bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating microglial modulation of endothelial inflammation through IL1RAP
Authors: Fisher Elizabeth S , Tubbesing Kate , Stevens Katherine , Lotz Steven , Bertucci Taylor , Temple Sally 
Published: January 2025

AbstractBackgroundUp to 84% of patients with Alzheimer’s Disease (AD) have vascular damage which precedes cognitive decline. Inflammation induces changes in blood‐brain‐barrier (BBB) integrity, though the link between induction of inflammation and AD is unclear. IL1β, a cytokine upregulated in patients with AD and in mouse models of the disease, is released and interacts with IL1R1 and its obligate co‐receptor, IL1RAP, to induce downstream signaling. A genome wide association study identified a SNP, rs12053868‐G, in IL1RAP associated with increased frequency of AD and higher rates of amyloid accumulation. This SNP exerts an independent, additive effect with APOE44, suggesting that IL1RAP could play a role in modification of AD progression.MethodAPOE33 or APOE44 allele‐containing human induced pluripotent stem cells (iPSCs) were differentiated into microglia or purified endothelial cells (ECs), which were validated via RNA sequencing. Differentiated cells were challenged with inflammation, and responses measured. Microglial inflammatory genes were analyzed via qPCR, as well as cytokine release. Barrier resistance of ECs was assessed via ECIS, and they were also evaluated with immunohistochemistry and gene expression changes. To interrogate the role of IL1RAP in microglial induction of inflammation, the gene was overexpressed and knocked down in each cell type.ResultECs upregulated E‐selectin upon challenge with inflammatory stimuli. ECs also showed alterations in localization of barrier proteins with immunohistochemistry upon inflammatory challenge, and between APOE33 and APOE44 cells. Microglia upregulated several cytokines in response to inflammatory challenge.ConclusionHuman iPSC‐derived microglia and ECs are altered by inflammatory challenge, and APOE44 ECs show differences in barrier protein localization at rest. Future experiments will investigate the interactions between microglia and ECs in both APOE alleles, as well as their response to overexpression or KD of IL1RAP. These experiments will establish the functional role of inflammation in microglia‐EC interactions, and the contributions of these interactions to the development of cerebral vascular damage.
Characterization of Alzheimer’s Disease‐Related Plasma Biomarkers in Gammaherpesvirus Infected Common Marmosets
Authors: Piotrowski Stacey L , Lee Amanda , Tucker Allison , Narver Heather , Stein Brianne , Oluoch Julia , Zhang Ting , Schaeffer Lauren K Hayrynen , Silva Afonso C , Carter Gregory W , Jacobson Steven , Rizzo Stacey J Sukoff 
Published: January 2025

AbstractBackgroundThe infectious hypothesis of Alzheimer’s disease (AD) suggests that microbes may play a role in pathogenesis by triggering the pathologic cascade or contributing to disease progression. Herpesviruses, such as Epstein‐Barr virus (EBV), have been of high interest in AD and related neurodegenerative diseases, in part due to their ability to establish lifelong latent infection and potentially reactivate. However, further research is needed to fully understand the role of herpesviruses in these diseases. The common marmoset (Callithrix jacchus) is not only a translationally relevant model of AD, but also herpesvirus infection. Callitrichine herpesvirus 3 (CalHV‐3) is a naturally occurring gammaherpesvirus in the marmoset that is phylogenetically and biologically similar to EBV. This study aimed to understand the contribution of persistent gammaherpesvirus infection to AD‐related pathology in the common marmoset.MethodsWhole blood from over 200 animals was collected from the NIH NINDS colony and the MARMO‐AD colony at the University of Pittsburgh during routine health surveillance and experimental procedures. Plasma was evaluated using MesoScale Discovery (MSD) multi‐plex ELISA Aβ peptide panel 4G8 and Neurology Panel 1 (GFAP, Neurofilament L, Total Tau). Peripheral blood mononuclear cells (PBMCs) were isolated using lymphocyte separation media. DNA was extracted from PBMCs and screened for CalHV‐3 using a droplet digital PCR (ddPCR) assay that amplified the virus and a housekeeping gene to allow for the quantification of viral loads (copies of CalHV‐3/106 cells).Results20‐30% of the tested colonies were positive for CalHV‐3, with a range of viral loads and the highest prevalence in aged animals (≥8 years old). There was significantly higher plasma Neurofilament L (NfL) and total tau in virally infected aged animals compared to uninfected aged animals.ConclusionsThe enhancement of plasma biomarkers, such as NfL and tau, in gammaherpesvirus infected aged marmosets suggests that viral infection may contribute to AD‐related pathology and neurodegeneration. Investigation is ongoing in additional animals to further characterize the relationship of plasma biomarkers to viral infection and viral load. The common marmoset is a unique translational model that allows for the investigation of AD and the potential role that herpesviruses play in disease manifestation and progression.
Pro‐inflammatory endothelial cell activation mediated by protofibrillar tau leads to loss of barrier function and integrity
Authors: Guzman‐Hernandez Roberto A , Fossati Silvia 
Published: January 2025

AbstractBackgroundNeurofibrillary tangles formed by hyperphosphorylated tau aggregates in the brain are one of the classical hallmarks of Alzheimer’s Disease (AD). Tau aggregates have been shown to elicit cytotoxicity, leading to overall neuronal loss and cognitive decline in AD. These aggregates can be transmitted from neurons and glial cells to other brain cells through a process known as tau spreading, and ultimately reach the endothelial cells (ECs) lining the vessel walls, thus, causing dysfunction of the neurovascular unit (NVU), a complex multicellular system surrounding brain vessels. The NVU is extremely important for blood flow regulation, amyloid and tau clearance, and proper brain function, however, the mechanisms responsible for the effects of tau on ECs remain understudied. We hypothesize that protofibrillar tau mediates pro‐inflammatory EC activation tied to bioenergetic alterations, culminating in loss of barrier function.MethodImmortalized (D3) and primary (hCECs) human brain microvascular ECs were challenged with protofibrillar 1N4R tau. Trans‐endothelial electrical resistance (TEER) was measured by the ECIS Zθ system as an in‐vitro model of the BBB. Cytokine production was assessed using a V‐Plex Neuroinflammatory Panel 1 (MSD). IL‐4 release was determined in cell supernatant. Immunocytochemical analysis of junction protein (ZO‐1 and VE‐Cadherin) expression and western blotting for EC activation markers (VCAM‐1 and ICAM‐1) and junction proteins was performed. EC bioenergetics were measured by Seahorse Extracellular Flux Analyzer and EC death was determined, as well as caspase activation.ResultReduced TEER was observed with protofibrillar tau, independently of EC death. VCAM‐1 expression significantly increased, whereas junction protein expression was decreased. Aggregated tau caused an increase in glycolysis at 24h, which reverted at further timepoints, whereas mitochondrial ATP production increased. IL‐4 production was increased at 24 hours, with similar trends at earlier timepoints. Blocking IL‐4 activity partially rescued TEER and decreased VCAM‐1 expression.ConclusionOur results suggest that tau protofibrils mediate pro‐inflammatory EC activation, coupled with metabolic alterations. These molecular changes can contribute to loss of barrier integrity, exacerbating cerebrovascular dysfunction.
Single‐cell spatial and non‐spatial RNA sequencing on herpes simplex virus 1 (HSV‐1) infected 2D and 3D cerebral organoids reveal molecular granularity on virus‐human gene interactions in Alzheimer’s disease
Authors: Dawes Pepper , Barton Nathaniel J , Orszulak Adrian R , Chigas Samantha M , Tran Khanh , Sundstrom Jonathan , Olson Meagan N , Murray Liam F , Oh HyungSuk , Church George M , Knipe David M , Readhead Benjamin , Chan Yingleong , Lim Elaine T 
Published: January 2025

AbstractBackgroundHerpes simplex virus (HSV‐1) has been associated with molecular and cellular signatures associated with Alzheimer’s disease (AD). We explored the use of both recent single‐cell and bulk transcriptomics technologies in dissecting the molecular and cellular virus‐human interactions with HSV‐1 infected cerebral organoids (2D and 3D). We compared the results with our previous observations from bulk RNA sequencing and discovered novel insights into HSV‐1 induced AD‐associated molecular pathology that were made possible by each transcriptomics technology.MethodWe used recent emerging technologies such as single‐cell spatial RNA sequencing (STOmics Stereo‐seq) and single‐cell non‐spatial RNA sequencing (Parse Evercode). In addition, we have data generated from our previous work using bulk RNA sequencing.ResultPreviously, we found that differentially expressed genes in HSV‐1 infected dissociated cells from cerebral organoids (2D cOrgs) using bulk RNA sequencing data were exclusively enriched for AD‐associated genes implicated through genome‐wide association studies (GWAS), but not for genes associated with other neurodegenerative or autoimmune diseases.UMAP analyses on single‐cell non‐spatial RNA sequencing data with GFP‐tagged HSV‐1 infected 2D cOrgs clustered by viral transcripts [Fig. 1] revealed huge differences in the proportions of true late viral transcripts but not of leaky late viral transcripts between clusters, while similar clustering of 3D cOrgs [Fig. 2] showed distinct proportions of both true late and leaky late transcripts.Pseudobulk analyses showed no enrichment for AD‐associated GWAS genes among the differentially expressed genes for HSV‐1 infected 2D cOrgs versus uninfected 2D cOrgs, but revealed significant enrichment for GWAS genes associated with autoimmune diseases such as Type 1 diabetes and multiple sclerosis. Similar analyses of HSV‐1 infected 3D cOrgs versus uninfected 3D cOrgs did not show enrichment in GWAS gene lists across the 21 common neurodegenerative, neuropsychiatric or autoimmune diseases that we had surveyed.ConclusionTaken together, our use of multi‐transcriptomics technologies has enabled us to gain course to fine molecular granularity into neuroinflammation‐induced AD viral‐human gene interactions and a careful dissection of the multi‐transcriptomics data enables us to gain insights into biomarkers and gene targets for AD therapeutics development in the near future.
Deciphering Microglial Contributions to Amyloid and Tau Pathology in Diverse Genetic Contexts
Authors: Onos Kristen D , Keezer Kelly J , Perkins Bridget M , Perkins Anne , Oblak Adrian L , Howell Gareth R 
Published: January 2025

AbstractBackgroundThere is strong evidence that underlying genetics of an individual can significantly modify response to development of amyloid and tau pathology with age. Genome‐wide association studies indicate that variation in more than 25 genetic loci relevant to microglial biology are predicted to increase susceptibility to Alzheimer’s disease (AD). This work aims to understand how genetic context can impact microglia function, how these differences relate to AD pathology, and ultimately, cognitive decline.MethodTo achieve this, we have introduced humanized amyloid‐β (with and without driver mutations) and MAPT sequences in two mouse strains, C57BL/6J (B6) and WSB/EiJ (WSB). In animals that carried amyloid driving mutations, we also performed injections of human‐derived tau at 6‐months and aged mice to 10‐months. Human brain tissue was obtained from the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) (ncrad.iu.edu). Immunohistochemistry was performed on mouse brain tissue to assess presence and degree of amyloid and tau pathology, differences in microglia and astrocyte activation and states, as well as neuronal and synaptic integrity. Measurements were also performed to assess degree of tau propagation. Plasma from animals was analyzed for a variety of biomarkers such as amyloid‐β, tau, neurofilament light, VEGFA and proinflammatory cytokines.ResultData analysis is ongoing, however, the impact of the individual humanized alleles has been assessed. B6 and WSB mice that carry humanized amyloid‐β without mutations did not exhibit significant amyloid pathology at 10 months. However, B6 and WSB mice that carry the Swedish‐Arctic‐Austrian mutations do show significant parenchymal deposition starting at 6 months of age, and WSB exhibit mature cerebral amyloid angiopathy.ConclusionWe expect our strategy of incorporating humanized amyloid and tau into genetically diverse mouse strains will significantly improve the alignment of neuroimmune responses in mouse to human AD. This will give the AD field a new way to determine mechanisms, identifying critical genes and pathways in early in disease onset or progression. Furthermore, this may pave the way for the development of microglia‐based therapies to reduce or prevent tau propagation and spreading in AD and related dementias.
Fecal microbiome transplantation from stroke donors promotes Alzheimer’s disease brain pathology and hypoperfusion in the 3xTg‐AD mice
Authors: Aware Chetan , Flemister Abeoseh , Chang Ya‐Hsuan , Ericsson Aaron , Gu Zezong , Cui Jiankun , Zuckerman Amitai , Ma Lixin , Lin Ai‐Ling 
Published: January 2025

AbstractBackgroundThe link between stroke and Alzheimer’s disease (AD) is recognized. However, the underlying mechanisms are not yet clear. This study seeks to determine if increased AD risk is linked to gut dysbiosis caused by acute ischemic stroke. Specifically, we examined whether fecal microbiome transplantation (FMT) from stroke patients to an AD mouse model would increase dysbiosis, reduce cerebral blood flow (CBF), and lead to increased levels of Aβ and tau of the mice.MethodStool samples were collected from acute stroke patients (n = 8) and age‐matched healthy controls (HC) (n = 8) (age 55‐80 yrs.). Samples were transplanted orally to male (FMT‐Stroke, n = 14 and FMT‐HC, n = 12) and female (FMT‐Stroke, n = 17 and FMT‐HC, n = 15) 3xTg‐AD mice (3 months of age) for 4 weeks after receiving antibiotics treatment. Another group of naive mice (CTL) without FMT (M:F = 5:8) were included. Both fecal DNA of the donors and mice were sequenced by 16S rRNA. A subset of mice (n = 4/group) was sent for CBF measurements by 7T MRI, and Aβ and tau determination using immunohistochemistry (IHC).ResultBray‐Curtis analysis on beta diversity revealed that stroke and HC donors, as well as recipient mice and CTL mice differ significantly from each other with strong sex differences (Fig. 1A). FMT‐Stroke‐treated mice showed decreased SCFA‐producing bacteria (Lactobacillus and Akkermansia muciniphila) and increased pathogenic bacteria (E. coli) compared to FMT‐HC mice (Fig. 1B). Further, the FMT‐Stroke group exhibited elevated levels of tau and Aβ in the cortex compared to the CTL and FMT‐HC groups (Fig. 2). MRI study demonstrated that FMT‐Stroke manifested in lower CBF in the cortex and hippocampus compared with the other two groups (Fig. 3).ConclusionOur study provides evidence that gut dysbiosis following a stroke may actively contribute to the development of AD pathology and decrease CBF, thereby increasing the risk of AD. Addressing gut dysbiosis through dietary changes or medication could be crucial in helping stroke survivors reduce their risk of developing AD. These findings could pave the way for novel treatments aimed at lowering the risk of stroke‐associated AD.
Analysis of ADNI phenotypic and mulit‐omic data identifies the role of microglial debris and lipid processing in Alzheimer’s Disease transition
Authors: Funk Cory C , Paterson Tom , Rohrs Jennifer , Hohman Timothy J. 
Published: January 2025

AbstractBackgroundMicroglial processing and recycling of debris is implicated in AD. AD GWAS loci are enriched for genes in efferocytosis, phagocytosis, endosomal trafficking and cholesterol efflux. Acting as a buffer, lipid droplets increase as a consequence of an imbalance between lipid debris influx and efflux rates. We hypothesize that a pivotal point in disease progression occurs when this buffering saturates, resulting in expanded lipid‐droplet accumulating microglia (LDAM). We anticipate a positive‐feedback effect where saturation accelerates neurodegeneration via inflammation and lipid processing via astrocytes. Susceptibility to this saturation may be connected to microglial AD GWAS loci—and would be reflected in progression rates. To explore this hypothesis, we analyzed lipidomic, proteomic, cognitive and genetic ADNI data to identify a signature indicative of this inflection point.MethodWe identified ADNI individuals in comparable states of disease progression, grouping them into ADAS13 (cognitive score) quartiles, then examined blood lipidomic and CSF proteomic data. This resulted in a cross‐sectional dataset of 608 subjects spanning from cognitively normal to demented. We examined protein/lipid correlations across each quartile, identifying and characterizing inflection points.ResultWe observed a stark and unique pattern of correlations in individuals with an ADAS13 score range from 13 to 19. We observed two subpopulations that differed in their rate of disease progression. CSF proteins in the rapid progressors point to microglial lipid droplet signaling and the lactate shuttle. We observed key changes in plasmalogens and cholesterol esters with DHA fatty acid tails, both indicative of neuronal debris processing and reverse cholesterol transport, as well as changes in acylcarnitines—indicative of reduced lipid hydrolysis. We also found differential enrichment of specific AD GWAS loci between the fast and slow progressors.ConclusionOur analysis provides evidence for the importance of lipid droplet saturation coinciding with correlational changes in CSF proteins and plasma lipids, occurring in individuals transitioning from cognitively normal to MCI. We connected microglial AD GWAS loci to differences in the progression rates at this transition. These results have potential clinical relevance for predicting progression rate at MCI diagnosis, and inform our understanding of the role of GWAS loci in key transitions.
Understanding the Impact of Mild Episodic Memory Difficulties on Everyday Tasks in Older Adults
Authors: Tassoni Molly B. , Cutrone Una , Simone Stephanie M. , Holmqvist Sophia L. , Mckniff Moira , Halberstadter Kimberly , Kaplan Marina , Chaturvedi Riya , Rosahl Melissa , Callahan Anna , Giovannetti Tania 
Published: January 2025

AbstractBackgroundThe Goal‐Control Model posits that episodic memory impairment leads to premature decay of everyday task goals, which contributes to task omissions (failure to accomplish task steps) in those with moderate to severe impairment. Although task omissions are not observed in those with mild episodic memory (mildEM) impairment, it has yet to be investigated if goal decay is reflected by subtle errors during task completion. We hypothesized that goal decay in mildEM impairment is reflected by imprecision in task performance at the end of everyday tasks.Method54 participants (M age = 73; 39 healthy control [HC], 15 MCI/mild dementia) were videorecorded while preparing a breakfast and a lunch according to specific instructions (Naturalistic Action Task). Performance errors were classified by two coders and another organized them into segments occurring in the beginning, middle or end of the task, all blind to participant diagnosis and study hypothesis. Analyses compared errors in each segment between those with mildEM impairment (MCI/mild dementia) and HC. Correlation analyses examined relations between errors and demographically adjusted standard scores on tests of episodic memory (HVLT and BVMT‐R delayed free recall) and executive function (Digits Backward, Trail Making Test B).ResultParticipants with mildEM impairment made significantly more errors than healthy controls only during the end task segment, t(52) = 2.83, p = .04. The groups did not differ in total errors during the beginning (p = .35) or middle task segments (p = .08). Correlations including the full sample showed significant relations between total errors during the end segment and scores on tests of episodic memory (HVLT r = ‐.33, p = .01; BVMT r = ‐.37, p <.01) but not scores on tests of executive function (Digits Backward r = .01, p = .92; TMT‐B r = .01, p = .97).ConclusionConsistent with hypotheses informed by the Goal‐Control Model, older adults with mildEM impairment exhibited increased imprecision towards the end of the task, suggesting that even those with mildEM deficits can experience premature decay of task goals. Behavioral strategies to strengthen goal activations, including reminder cues and/or overt verbalization of task goals, should be investigated as an avenue to improve everyday function in older adults with mild memory difficulties.
Heterogenous Tau Pathology in the Hippocampus of Progressive Supranuclear Palsy
Authors: Best Merci N , Levy Jonathan , Spencer Amber , Min Lia , Olafasson Einar , Pinarbasi Emile , Sexton Jonny , Jenkins Paul M , Carruthers Vernon B , Paulson Henry L 
Published: January 2025

AbstractBackgroundGlobose neurofibrillary tangles (NFTs) are found in subcortical areas of post‐mortem brain from individuals with the second most common primary tauopathy, progressive supranuclear palsy (PSP). The degree of cognitive impairment in secondary tauopathies such as Alzheimer’s disease (AD) correlates with the presence of NFTs, which originally appear in the entorhinal cortex before spreading throughout the hippocampus. In contrast, the degree of hippocampal tau pathology in PSP is thought to be limited, consistent with the view that cognitive impairment in PSP is predominantly subcortical. To better define the extent and variability of tau pathology in subregions of the hippocampus (dentate gyrus, CA4, CA3, CA2, CA1, subiculum, and parahippocampal gyrus), we examined PSP brains available through the Michigan Brain Bank.MethodWe identified 33 brains collected since 2011 where the primary neuropathology was PSP. For further analysis, we selected 15 brains (10 male), 14 of which lacked beta amyloid pathology. In 12 cases, clinical and neuropathological diagnoses of PSP were concordant (three other cases had been clinically identified as corticobasal degeneration or “other cognitive disorder”). Immunofluorescence microscopy and western blot analysis were performed with an antibody specific for phosphorylated tau, TaupS202/pT205. A semi‐quantitative scale was used to determine the degree of NFT pathology (0 = negative, 1 = sparse, 2 = intermediate, and 3 = robust) in hippocampal regions of PSP.ResultImmunofluorescence demonstrated wide variability in the degree and range of tau pathology within the hippocampus. Five of 15 PSP brains demonstrated robust NFT pathology in at least one hippocampal subregion. Within the hippocampus, the CA1 and subiculum most commonly displayed denser NFT pathology whereas the dentate gyrus typically was spared. Western blot analysis likewise demonstrated marked heterogeneity in TaupS202/pT205 signal, ranging from 0 to 161 arbitrary units.ConclusionThese findings support the view that hippocampal NFT pathology is not uncommon in PSP and may contribute to cognitive impairment in a subset of patients. Furthermore, the high variability in hippocampal NFTs nominates this region in PSP as a compelling brain area in which to assess correlations between tau accumulation and perturbations in neuronal cytoarchitecture.