bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ancestry‐specific studies on Alzheimer’s disease using iPSC‐derived microglia
Authors: Moura Sofia , Nasciben Luciana Bertholim , Shepherd Jihanne J , Coombs Lauren , Ramirez Aura M , Simon Shaina A. , Van Booven Derek , Rivero Joe , DeRosa Brooke A. , Whitehead Patrice L. , Adams Larry D. , Starks Takiyah D. , Mena Pedro R. , Illanes‐Manrique Maryenela Z. , Tejada Sergio J. , Byrd Goldie S. , Cornejo‐Olivas Mario , Feliciano‐Astacio Briseida E. , Rajabli Farid , Wang Liyong , Griswold Anthony J. , Young Juan I , Pericak‐Vance Margaret A. , Dykxhoorn Derek M. , Vance Jeffery M. 
Published: January 2025

AbstractBackgroundIn the US, African Americans (admixed with African and European) followed by Hispanics (admixed with Amerindian, African, and European) are the most affected groups compared to non‐Hispanic Whites (NHW). While genetic diversity and admixture play crucial roles in disease risk, the ancestry‐specific mechanisms remain poorly understood with most AD‐related studies focusing on NHW. Despite the recent field efforts to include genetically admixed populations, there continues to be a lack of functional studies in AD across the different cell types in these populations. Given the importance of Microglia in AD, we here characterize the genetic regulatory architecture (GRA) on iPSC‐derived Microglia (MGL) in African and Amerindian genomes.MethodiPSC lines derived from controls and AD patients with >90% genomic content from different ancestries (Amerindian, African, and European) were differentiated into MGL. We performed bulk RNA‐seq and ATAC‐seq, followed by differential expression and accessibility analyses to study the GRA of these admixed populations and its contributions to AD.ResultWe identified 1,103 differentially expressed genes (DEGs) and 267 differentially accessible genes (DAGs) across ancestries. We observed the most differences on both chromatin accessibility and gene expression levels between AI and AF. On the chromatin level and in the context of AD, we observed 2 DAGs (PRDM7 and SCIMP) between AI and AF, and 1 DAG between AI and EU (PRDM7). In addition, we identified 10 AD‐risk modifying genes that are differentially expressed between AI and AF ancestries (ABI3, CTSB, JAZF1, MS4A6A, PILRA, PLEKHA1, RASGEF1C, SORL1, TREM2, and TREML2) and 3 DEGs between AI and EU (JAZF1, MS4A6A, and SORL1). We identified several DEGs to be involved in lipid metabolism, cholesterol biosynthesis and metabolism, lysosomal activity, and immune response ‐ all highly relevant processes in AD pathology.ConclusionWe provide new insights into ancestry‐specific genetic risk factors in AD pathophysiology. Here, we report novel transcriptomic and chromatin accessibility data in microglia of AI and AF ancestries that potentially contribute to a differential genetic risk in AD in the different ancestries. Interestingly, those ancestries with greatest migratory differences revealed the largest DEG.
Localization, induction, and functional effects of tau phosphorylated at threonine 217
Authors: Bloom George S 
Published: January 2025

AbstractBackgroundTau phosphorylated at threonine‐217 (taupT217), which can be measured in plasma and CSF using antibodies, is one of the most promising early biomarkers for Alzheimer’s disease (AD). Little was known, however, about the cellular and subcellular distributions of taupT217, how those levels change during disease progression, the factor(s) that provoke taupT217 accumulation, or functional consequences of tau phosphorylation at T217. This study addressed all of those issues.MethodWe defined the taupT217 distribution in vivo by surveying brains of human AD patients at various disease stages and in age‐matched, cognitively normal controls, in AD model mouse brains, and in vitro in cultured mouse neurons. We also used cultured neurons to determine if extracellular oligomers of amyloid‐β (xcAβOs) or tau (xcTauOs) affect the abundance or localization of taupT217. Finally, to determine if tau phosphorylation at T217 affects its affinity for microtubules, we expressed EGFP‐tagged wild type (WT) and pseudo‐phosphorylated tau in fibroblasts, and used fluorescence recovery after photobleaching to measure turnover rates of microtubule‐bound tau.ResultWe first discovered that the taupT217 epitope is found in 19 human proteins, but that specific and exclusive antibody recognition of taupT217 can be achieved when suitable precautions are taken, We next determined that: 1) taupT217 appears in neurons at Braak stages I‐II, and becomes more prevalent at later disease stages in axons, dendrites, neuronal cell bodies, neuropil threads, pre‐tangles and tangles that are extensively co‐labeled by the AT8 (taupS202/pT205) and PHF1 (taupS396/pS404) antibodies; 2) in cultured neurons, taupT217 is increased by xcTauOs, but not by xcAβOs, and is associated with developing post‐synaptic sites; and 3) pseudo‐phosphorylation by a T217E amino acid substitution reduces tau’s affinity for microtubules.ConclusionEarly AD biomarker assays based on taupT217 detection with antibodies are at risk of artifactual signal inflation unless rigorous steps are taken to ensure antibody specificity. Neuronal levels of taupT217 rise steadily in brain as AD progresses. Finally, our collective results raise the possibilities that xcTauOs drive T217 phosphorylation of tau in vivo, and that taupT217 contributes to synaptic decline and favors formation of tau‐tau interactions at the expense of tau binding to microtubules.
Long‐read transcript sequencing identifies differential isoform expression in the entorhinal cortex in a transgenic model of tau pathology
Authors: Leung Szi Kay , Jeffries Aaron , Castanho Isabel , Bamford Rosemary , Dempster Emma , Ahmed Zeshan , Hannon Eilis , Mill Jonathan 
Published: January 2025

AbstractBackgroundIncreasing evidence suggests that alternative splicing plays an important role in Alzheimer’s disease (AD), a devastating neurodegenerative disorder involving the intracellular aggregation of hyperphosphorylated tau.MethodWe used whole transcriptome and targeted long‐read cDNA sequencing to profile transcript diversity in the entorhinal cortex of wild‐type (WT) and transgenic (TG) mice harbouring a mutant form of human tau.ResultWhole transcriptome profiling showed that previously reported gene‐level expression differences between WT and TG mice reflect changes in the abundance of specific transcripts. Ultradeep targeted long‐read cDNA sequencing of genes implicated in AD revealed hundreds of novel isoforms and identified specific transcripts associated with the development of tau pathology.ConclusionOur results highlight the importance of differential transcript usage, even in the absence of gene‐level expression alterations, as a mechanism underpinning gene regulation in the development of neuropathology. Our transcript annotations and a novel informatics pipeline for the analysis of long‐read transcript sequencing data are provided as a resource to the community.
White matter hyperintensity onset, trajectories, and associations with cognitive decline in the presence of amyloid and tau
Authors: Du Lianlian , Langhough Rebecca E. , Hermann Bruce P , Betthauser Tobey J. , Planalp Elizabeth M. , Jonaitis Erin M. , Reyes Ramiro Eduardo Rea , Rivera‐Rivera Leonardo A. , Cody Karly Alex , Chin Nathaniel A. , Cadman Robert V. , Johnson Kevin M. , Field Aaron S , Rowley Howard A. , Pompa Christian C. , Hudson Sarah C. , Ryther Brenda , Sparks Lia J. , Miess Beryl , Norris Nia , Ramsey Celena M , Mueller Kimberly D , Asthana Sanjay , Eisenmenger Laura B. , Christian Bradley T. , Johnson Sterling C. 
Published: January 2025

AbstractBackgroundCognitive decline is often influenced by Alzheimer’s disease (AD) pathology (e.g., beta‐amyloid burden) and other pathology (e.g., vascular abnormalities). Amyloid onset and chronicity estimation using Sampled Iterative Local Approximation (SILA), enhanced our understanding of AD progression and its preclinical phase. This study has three aims: 1) estimate White Matter Hyperintensities (WMH) onset and chronicity; 2) assess whether baseline WMH chronicity/burden moderates the association between Aβ chronicity/burden and Clinical Dementia Rating‐sum of boxes (CDR‐SB) trajectories; 3) explore whether tau burden mediates WMH and amyloid associations with CDR‐SB.MethodParticipants were from the University of Wisconsin WRAP and ADRC cohorts and had completed at least one T1‐weighted and T2‐weighted FLAIR scans (Aim 1: n = 877, age 43‐93y). WMH values were aligned to a duration scale using SILA and WMH positivity threshold of ∼2.06 mL for WMH+ chronicity = 0. We compared mixed effects models with up to cubic time (age vs WMH chronicity) terms for characterizing WMH trajectories. We also examined baseline WMH burden*amyloid burden at each CDR‐SB assessment (PiB A+ DVR threshold ∼17CL; linear and quadratic amyloid burden) relative to longitudinal CDR‐SB (Aim 2; n = 426), and tau PET SUVR’s mediating effects on WMH*amyloid associations with last CDR‐SB (Aim 3; n = 385; meta‐temporal (MTC) SUVR; florquinitau tracer).ResultMean(SD) age at baseline and last MRI were 65.36(8.49) and 67.26(8.14) years, respectively (sample details in Table 1). Comparisons of simple slopes (95%CI) show overlapping annualized WMH‐ slope estimates using age (0.028(0.022,0.034)) or chronicity (0.037(0.033,0.040)); in contrast, the WMH+ slopes are 2.26 times larger when aligned to WMH chronicity vs age (WMH+: 0.042(0.036,0.047), WMH‐: (0.095(0.091,0.10); Figure 1A&B). Whether biomarker “burden” was modeled as ±, estimated DVR, or chronicity (Figure 1C&D), significant interactions showed a synergistic effect of WMH and amyloid on accelerated CDR‐SB trajectory. Moderated mediation models revealed MTC‐tau accumulation partially mediated (∼65%) the synergistic effect of WMH and amyloid on last CDR‐SB (Figure 2).ConclusionWMH accumulation follows a predictable trajectory post‐onset and appears to exacerbate cognitive decline in those with amyloid pathology. Future analyses will further elucidate the complex relationships between vascular risk, amyloid, tau accumulation and cognitive decline.
Identification of Protein Tyrosine Phosphatase Receptor Zeta as a Novel Complement C1q Synaptic Interacting Partner
Authors: Benskey Matthew John 
Published: January 2025

AbstractBackgroundThe pathological correlate most tightly associated with cognitive decline in AD is synapse loss. The presence of pathological tau significantly correlates with synaptotoxicity and cognitive decline in AD, yet it is currently unclear how pathological tau causes synapse loss. Within the brain, complement component C1q coats the outer membrane of weak or damaged synapses, resulting in the phagocytic removal of tagged synapses by microglia. This process is tightly regulated within healthy individuals to prevent aberrant synaptic pruning. For example, synaptic deposition of C1q requires presentation of a C1q‐binding partner in the outer membrane of weak/damaged synapses. In contrast, C1q synaptic deposition is increased in the brains of AD patients where it colocalizes with pathological tau. C1q synaptic deposition is also increased in animal models of tauopathy and blocking C1q synaptic deposition in these models rescues synapse loss. However, it is currently unclear how C1q can recognize tauopathy affected synapses. The goal of the current study is to identify molecules that recruit C1q to AD‐affected synapses.MethodTo identify proteins that facilitate C1q synaptic deposition in response to tauopathy we immunoprecipitated (IP’d) C1q from postmortem human AD (Braak stage V‐VI) or control (Braak stage I‐II) frontal cortex tissue and performed unbiased mass spectrometry to identify proteins that Co‐IP’d with C1q. Identified proteins were compared between AD and controls to identify disease specific C1q interactors, after which AD‐specific C1q interacting proteins were analyzed to identify transmembrane proteins that localize to the synapse. To validate C1q interactors identified by mass spec, IPs were repeated, and elution’s were immunoblotted for the identified interactor.ResultFrom this analysis we have identified protein tyrosine phosphatase receptor zeta (PTPRZ) as a novel C1q synaptic interacting protein. Subsequent validation analysis revealed that PTPRZ interacts with oligomeric tau in postmortem human AD tissue and is also increased in the hippocampus and cortex of PS19 mice.ConclusionIn conclusion, we present data identifying and validating a novel AD‐associated C1q synaptic binding partner. Future studies will determine if preventing the synaptic presentation of PTPRZ will rescue synapse loss in models of tauopathy.
Interrogating the molecular interaction between apolipoprotein E and the beta‐amyloid peptide
Authors: Araujo Mateus V , Lourenco Mychael V , Torres Pedro H M 
Published: January 2025

AbstractBackgroundThe apolipoprotein ε4 (ApoE4) allele is a major risk factor for sporadic Alzheimer’s disease (AD) and was shown to promote amyloid‐β (Aβ) accumulation and mediate pathophysiological processes in AD. Although the molecular interaction between Aβ and ApoE is acknowledged, the precise nature of this interaction remains unclear. This study aims to explore the biophysical and biochemical nature of the interaction between Aβ and ApoE in the ε3 and ε4 isoforms.MethodWe initially reverted 5 point mutations to generate the original ApoE3 structure from its full‐length structure (PDB: 2L7B), by using the Swiss‐Model software. We then inserted the 112CtoR mutation to generate ApoE4. We further used a previously published open‐state structure of ApoE4. Three distinct Aβ42 structures (PDB: 1IYT, 6SZF, 1Z0Q) were used. Docking preparations were performed using ChimeraX with PDB2PQR and APBS used to generate electrostatic surfaces. ClusPro and Haddock software facilitated rigid and flexible molecular docking, respectively. This study performed nine dockings in total, selecting six suitable complexes for coarse‐grained molecular dynamics in triplicate using GROMACS.ResultThe Aβ42 structure that emulates a membrane‐associated environment (1IYT) provided the best fits in the molecular docking, followed by the pre‐transition to β‐sheet structure (1Z0Q). The “intermediate structure” (6SZF), a stage between the two other structures, resulted in unspecific docking. The molecular dynamics from the promising structures are being carried out to understand the different behavior and stability at pH 7.4. We are also undertaking additional dynamics experiments to investigate the influence of an acidic pH (5.5).ConclusionWe initially confirmed the molecular interaction between Aβ42 and ApoE isoforms. This interaction is influenced by the local environment. Further results are expected to elucidate molecular details of this interaction hold potential to enhance our understanding of AD pathophysiology.
Targeting Endogenous Tau in a Human Tau Seeded Tauopathy Models Inhibits Tau Spread
Authors: Xu Hong 
Published: January 2025

AbstractBackgroundNeurodegenerative diseases with the presence of tau pathology account for 90% of dementia in human patients, the most common of which is Alzheimer’s disease (AD). Although therapeutic approaches targeting tau and tau pathology are still under development, it remains unclear how tau targeting antibodies can inhibit the development of tau pathology.MethodWe hypothesize tau antibodies enter neurons and inhibit the seeding of tau pathology without direct interaction to the pathogenic tau seeds. To tackle this, we designed a study using the human tau seeds‐induced sporadic spreading model of tauopathy to evaluate the effect of a mouse tau‐specific antibody (mTau8) on tau spreading in vitro and in vivo.ResultOur results show that mTau8 enters the cerebrospinal fluid by bypassing the blood‐brain barrier and effectively decreases AD‐tau‐seeded tau pathology in the wild‐type mouse and cell models. Moreover, the analysis of the spread of tau pathology in vivo and live imaging study in vitro suggest a mechanism that is independent of neutralizing the pathogenic tau seeds.ConclusionOur findings provide a mechanistic view of antibody‐based tau therapy for treating tauopathies.
Neuronal Cell‐Type Susceptibility in the Ventral Subiculum of 5xFAD Mice
Authors: Pachicano Maricarmen , Khanjani Neda , Hurtado Angela , Mehta Shrey , Smith Zion MK , Bienkowski Michael S 
Published: January 2025

AbstractBackgroundIdentification of cell‐type vulnerability in Alzheimer’s Disease (AD) is critical to the clinical development of targeted treatments. Neurodegeneration of the subiculum (SUB) is an early biomarker of AD, but it is unknown if specific SUB cell‐types are susceptible to AD neurodegeneration. In the 5xFAD mouse model, significant cell loss occurs within the SUB by 8 months of age. Our previous work creating the mouse Hippocampus Gene Expression Atlas (HGEA) has defined cell‐type specific gene markers that can identify cell‐types within the SUB (Bienkowski et al, 2018). Within the ventral SUB (SUBv), three relatively discrete layers of gene expression define cell‐type organization. Quantification of SUBv cells identified by these gene markers can be utilized to determine SUB cell‐type susceptibility across disease timepoints.MethodTo label SUBv gene expression patterns, we used RNAscope single molecule fluorescent in situ hybridization (smFISH) to label and quantify individual RNA transcript levels within SUB cell types. 5xFAD and wildtype (WT) mice (2, 6, 12, and 14 mo.) were perfused, dissected, and coronally sectioned into 20µm thick sections. SUBv tissue sections were hybridized with probes designed to target SUBv gene expression markers using RNAscope Multiplex Fluorescent V2 kit (Advanced Cell Diagnostics). Tissue sections were counterstained for DAPI cytoarchitecture, imaged at 40X with a spinning disk confocal microscope, and quantification was performed using QuPath (Quantitative Pathology and Bioimage Analysis) cell segmentation and SCAMPR analysis software (Ghoddousi et al, 2022).ResultRNAscope labeling produced robust datasets enabling quantification of single RNA transcript levels for each gene expression marker within 10,000+ SUBv cells. At late disease timepoints, we found that the number of SUBv layer 3 cells were significantly diminished compared to WT controls suggesting that SUBv layer 3 cells are primarily susceptible to AD neurodegeneration. No significant difference was found between 5xFAD and WT mice at 2 mo. of age.ConclusionIn the SUBv, layer 3 neurons are primarily susceptible to AD neurodegeneration in the 5xFAD mouse model. Future studies will investigate the transcriptomic changes that occur within SUBv layer 3 neurons that precede death.
Genomic landscape of RNA editing and genome regulatory signatures in aged human brains with Alzheimer’s disease
Authors: Gupta Amit Kumar , Martin William , Feng Yayan , Cheng Feixiong 
Published: January 2025

AbstractBackgroundRNA editing represents one of the most common post‐transcriptional modifications that contribute to transcriptomic diversity, impacting RNA stability and regulations. To this end, we sought to investigate brain region‐specific RNA‐editing signatures (RNA‐editings) associated with Alzheimer’s disease (AD) and the human aged brain with regulatory elements.MethodWe investigated the genome‐wide landscape of RNA‐editings from 4,208 (1,364 AD case vs. 742 healthy controls [HC]) RNAseq samples across nine brain regions from three large biobanks (Mount Sinai, Mayo, ROSMAP) cohorts. We performed association and enrichment analysis of RNA‐editing enriched genes. We further identified sex‐specific and APOE4‐specific RNA‐editing. We inspected brain‐wide cis‐regulatory variants (RNA editing quantitative trait loci or cis‐edQTLs) considering two different cis‐distances (±100 KB and ±1 MB) utilizing matched whole‐genome genotyping data for 3,627 samples. Age, PMI, gender (sex), and APOE4 status are used as adjusting covariates. GWAS and cis‐edQTLs (1 MB) colocalization were performed with downstream functional and genome regulatory analysis.ResultWe have identified ∼14,687 significant RNA editing events across nine brain regions while comparing AD cases versus HC. We showed that two brain regions namely the parahippocampal gyrus (PHG), and cerebellum cortex (CBE) exhibit the highest editing abundance followed by the inferior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC). Overall, we pinpointed 127 genes harboring significant RNA editing loci (5*10‐3) shared by two or more brain regions. Further, we uncovered a large repertoire (9650‐30386) of cis‐edQTLs (distance ±100 KB) among distinct brain regions potentially influencing RNA editing sites. A total of 76 colocalized GWAS and cis‐edQTL (±1 MB) genomic variants in about 43 genes were identified. Some of these genomic loci (genes + variants) are CLU (rs867230), DGKQ (rs4690197, rs3733347), TRANK1 (rs7624498), BIN1 (rs1060743), PICALM (rs639012), FERMT2 (rs17125924), and TSPAN14 (rs7098414). Functional enrichment analysis shows these genes are allied to synaptic cycles, amyloid‐beta formation, neurofibrillary tangle, immune pathways, AD disease pathways, protein metabolism and signal transduction.ConclusionOur study offers brain‐wide region‐specific and common RNA editing signatures in AD. This underlying altered landscape of RNA‐editing and cis‐edQTLs may account for the genetic etiology and pathobiology of AD and other neurodegenerative diseases.
Feasibility of implementing time‐restricted eating in women with mild cognitive impairment
Authors: Thomas Matthew , Jicha Gregory A , Harp Jordan P. , Kern Philip A , Sears Dorothy D , James Dara L , Katsumata Yuriko , Pendergast Julie S 
Published: January 2025

AbstractBackgroundDisruption of sleep and circadian rhythms are associated with cognitive decline, preclinical Alzheimer’s Disease (AD) pathology, and increased risk of dementia. Alleviating circadian rhythm and sleep disruption may improve cognition and reduce the progression of AD and related dementias (ADRD). Time‐restricted eating (TRE), a circadian behavioral intervention that corrects disrupted eating rhythms by aligning food intake to the daytime, has demonstrated improvements in metabolic dysfunction and sleep quality. Individuals who adhere to TRE are less likely to have cognitive impairment compared to those who consume meals with no time restrictions. To date, no studies have investigated the potential efficacy of a TRE intervention to improve cognition among individuals living with cognitive impairment. This study will determine the feasibility of TRE in women with mild cognitive impairment (MCI).MethodWomen diagnosed with MCI will be recruited from the University of Kentucky Sanders‐Brown Center on Aging cohort to participate in a pre‐post study. Data will be collected during a 2‐week baseline period and an 8‐week TRE intervention period. During baseline, measures of cognition, food timing, activity/sleep, and metabolic parameters will be collected. For the duration of the enrollment, first and last calorie intake times will be collected from participants with an SMS texting system. Participants with mean daily calorie durations of at least 12 hours and calorie intake after 8:00pm on the majority of nights during baseline will be eligible for the TRE intervention. During the TRE intervention, each participant will self‐select a 10‐h window (ending by 8:00pm) during which they will consume all daily calories during the 8‐week TRE intervention. At the end of the intervention, baseline measures will be repeated. Adherence to the TRE protocol is the primary outcome of this study.ResultWe anticipate enrolling 22 participants in a screening, baseline phase to enroll 15 eligible participants for the TRE intervention.ConclusionThis pilot study will provide insight into the feasibility of conducting a TRE intervention among women living with MCI and provide preliminary data to calculate sample size for a future randomized controlled trial testing the efficacy of TRE in improving, or preventing further decline, in cognition.