (CD+RT x HFD+RT p < 0.0001), however, cold exposure was able to reverse this metabolic outcome (male HFD+RT x HFD+Cold p = 0.01). Cold exposure increased BAT temperature (female: CD+Cold x HFD+RT p = 0.0005; male CD+RT x CD+Cold p = 0.0005, CD+RT x HFD+Cold p = 0.024, HFD+RT x HFD+Cold p = 0.035). Regarding oxygen consumption, UCP‐1‐linked respiration decreased in the female mice fed a HFD (CD+RT x HFD+RT p = 0.04), however, cold exposure reverted this effect (HFD+RT x HFD+Cold p = 0.03). Interestingly, we observed that the consumption of HFD caused recognition memory deficits in both female (p = 0.0728) and male (p = 0.51) mice that were reversed by cold exposure (female: p = 0.04, and male: p = 0.002).ConclusionsWith the present data we can infer that cold exposure can increase the activity of BAT, thereby mitigating the harmful effects of HFD on cognition and metabolism. In summary, chronic and intermittent cold exposure has proven capable of attenuating the deleterious metabolic and cognitive effects induced by HFD consumption in mice.
Utilizing Latent Dirichlet Allocation and Differential Abundance to Identify Microbial Communities in both the Oral and Fecal Microbiome Associated with Alzheimer’s Disease
Authors: Huang Ziyuan , Zeamer Abigail L , Ward Doyle , Jo Cynthia , Bucci Vanni , Haran John P 
Published: January 2025

AbstractBackgroundSeveral studies have found that oral and gut microbiome and their byproducts can impact Alzheimer’s Disease (AD). The objective of our study is to analyze metagenomic sequencing data from paired oral and fecal microbiomes, along with clinical variables, to identify communities of bacteria associated with AD. This research aims to improve our understanding of the microbiome community matrix, and how these communities interact and correlate with AD status compared to healthy controls (HC) through an oral‐gut microbial axis.MethodThe study includes 223 HC and 43 individuals with AD. During each visit, paired oral and fecal samples were collected, along with clinical variables. Metagenomic profiling was done on all samples. Latent Dirichlet Allocation (LDA) was applied to identify differences in microbial species groups between these two body sites in realtion to AD status. LDA is used as a topic modeling method to uncover the complex structure and function of microbial communities. Subsequently, differential abundance (DA) analysis was performed to identify species with differential abundance at each body site.ResultWe identified microbiotal communities sharing similar characteristics and pinpointed representative bacteria within these communities that are highly relevant to AD. Within the oral microbiome, we have identified 27 topics, including several bacteria that are highly relevant to AD. These included Alistipes (beta = 3.919232e‐01), Paraprevotella xylaniphila (beta = 1.227791e‐01), Desulfovibrio (beta = 6.013213e‐02), and Lachnospiraceae (beta = 2.304369e‐02). In the gut, we have identified 50 topics, reflecting the gut is more complex the oral microbiome. Notable bacteria in the gut microbiome include Actinomyces oricola (beta = 6.959554e‐01), Roseburia (beta = 8.861444e‐02), Bacteroidetes (beta = 5.010610e‐01), and Actinomyces gerencseriae (beta = 3.048668e‐02).ConclusionOur study has identified a variety of bacteria that exhibit novel community patterns that associate with AD. In the gut, A. gerencseriae and other oral microbiomes were observed in AD patients. Also, the microbial communities differ between AD and HC. Thereforth, we conclude that translocation of oral and gut microbiota may contribute to AD through an oral‐gut‐microbiome axis.
Induction of VCID via hyperhomocysteinemia leads to vision and retina changes in mice
Authors: Weekman Erica M. , Rogers Colin B , Sudduth Tiffany L. , Wilcock Donna M. 
Published: January 2025

AbstractBackgroundDiagnosis of Alzheimer’s disease (AD) via MRI is costly and can be limited by regional availability. With the recent advancements and discovery of amyloid in the retina, diagnosis of AD and the effect of AD pathology on the retina is becoming well characterized. However, the prevalence of vascular contributions to cognitive impairment and dementia (VCID) and its effects on the retina are less well known. With the retina being a highly vascularized tissue and the considerable overlap of AD with VCID, it is imperative to understand the effect of VCID on vision.MethodWe placed 6‐month‐old mice on a diet deficient in B vitamins and enriched in methionine to induce hyperhomocysteinemia (HHcy). HHcy is a risk factor for VCID, stroke and AD, and has been well characterized in our lab. After 14 weeks on diet, mice underwent the Visual‐Stimuli 4‐arm Maze (ViS4M) to identify visual and cognitive abnormalities. After behavior, brains and eyes were harvested with the left eye fixed in 4% PFA for 24hrs and the right eye flash frozen for RNA extraction. The fixed retina was flat mounted and stained for vessels, GFAP, and IBA‐1 and the flash frozen retina was used for RNA isolation and NanoString analysis.ResultOver the seven days the mice were tested on the ViS4M, the mice on the HHcy diet showed impaired cognition and altered colored arm entries compared to control mice. HHcy mice made more 2 arm alternations than 3 or 4 arm alternations, suggesting diminished exploration. When we determined their arm transitions, we saw that the HHcy mice tended to avoid the blue arm, suggesting sensitivity to blue light. In the retina, we saw slightly less vessel volume in the HHcy diet mice along with reduced coverage of vessels by microglia and astrocytes combined.ConclusionThe high prevalence of VCID with AD along with the impact of AD pathology on the eye makes it critical to understand the effect of VCID on the retina. In our model of HHcy induced VCID, we determined that HHcy does impair both cognition and vision and affects vessels within the retina.
Genetic Deletion of the Presinilin‐Like Peptidase SPPL2B Significantly Reduces Neuroinflammation and Halts Production and Plaque Deposition in Pre‐Clinical Models of Alzheimer’s Disease
Authors: Badman Jack , Chen Gefei , Garcia Sandra Pérez , Nilsson Per , Tambaro Simone 
Published: January 2025

AbstractBackgroundSignal Peptide Peptidase‐Like 2b (SPPL2b) is relevant for AD, being a brain‐specific intramembrane protein involved in the cleavage of Alzheimer’s disease (AD)‐related proteins, such as BRI2, inflammatory‐related proteins like CD74, TNFalpha, and Clec7a, and synaptic proteins Neuregulin‐1 and VAMP 1‐4. SPPL2b is specifically expressed in the hippocampus and cortex. The cleavage of TNFalpha by SPPL2b promotes the inflammatory pathway. Conversely, the SPPL2b substrate BRI2 regulates amyloid precursor protein (APP) cleavage and subsequent Aβ production. This work explores the pathophysiological role of SPPL2b in AD pathogenesis and investigates the potential of inhibiting SPPL2b activity as a novel therapeutic strategy.MethodTo characterize the role of SPPL2b in the APP cleavage process and neuroinflammation, we used neurons and glia primary cell cultures from WT and SPPL2b‐deficient mice. Furthermore, we assessed the therapeutic potential of inhibiting SPPL2b by employing a new AD mouse model generated through crossbreeding state‐of‐the‐art AppNL‐G‐F knock‐in mice with SPPL2b‐deficient mice. Cells and mouse brain samples were analyzed through western blotting, immunoprecipitation, and immunofluorescence. Aβ levels were quantified using ELISA kits.ResultThe results showed a significant increase in BRI2, followed by a substantial reduction in soluble APP, Aβ40, and Aβ42 levels in the conditioned media of SPPL2b KO neurons. Immunoprecipitation of BRI2 from the cortex of those mice revealed an increased interaction between BRI2 and APP in SPPL2b KO/AppNL‐G‐F mice. Most importantly, a notable decrease in brain Aβ plaque deposition and a significant decrease in both cortical and hippocampal gliosis were observed at 4 months‐of‐age in SPPL2b KO/AppNL‐G‐F mice.ConclusionThe results outlined in this study support a relevant connection between SPPL2b and the development of Aβ pathology in AD. In a global scenario characterized by the need to identify novel strategies to prevent and counteract AD progression, this study highlights and strengthens the importance of SPPL2b as a novel therapeutic approach for AD.