bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic thymulin overexpression mitigates cognitive and molecular impairments in a rat model of sporadic Alzheimer’s Disease
Authors: Peralta Facundo , Escobedo Ana Abril Vidal , Hanotte Juliette López , Pardo Joaquín , Reggiani Paula Cecilia 
Published: January 2025

AbstractBackgroundSporadic Alzheimer’s Disease (sAD) is the most prevalent progressive neurodegenerative disease worldwide, without a cure. We propose to investigate therapies that contribute to the current state of this problem using a model of sAD in rats based on a single intracerebroventricular (icv) injection of streptozotocin (STZ). In this sense, thymulin (originally known as serum thymic factor, FTS), a thymic peptide, emerges as a potential therapeutic agent due to its proven anti‐inflammatory effects. Since the cerebral hippocampus (hc) is one of the key vulnerable areas in sAD, our study focuses on the analysis of this region.MethodWe used an adenoviral vector (RAd‐FTS) for systemic thymulin overexpression via intramuscular (IM) injections. Animals were divided into 3 groups (n = 8): SHAM, STZ and STZ+FTS. Rats received bilateral icv injections of artificial cerebrospinal fluid (SHAM) or STZ (STZ and STZ+FTS groups) (3 mg/kg). At weeks 1 and 6 post‐STZ, STZ+FTS animals received IM injections of RAd‐FTS. Prior to sacrifices (week 13), behavioural tests were performed to evaluate species‐typical, exploratory, anxious and depressive behaviours, and recognition memory. At the tissue level, immunohistochemical staining for immature neurons, microglia and astrocytes were performed.ResultA significant deterioration in all assessed behaviours was observed in the STZ group. However, the STZ+FTS group did not show significant differences compared to the SHAM group in species‐typical, exploratory, anxious, and depressive behaviours. Moreover, it restored the recognition memory that was impaired in STZ animals. At the tissue level, systemic expression of FTS did not ameliorate the impact of STZ on immature neurons but showed an effect on microglia and astrocytes in the hc.ConclusionWe explored a minimally invasive therapeutic strategy that allowed us to fully or partially reverse behavioural and molecular changes in our animals with sAD. Therefore, our results are encouraging and suggest that thymulin administration may be a promising therapeutic approach, warranting consideration in sAD studies.
Genetic overlap between Alzheimer’s disease and immune‐mediated diseases: An atlas of shared genetic determinants and biological convergence
Authors: Enduru Nitesh , Fernandes Brisa S. , Bahrami Shahram , Dai Yulin , Andreassen Ole , Zhao Zhongming 
Published: January 2025

AbstractBackgroundAn increasing body of evidence has suggested that the pathogenesis of Alzheimer’s disease (AD) is not confined to the neurons but instead that neuroinflammation plays a significant role in the disease, with an interplay between the brain and the immune system. So far, their shared genetic components have not been systematically studied.MethodWe investigated the shared genetic architecture between AD and a plethora of immune‐mediated diseases using the genome‐wide association studies (GWAS) summary statistics data: allergic rhinitis, asthma, atopic dermatitis, celiac disease, Crohn’s disease, hypothyroidism, primary sclerosing cholangitis, RA, systemic lupus erythematosus, ulcerative colitis, and vitiligo. We developed a pipeline for global and local genetic correlation analysis between diseases and quantifying the shared loci among diseases using MiXeR. We used the conditional/comjunctional FDR to identify the shared loci and, finally, performed bi‐directional MR to assess the causal relationship between AD and the 11 immune‐mediated diseases.ResultOur results unveiled a significant genetic overlap between AD and 11 individual immune‐mediated diseases despite negligible genetic correlations, suggesting a complex shared genetic architecture distributed across the genome. With conjFDR <0.05, we identified 76 shared genomic loci. After excluding the 6 loci jointly associated with more than one pair of diseases, we had 70 unique shared genomic loci between AD and immune‐mediated diseases. Among them, 38 loci were novel for AD only, 25 were novel for immune‐mediated diseases only, and 17 were novel to both AD and immune‐mediated diseases. The shared loci between AD and immune‐mediated diseases implicated several genes, including GRAMD1B, FUT2, ADAMTS4, HBEGF, WNT3, TSPAN14, DHODH, ABCB9 and TNIP1, all of which are protein‐coding genes and thus potential drug targets. Enrichment analysis of these shared genes revealed pathways related to the immune system and cell adhesion. Finally, in silico single‐cell analyses showed enrichment of immune and brain cells, including neurons and microglia.ConclusionOur results suggest a genetic relationship between AD and the 11 immune‐mediated diseases, pinpointing the existence of a shared however non‐causal genetic basis. These identified protein‐coding genes have the potential to serve as a novel path to therapeutic interventions for both AD and immune‐mediated diseases and their comorbidities.
MiR‐223‐3p plays a role in sex‐biased intercellular communication between macrophages and microglia
Authors: Prajapati Paresh , Geleta Urim , Wang Wang‐Xia 
Published: January 2025

AbstractBackgroundThe characterization of intercellular communication between peripheral immune cells and the central nervous system (CNS) are essential for understanding the brain’s response to aging and disease states, such as Alzheimer’s disease. MicroRNAs (miRNAs) constitute a class of small non‐coding RNAs that play a crucial role in regulating various biological and pathological processes, including those related to immunity and inflammation. MiR‐223‐3p, residing on the X chromosome, is a pivotal miRNA involved in the inflammatory response, with its expression being enriched in macrophages/microglia. However, the impact of miR‐223‐3p on the intercellular communication and the subsequent neuroinflammation remains unclear.MethodMiR‐223‐3p knockout (KO) and genetic background matched wildtype (WT), female and male mice were used in the studies. Microglia were isolated from the brain tissues of 3‐week‐old pups and enriched using the EasySep™ Mouse CD11b Positive Selection Kit. Bone marrow‐derived macrophages (BMDMs) were isolated from 6 months old mice. Microglia isolated from WT mice were co‐cultured with BMDMs isolated from 1) female miR‐223‐3p KO, 2) male miR‐223‐3p KO, 3) female WT, and 4) male WT mice. The BMDMs were pre‐treated with LPS/IFNγ or vehicle control media before incubating with microglia for 24 hrs. RNAs were then extracted from microglia for RT‐qPCR quantification of inflammatory markers.ResultOur initial screening of gene expression through RNA‐seq studies reveals that the absence of miR‐223‐3p in bone BMDMs leads to a notable sex‐specific alteration in the expression of immune and inflammatory genes. RT‐qPCR analysis of microglia revealed a distinct alteration in the expression of inflammatory genes when co‐cultured with KO BMDMs relative to WT BMDMs. In particular, microglia co‐cultured with BMDMs from KO mice induced a substantial expression of IL1b, TNFα, CXCL10, H2Aa, H2EB1, and APOE compared to WT mice. Nevertheless, strong induction of CD86 was observed in microglia co‐cultured with male KO BMDMs compared to that of female KO BMDMs, while APOE, H2Ab1, and CD74 were higher in microglia co‐cultured with female KO BMDMs.ConclusionThese preliminary results suggest that the expression of miR‐223‐3p in peripheral macrophages may play an important role in sex‐biased inter‐cellular communication that ultimately will impact the inflammatory response in the CNS.
Alterations in gut microbiome composition, function, and rhythmicity are modulated by time‐restricted feeding in Alzheimer’s disease mice accompanying rescue of brain pathology and memory
Authors: Whittaker Daniel S. , Maissy Erica S , Richter R. Alexander , Zuffa Simone , Ramos Stephany Z Flores , Zarrinpar Amir , Desplats Paula 
Published: January 2025

AbstractBackgroundStudies using Alzheimer’s disease (AD) models suggest that gut bacteria contribute to amyloid pathology and systemic inflammation. Further, gut‐derived metabolites serve critical roles in regulating cholesterol, blood‐brain barrier permeability, neuroinflammation, and circadian rhythms. Recent studies from the Alzheimer’s Disease Neuroimaging Initiative have shown that serum‐based gut‐derived metabolites are associated with AD biomarkers and cognitive impairment. We recently reported a time‐restricted feeding (TRF) intervention that restored brain transcription, increased Aβ clearance, reduced amyloid deposition, and improved memory deficits in AD mice (PMID:37607543). Here we investigated gut microbiome alterations in the APP23 mouse stool and terminal ileum and evaluated the role of the microbiome and metabolome in the beneficial effects of TRF.MethodsAdult male and female APP23 transgenic (TG) and littermate non‐transgenic (NTG) mice (n = 3‐4/sex/genotype/condition) underwent ad libitum feeding (ALF) or a TRF protocol consisting of 6‐hours of active‐phase feeding followed by 18‐hours fasting for 3‐months. Metabolomics, metagenomics and metatranscriptomics were performed on ileum and stool (collected every 4‐hours for 24‐hours) from mice used in our TRF intervention study.ResultsMetagenomic analyses revealed that the stool microbiome composition and genomic functions were altered in APP23 TG compared to NTG mice and were further uniquely modulated in TG mice on TRF. Notably, stool metabolites relating to metabolism and neuroimmune function were differentially abundant in TG mice and partially restored by TRF. The stool microbiome and metabolome presented distinct diurnal cycling dynamics. TG mice showed a significant loss of rhythmic genomes which were markedly increased by TRF, indicative of broad entrainment of microbial rhythmicity. Ileal diurnal dynamics further differentiated TG mice on TRF. Ileal metatranscriptomic analysis revealed that TRF also reversed bacterial compositional and functional alterations in TG mice, including the attenuation of elevated inflammation‐related bacterial transcripts.ConclusionsTG mice showed alterations in microbiome composition, function, and rhythmicity. The unique microbiome induced by TRF regulated functions and metabolites implicated in AD and may represent one of the pathways by which TRF rescued pathology and cognition in AD mice.
Antagonism between Hyperphosphorylated Tau and Heme Oxygenase‐1 in Alzheimer’s Disease
Authors: Hagar Hsiao‐Tien Chien , Kuo Min‐Hao 
Published: January 2025

AbstractBackgroundAbnormal phosphorylation of tau is key to Alzheimer’s disease progression. The details of cellular dysfunction or death caused by hyperphosphorylated tau remain unclear. It is crucial to understand the mechanism for drug design. We use our PIMAX system to synthesize hyperphosphorylated tau that causes cell and neuron death at low‐micromolar concentrations. This work reveals the likely relationship between heme oxygenase 1 and pathological tau.MethodsTo understand the molecular underpinnings by which p‐tau kills cells, we used label‐free mass spectrometry to examine the proteomic changes of the SH‐SY5Y neuroblastoma cells after six‐hour treatment with 1 µM of recombinant hyperphosphorylated tau (p‐tau). HO‐1 reduction was among the most prominent alterations instigated by p‐tau. Accordingly, we then tested the hypothesis that HO‐1 deficiency was key to cell death following p‐tau treatment by examining whether supplying extra HO‐1 to cells treated with p‐tau would exhibit resistance. Lastly, we examined the physical interaction between HO‐1 and p‐tau by photo‐crosslinking.ResultOne micromolar of p‐tau causes drastic morphological changes and death of cells after 16 – 20 hours of treatment. Six hours after the addition of p‐tau, SH‐SY5Y cells still maintained normal morphology, but mass spectrometry revealed conspicuous proteomic changes, among which heme oxygenase‐1 (HO‐1) showed the most significant reduction, whereas several other proteins were upregulated under the same condition. The role of HO‐1 in p‐tau mediated cell death was confirmed by the observations that SH‐SY5Y cells exhibited increased resistance to p‐tau if HO‐1 was overexpressed or when cells were co‐treated with recombinant p‐tau and HO‐1 proteins. HO‐1 protects cells likely through a direct interaction with p‐tau because photo‐crosslinking resulted in a high‐molecular‐weight protein complex detectable by both tau and HO‐1 antibodies.ConclusionHyperphosphorylated tau likely physically sequesters HO‐1 as part of the mechanisms of tau pathology. Upregulating HO‐1 confers cellular resistance to hyperphosphorylated tau. Our observations can help the design of reagents targeting the interface between p‐tau and HO‐1. Such reagents may have therapeutic potentials for Alzheimer’s disease and other tauopathies.
Persistently elevated AD risk in hiPSC‐derived cortical neurons after developmental and adult Pb exposure
Authors: Xie Junkai , Zhao Han , Wu Shichen , Bowman Aaron B , Freeman Jeniffer , Yuan Chongli 
Published: January 2025

AbstractBackgroundExposure to environmental chemicals such as lead (Pb) during vulnerable developmental periods and even in adult stage can result in adverse health outcomes later in life. Human cohort studies have demonstrated associations between Pb exposure and Alzheimer’s Disease (AD) onset in later life which were further corroborated by findings from animal studies. The molecular pathway linking Pb exposure and increased AD risk, however, remains elusive.MethodIn this work, we used human iPSC‐derived cortical neurons as a model system to study the effects of Pb exposure on AD‐like pathogenesis in human cortical neurons. We exposed neural progenitor cells and differentiated neurons derived from human iPSC to Pb concentrations of 0, 15, and 50 ppb for 48 hours, simulating developmental and adult Pb exposure, respectively. Various techniques, including immunofluorescence, Western blotting, RNA‐sequencing, enzyme‐linked immunosorbent assay (ELISA), microelectrode array (MEA), and Förster resonance energy transfer (FRET) reporter cell lines, were employed to assess changes in AD‐like pathogenesis in differentiated cortical neurons. The susceptibility of Pb‐exposed neurons to cellular stressors such as PHF‐Tau and MPP+ was evaluated through secondary stress assays.ResultExposing neural progenitor cells to low dose Pb, mimicking a developmental exposure can result in altered neurite morphology. Differentiated neurons exhibit altered calcium homeostasis, synaptic plasticity, epigenetic landscape along with elevated AD‐like pathogenesis markers, including phosphorylated Tau, Tau aggregates and Aβ42/40. Furthermore, Pb‐exposed cortical neurons exhibited significantly increased calcium dynamics and overall neuronal activity. Adult neurons exposed to Pb demonstrated heightened vulnerability to PHF‐Tau and MPP+‐induced cytotoxicity, with these changes persisting even after Pb withdrawal.ConclusionCollectively, our findings propose a plausible molecular mechanism to account for the increased risk of AD in populations with a history of Pb exposure.
Aβ‐ and Tau‐Mediated Neuronal Excitability Derived from fMRI Predicts Grey Matter Atrophy in Alzheimer’s Disease
Authors: Sanchez‐Rodriguez Lazaro M , Bezgin Gleb , Carbonell Felix , Therriault Joseph , Arias Jaime Fernandez , Servaes Stijn , Rahmouni Nesrine , Tissot Cécile , Stevenson Jenna , Rosa‐Neto Pedro , Medina Yasser Iturria 
Published: January 2025

AbstractBackgroundDespite amyloid‐β (Aβ) plaques and tau neurofibrillary tangles being recognized as major Alzheimer’s Disease (AD) hallmarks, their synergistic contribution to neuronal activity remains unclear. We developed a neuroimaging‐based personalized brain activity model to assess the in‐vivo functional impact of AD pathophysiology. In previous reports, model‐inferred neuronal excitability predicted disease progression (i.e., cognitive performance and certain biological markers) [1,2]. Here, we investigate its relationship with brain tissue atrophy.MethodWe used Aβ and tau PET scans, structural T1‐weighted 3D MRI and resting‐state functional MRI from 132 subjects in the TRIAD cohort (https://triad.tnl‐mcgill.com/, Fig. 1a). The participants were diagnosed as cognitively unimpaired (CU, N = 81, 71.15 ±7.73 yrs, 63 F), mild cognitive impairment (MCI, N = 35, 72.1±7.84 yrs, 17 F) or Alzheimer’s disease (AD, N = 16, 69.45 ± 9.10 yrs, 8 F).In our whole‐brain neuronal activity model, the individual regional Aβ and tau burdens mediate neuronal excitability (Fig. 1b). By maximizing the similarity between simulated and real resting‐state signals, we estimated the contributions by Aβ, tau and their interaction (Aβ∙tau). A post‐hoc correlation analysis sought to determine if the reconstructed excitability values aligned with grey matter atrophy assessed via voxel‐based morphometry.ResultFig. 1c (left) presents the relationship between average intra‐brain grey matter volume and the obtained excitability values. Reduced grey matter volume significantly associated with the participants’ neuronal hyperactivation. Such a behaviour was additionally observed in region‐specific analyses, particularly at brain regions with grey matter alterations by AD, including the parahippocampal gyrus, fusiform gyrus, amygdala, hippocampus, entorhinal cortex and posterior cingulate gyrus (Fig. 1c, center). The effect of Aβ and tau’s interaction on neuronal excitability was the only variable of interest predicting grey matter volume (Fig. 1c, right).ConclusionThe computationally derived excitability values inversely correlated with grey matter volumes at the brain regions that most prominently showcase neurodegeneration in AD. Our results are consistent with previous observations [1,2] of increased excitability in parallel with pathological spread and the loss of neurons in the AD brain, also highlighting the fundamental role played by Aβ and tau functional interactions.References[1] Sanchez‐Rodriguez et al, 2023 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10370127[2] Sanchez‐Rodriguez et al, 2023 https://doi.org/10.1101/2023.09.15.557737
Proteomic characterization of the TgF344 AD rat model of Alzheimer’s disease as a function of disease and therapeutic treatment
Authors: Chaubey Kalyani , Voorhees Jaymie , Vázquez‐Rosa Edwin , Yu Youngmin , Wang Xinming , Barker Sarah , Franke Kathryn , Cintrón‐Pérez Coral , Williams Noelle S. , Paul Bindu D , Pieper Andrew A. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a severe neurodegenerative condition that affects millions of people worldwide. The TgF344 AD rat model, which exhibits early depression‐like behavior followed by later cognitive impairment, is widely used to evaluate putative biomarkers and potential treatments for AD. The P7C3 neuroprotective compounds have shown protective efficacy for both brain pathology and neuropsychiatric impairment in this model. To better understand the underlying pathophysiology and the mechanisms underlying therapeutic protection, we are investigating the associated changes in signaling pathways.MethodWe conducted unbiased label‐free proteomic analysis of AD rat brains. Animals were treated daily for 6 months with either P7C3 compounds or vehicle, from 9 months of age to 15 months of age. At 15 months of age, cognitive function and depression‐like behavior were evaluated, and brain tissue was isolated for the proteomic study. Differentially expressed proteins in AD and AD animals treated with P7C3 compounds were categorized into functional categories and pathways to provide insight into disease pathology and treatment.ResultAt this stage, rats had developed depression‐like behavior, but did not yet display cognitive impairment. We found 855 differentially expressed proteins in AD vehicle rats compared to WT littermate vehicle rats. Interestingly, 125 of these proteins returned to normal WT levels in AD animals treated with P7C3. Our study showed that major metabolic pathways and pathways related to neurodegeneration were highlighted at this time point. Most of these metabolic and neurodegenerative pathway‐related proteins returned to normal levels in TgF344 AD rats treated with P7C3 compounds.ConclusionPathway analysis of the differentially expressed proteins in AD that were normalized by P7C3 treatment were enriched in oxidative phosphorylation, glycolysis, tricarboxylic acid cycle, autophagy, tight junction, steroid and bile acid biosynthesis pathways. This provide insights into the pathophysiology of this AD model and complementary insights into future therapeutic opportunities.
Cross‐species systems biology target prioritization leads to the development of antisense oligonucleotides as a potential therapeutic approach for progressive supranuclear palsy
Authors: Min Yuhao , Wang Xue , Bergman Jeremiah , Sotelo Katie D , Reddy Joseph S. , Quicksall Zachary , Nguyen Thuy , Mitchell Adriana O , Dickson Dennis W. , Kawatani Keiji , Inoue Yasuteru , Kanekiyo Takahisa , Allen Mariet , Is Ozkan , Ertekin‐Taner Nilüfer 
Published: January 2025

AbstractBackgroundProgressive supranuclear palsy (PSP) is a devastating primary tauopathy with rapid progression to death. Although several therapies currently in the development pipeline show promising safety profiles and robust target engagement, few demonstrated significant efficacy in patients, underscoring the need to interrogate additional targets with novel therapeutic modalities to expand the potential therapeutic arsenal. To diversify the therapeutic avenues for PSP and related tauopathies (e.g. Alzheimer’s disease), we systematically integrated multi‐omics data from human brains of PSP and control donors with cross‐species validation to nominate high‐confidence therapeutic targets. We plan to translate our findings into safe and effective treatments for PSP using antisense oligonucleotides (ASO).MethodWe analyzed brain gene expression profiles in PSP and control individuals at bulk tissue (N = 408) and single‐cell levels (snRNAseq, N = 36). Cell‐type‐specific expression perturbations were systematically prioritized using a cross‐species validation paradigm, including rTG4510 tau mice and tau‐overexpressing Drosophila models. We conducted in vitro screening of ASO candidates against our prioritized target genes. ASO efficacy and toxicity were measured. RNAseq experiments will be performed to interrogate off‐target effects. The safety and efficacy of the lead ASOs will be assessed in PSP‐patient‐derived iPSC models.ResultWe previously reported discovery of novel genes with significant differential expression in PSP brains, characterized their brain cell‐specificity and validated them using snRNAseq data. We prioritized 21 genes using gene expression data from a mouse tauopathy model. Validation of these 21 high‐priority genes using a Drosophila tau model nominated astrocytic STOM, KANK2, and DDR2 as potential therapeutic targets for PSP. Knocking down their expression in Drosophila significantly rescues tau‐mediated neurodegenerative pathology. In vitro screening identified ASO leads that reduced the target expressions at mRNA and protein levels with low cellular toxicity.ConclusionWe developed a systems biology pipeline and nominated STOM, KANK2, and DDR2 as candidate gene targets for PSP. We identified ASOs that modulate these targets’ expression without cellular toxicity, suggesting they may be suitable as potential therapeutic candidates. Importantly, the shared pathophysiology and molecular aberrations between PSP and other tauopathies, such as Alzheimer’s disease, suggests that such therapeutic candidates may be repurposed for multiple neurodegenerative diseases, further accelerating, and streamlining the therapeutic pipeline.