bluuebunny/crossref_metadata_2025_split huggingface dataset:
Argonaute 2 in Neurons is essential for healthy Blood Brain Barrier Formation
Authors: Sona Chandan , Yeh Yu‐Te , Ghosh Adhideb , Hinte Laura C. , von Meyenn Ferdinand , Yan Xin , Poy Matthew 
Published: January 2025

AbstractBackgroundArgonaute2 (Ago2) plays an essential role in RISC‐mediated silencing of target mRNAs, which are critical for cellular functions. Argonaute2 Syndrome, also known as Ago2 Syndrome, is a rare neurological disorder recently discovered in humans. It has significant implications for brain development, yet it remains unstudied to dateMethodTo study this effect, we deleted the Ago2 gene in GABAergic (Slc32a1 cre) and Glutamatergic (Slc17a6 cre) mice. We conducted Western blotting and Immunohistochemistry to analyze the defects in knockouts. Additionally, we performed single‐cell experiments and analysis on the knockouts.ResultOur study highlights the crucial role of Ago2 in glutamatergic neurons, leading to postnatal lethality due to disruption in the neurovascular unit (NVU) and neuronal positioning in the developing cortex. Surprisingly, the absence of Ago2 only affected postnatal survival when removed from glutamatergic, not GABAergic neurons. Through single‐cell analysis, we found that loss of Ago2 in this specific subset led to impaired synapse formation and endothelial cell connections, resulting in neuroinflammation. Dysregulation of the microRNA pathway and upregulation of Pten were observed, and de‐repression of Pten in Ago2‐deficient mice partially rescued the blood brain barrier (BBB) and increased survivalConclusionOur study identifies a vital neuronal population where miRNA function is essential for blood‐brain barrier formation. The loss of functional Ago2 in this neuronal population leads to BBB collapse and neuroinflammation. These observations warrant studies to be conducted in subjects with vascular dementia to investigate if mutations exist in functional Ago2 that correlate with Ago2 syndrome.
5xFAD/Abi3S209F mice display distinct age‐dependent effects on amyloid beta pathology and microglia dynamics
Authors: Butler Claire Ann , O'Gara Katie , Mendoza‐Arvilla Adrian , Milinkeviciute Giedre , Da Cunha Celia , Kawauchi Shimako , Rezaie Narges , Liang Heidi Yahan , Thach Annie , Wang Shuling , Collins Sherilyn , Walker Amber , Shi Kai‐Xuan , Neumann Jonathan , Gomez‐Arboledas Angela , Tenner Andrea J , LaFerla Frank M , Mortazavi Ali , MacGregor Grant R , Green Kim N. 
Published: January 2025

AbstractBackgroundIn several large genome‐wide association studies (GWAS), genetic polymorphisms of Abi3 have been identified as a risk factor for late‐onset Alzheimer’s Disease (LOAD). ABI3 along with ABI1 and ABI2, regulate the formation of the WAVE complex which in turn, regulates actin dynamics. ABI3 is highly expressed in microglia in the brain, however, the function of ABI3 in microglia is relatively unknown. In recent studies knock‐out of ABI3 has been shown to exacerbate amyloid beta (Aβ) pathology and associated inflammation. To date, there have been no studies on variant specific effects on amyloid beta pathology.MethodsTo study the effects of ABI3 on the development of Alzheimer’s disease (AD) relevant pathologies we introduced an equivalent coding sequence change that has been identified as a risk variant for LOAD (S212F) into the C57BL/6 mouse genome using CRISPR/Cas9 (S209F). We set out to characterize the Abi3S209F variant and investigate its impact on AD pathology when crossed with 5xFAD transgenic mice, generating four distinct groups: WT, Abi3S209F homozygous, 5xFAD, and 5xFAD/Abi3S209F homozygous. Characterization was performed using histological staining and biochemical approaches at 4‐, 12‐ and 18‐months of age.Results5xFAD/Abi3S209F mice displayed an age‐related decrease in dense core‐Aβ plaque burden, characterized by reduced Thioflavin‐S staining, accompanied by changes in fibrillar Aβ (OC) staining, in confocal images of both subiculum and visual cortical regions of 5xFAD/Abi3S209F mice compared to 5xFAD mice. Broadly, microglial numbers mimic plaque load, however by 18‐months of age 5xFAD/Abi3S209F mice display dramatic reductions in IBA1+ microglia number – to levels comparable to WT/Abi3S209F homozygous mice, suggesting a general loss of plaque associated microglia. By 12 months of age, Abi3S209F homozygous and 5xFAD/ Abi3S209F mice displayed increased synaptic density, independent of pathology in visual cortex, subiculum and CA1 regions.ConclusionsTogether, these results characterize the effects of the Abi3S209F missense mutation on 5xFAD‐mediated pathology, specifically in Aβ plaque development, glial morphology, and synapses. Our data suggests that this mutation may affect microglia dynamics in an age‐dependent manner and may result in dysfunctional microglia at later stages of disease.
Increased fibrin deposition in the brains of individuals with Down syndrome and Alzheimer’s disease
Authors: Du Annie , Flores‐Aguilar Lisi , Edwards Natalie C. , Lao Patrick J. , Ryu Jae Kyu , Akassoglou Katerina , Wilcock Donna M. , Kofler Julia , Ikonomovic Milos D , Lai Florence , Brickman Adam M. , Head Elizabeth 
Published: January 2025

AbstractBackgroundIndividuals with Down syndrome (DS) have an increased genetic risk of developing Alzheimer’s disease (AD), with most adults developing AD neuropathology in their 40s. Despite having a low frequency of systemic vascular risk factors such as hypertension and atherosclerosis, adults with DS display cerebrovascular pathology, including microbleeds, microinfarcts, and cerebral amyloid angiopathy. This suggests that blood‐brain barrier (BBB) integrity may be compromised allowing the extravasation of blood proteins in the brain parenchyma. The blood coagulation factor fibrin promotes immune‐mediated neurodegeneration and is a marker of BBB disruption in a wide range of neurological diseases. This study investigated the severity of fibrin deposition as a measure of BBB integrity in the brains of adults with DS and AD pathology (DSAD). We hypothesized that fibrin deposition is increased in DSAD in comparison to neurotypical controls without DS or AD.MethodFibrin immunoreactivity was assessed by free‐floating immunohistochemistry in 30µm tissue sections from the occipital cortex from neurotypical controls (n = 12; 41‐65 years old) and DSAD (n = 12; 46‐66 years old). Using whole slide imaging, brain sections were digitized, and the severity of fibrin deposition was scored using Aperio Imagescope.ResultIndividuals with DSAD display significantly higher fibrin deposition in the white and grey matter of the occipital cortex in comparison to the age‐matched neurotypical controls (p<0.0001).ConclusionNeurotypical controls display minimal fibrin deposition in the brain parenchyma and perivascular space. However, compared to neurotypical controls, adults with DS at advanced stages of AD neuropathology display significant fibrin deposition in the occipital cortex, suggesting that the BBB may be compromised in this population.Funding: NIH U19AG068054, RF1AG079519, P30AG066519 and 23AARFD‐1022715.
Comprehensive Multi‐Neuron Imaging During Aging and Degeneration in C. elegans
Authors: Yadav Dilip , Wirak Gregory , Connor Christopher , Gabel Chritopher 
Published: January 2025

AbstractBackgroundDespite the prevalence of Alzheimer’s Disease in the aged human population and advancements in our understanding of the disease at the molecular level, we still lack a fundamental understanding of how cognitive dysfunction stems from alterations in cellular neuron dynamics and how it relates to the normal aging process. To address this gap in knowledge, we measured the breakdown of nervous system function with cellular resolution during normal aging and in an Alzheimer’s Disease model.MethodEmploying comprehensive multi‐neuron florescence microscopy in the nematode worm, C. elegans, a simple yet powerful model animal, we can measure neuron activity across the majority of the animal’s nervous system with single cell resolution. To measure how system‐state dynamics and neuronal connectivity breakdown during normal aging and in the disease model, imaging was performed throughout the animal’s lifespan in wild‐type as well as a transgenic strain in which human amyloid‐β (Aβ) peptide (1‐42) is pan‐neuronally expressed.ResultsDuring normal aging we measure a breakdown in system‐state dynamics that accompany shifts in activity to higher frequencies and a global loss of inhibitory signaling. In Aβ expressing animals this process is accelerated and includes loss of both inhibitory and excitatory signaling.ConclusionOur work is defining the functional degradation of a complete nervous system from single neurons to system‐wide dynamics during normal aging and in the disease model. In doing so we are revealing the specific changes in neuron activity at the cellular level that cause the breakdown of global nervous system dynamics. These results will enable a knowledge‐based approach to novel neurotherapeutic strategies in the treatment and prevention of dementia.
Identification of pathological pathways centered on circRNA dysregulation associated with early pathogenic progression of Alzheimer’s disease
Authors: Wang Feng , Li Yangping , Shen Huifeng , Feng Yue , Yao Bing 
Published: January 2025

AbstractBackgroundCircular RNAs (circRNAs) play multifaceted roles to precisely control expression of broad gene networks. These highly stable molecules are often accumulated in the mammalian brain and thought to serve as “memory molecules” that govern the long process of aging. Mounting evidence demonstrated circRNA dysregulation in the postmortem brains of Alzheimer’s disease (AD). However, whether and how circRNAs dysregulation underlies AD disease progression remain unexplored.MethodsPoly(A)‐tailing/RNase R digestion was coupled with a recently published computational algorithm called CARP to examine circRNA landscapes alteration and identify functional circRNA‐pathways progressively dysregulated in the cerebral cortex of the 5xFAD mouse model of AD between 5‐ and 7‐month, a critical window for the transition of starting pathology to full manifestation. We have also employed comprehensive biochemical approaches to identify circRNA interactome, as well as short hairpin RNA‐based genetic approaches to manipulate circRNAs and their key regulators to pinpoint their mechanistic contributions to AD.ResultsWe discovered genome‐wide alterations of brain circRNAs within the above age window critical for AD progression. Further analysis revealed co‐operation of distinct circRNAs and age‐dependent switch of circRNA isoforms derived from internal alternative splicing and alternative back splicing, which offered new means for regulating miRNA‐mRNA pathways in the 5xFAD cortex. In particular, we focused on conserved circRNAs that were progressively downregulated with increased severity of dementia in human AD brains. During circRNA biogenesis, we identified several previously established AD‐affected splicing factors, such as hnRNPL, regulate the production of AD‐associated circRNAs. Mechanistically, we found these circRNAs contained binding sites for many miRNAs and demonstrated its activity in sponging several AD‐relevant miRNAs to regulate their target mRNAs indicated in AD pathogenesis. Furthermore, we identified multiple circRNA‐interacting RNA binding proteins associated with AD, including the cleavage and polyadenylation factor 6 (CPSF6). In fact, altered polyadenylation efficiency was observed, which results in aberrant upregulation of many known CPSF6 target mRNAs indicated in AD pathogenesis.ConclusionsTogether, our results unveiled pathological brain circRNA landscape alterations within a critical window for phenotypic progression in a mouse model of AD and identified novel molecular mechanisms underlying dysregulation of conserved circRNA pathways that contribute to AD pathogenesis.
Increase the amyloid pathology in meningitis‐induced cognitive impairment: sex differences
Authors: Danielski Lucineia , Giridharan Vijayasree V , Iwunze Ngozi , Catumbela Celso , Morales Rodrigo , Barichello Tatiana 
Published: January 2025

AbstractBackgroundPneumococcal meningitis is a type of meningitis that may face long‐term neurological complications, leading to the hypothesis that it might contribute to the deposition of beta‐amyloid (Aβ) and predispose individuals to Alzheimer’s pathology.MethodMale and female APP/PS1 mice, 50 days old, were divided into control (n = 5) and meningitis (n = 6). Under anesthesia, an intracisternal injection of either artificial cerebrospinal fluid (CSF) as a placebo or 5 × 109 colony‐forming units (CFU) of S. pneumoniae suspension was injected. Meningitis was confirmed through culture incubation. The Open Field Test (OFT) and Novel Object Recognition (NOR) tasks were conducted when the mice reached 180 days of age; after this, the hippocampus and prefrontal cortex (PFC) were stained to be evaluated by immunofluorescence.ResultMice of both sexes experiencing meningitis displayed cognitive impairment (p < 0,001) evaluated for NOR, but the distribution of Aβ burden differed between males and females. Males exhibited elevated Aβ predominantly in the hippocampus (p < 0,05), while females showed heightened Aβ levels exclusively in the PFC (p < 0,05). Interestingly, only females with meningitis showed increased levels of IBA‐1, a marker for microglial reactivity, in both the hippocampus (p = 0,0048) and PFC (p = 0,0023) compared to their controls.ConclusionThe distinct patterns observed in Aβ distribution and microglial activation between sexes suggest a potential association, indicating that meningitis can induce elevated Aβ deposition, with microglia potentially playing a role in this divergent response.
Cellular overexpression of mutant TDP‐43 results in a decrease in solubility of phosphorylated TDP‐43
Authors: Dopler Matthew B , Cox Keyshawn E , Petersen Tyler L , Abeer Muhammad I , Pressley Juneessa M , Arezoumandan Sanaz , Gitcho Michael A. 
Published: January 2025

AbstractBackgroundAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by upper and lower motor neuron death that leads to paralysis with the average survival being 3‐5 years after diagnosis. The major pathological protein in ALS is TDP‐43. TDP‐43 becomes hyperphosphorylated and forms inclusions mainly in the cytoplasm. Although only 5‐10% of familial cases are caused by mutations in TDP‐43; over 90% of all sporadic and familial ALS have TDP‐43 pathology. We have developed a cellular over expression model of TDP‐43 aggregation.MethodsThree familial ALS mutations (A315T, M337V, and S379P) were introduced in the TARDBP gene (3X‐TDP‐43) and cloned into pcDNA 3.1+ then transfected into HEK293 cells. Techniques used: Cell culture, Western blot, immunoprecipitation, immunofluorescence, nuclear/cytoplasmic fractionation, cellular solubility fractionation, and proteomics.ResultsOverexpressing 3X‐TDP‐43 in HEK cells results in an increase in TDP‐43 C‐terminal fragments, time dependent change in TDP‐43 localization from nucleus to the cytoplasm, and an increase in cytoplasmic phosphorylated TDP‐43. We observed reduced solubility of phosphorylated TDP‐43 and a time dependent flux of LC3B and an increase in P62 which may indicate potential autophagy dysfunction. Global shotgun proteomics reveal changes in protein expression in importin subunit alpha‐1 (KPNA2), heat shock 70 kDa protein 1A (HSPA1A), H2B clustered histone 17 (H2BC17), and protein disulfide‐isomerase A3 (PDIA3). TDP‐43 also interacts in complex with KPNA2 and PDIA3.ConclusionThis cellular overexpression model shows a change in solubility and aggregation of phosphorylated TDP‐43. Hopefully this model will provide a better understanding of the pathogenesis of TDP‐43 proteinopathies
Polygenic scores for Alzheimer’s disease risk and resilience predict age at onset of amyloid‐β
Authors: O’Brien Eleanor K. , Porter Tenielle , Fernandez Shane , Cox Timothy , Dore Vincent , Bourgeat Pierrick , Goudey Benjamin , Doecke James D. , Masters Colin L. , Rowe Christopher C. , Villemagne Victor L , Cruchaga Carlos , Saykin Andrew J. , Laws Simon M ,   ADOPIC Consortium (AIBL, ADNI, OASIS)
Published: January 2025

AbstractBackgroundGenome‐wide association studies (GWAS) have identified numerous genetic variants associated with Alzheimer’s disease (AD) risk, but genetic variation in the onset and progression of AD pathology is less understood. Accumulation of amyloid‐β (Aβ) in the brain is a key pathological hallmark of AD beginning 10 – 20 years prior to cognitive symptoms. We investigated the genetic basis of variation in age at onset (AAO) of brain Aβ by comparing the performance of polygenic scores (PGSs) based on AD risk and resilience with a Aβ‐AAO trait‐specific PGS.Method1122 participants from the Alzheimer’s Dementia Onset and Progression in International Cohorts (ADOPIC) study underwent genome‐wide SNP genotyping and assessment of brain Aβ using positron emission tomography (PET) imaging at two or more timepoints. AAO was the age at which participants were estimated to have crossed the 20 centiloid (CL) threshold for high Aβ. We utilised AD risk and resilience GWAS summary statistics and conducted a GWAS for AAO using a cross‐validation approach (10 test‐validation folds). We used PRSice to identify optimal PGSs for Aβ‐AAO for risk (PGSRisk), resilience (PGSResilience) and Aβ‐AAO (PGSAAO).ResultPGSRisk and PGSResilience were both significantly associated with Aβ‐AAO, such that higher PGSRisk and lower PGSResilience were associated with an earlier Aβ‐AAO. PGSRisk showed the strongest association and explained more variance in Aβ‐AAO than did PGSAAO. When stratified by APOE ε4 carriage, the strongest genetic risk factor for AD, the association of PGSRisk with Aβ‐AAO was stronger among ε4 non‐carriers, whilst PGSResilience, was more strongly associated with Aβ‐AAO in ε4 carriers.ConclusionPGS based on genetic risk and resilience for AD are both significant predictors of the age at which people are estimated to cross the threshold for high brain Aβ burden. Predicting the age at which a person will pass this threshold would enable treatment at an earlier stage, when it may more effectively delay or prevent symptom onset.
Utility of Embic digital cognitive biomarkers in predicting dementia conversion, brain volumetrics, and AD biomarkers in ADNI
Authors: Chen Michelle H. , Hu William T. 
Published: January 2025

AbstractBackgroundEarly identification of preclinical Alzheimer’s disease (AD) is key to timely interventions. However, existing neuropsychological test scores are not sensitive to subtle cognitive decline during preclinical AD. There is a need to develop cognitive measures that are more sensitive to early stages of decline. Embic digital cognitive biomarkers (DCBs) apply hierarchical Bayesian cognitive processing model to item‐level data of word list memory measures and attempt to delineate latent processes of memory encoding and retrieval, which may be more sensitive to subtle cognitive decline. The current study examined the utility of Embic DCBs in predicting dementia conversion and changes in brain volumetrics, as well as the relationship between AD biomarkers and Embic DCB trajectories.MethodA total of 2,425 participants (596 were cognitively normal [CN] at baseline, 874 had mild cognitive impairment [MCI] at baseline, and 298 had dementia at baseline) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with at least 3 visits were included in the current study. Cox proportional hazards models were conducted to determine conversion from CN to MCI and from MCI to dementia based on Embic DCB performance. Linear mixed effects models were performed to examine cross‐sectional and longitudinal associations between Embic DCBs and volumes of brain regions involved in memory, as well as Embic DCB trajectories based on cerebrospinal fluid (CSF)‐based AD biomarker profile.ResultHigher encoding and retrieval performances based on Embic DCBs were associated with increased risks of conversion from CN to MCI and from MCI to dementia. Specifically, measures related to encoding to and retrieval from long‐term “durable storage” were most predictive of conversion. Higher Embic DCB scores were associated with greater hippocampus and entorhinal cortex volumes at baseline, and those with lower Embic DCB scores exhibited greater decline in hippocampus and entorhinal cortex volumes over time. Participants with positive CSF‐based AD biomarkers showed steeper decline in Embic DCBs compared to those who were AD biomarker negative.ConclusionThe current study provided initial validation of Embic DCBs in predicting MCI/dementia conversion, brain volumetrics, and AD biomarkers in the ADNI sample. Future studies should examine the utility of Embic DCBs in predicting early stages of cognitive decline.
Impact of severe systemic infections on neuroimmune interactions in neurodegenerative diseases
Authors: Villareal Jonathan Anthony B. , Bathe Tim , Phillips Jennifer L , Prokop Stefan 
Published: January 2025

AbstractBackgroundSevere systemic infections can trigger cognitive decline, but the underlying mechanisms and their impact on the manifestation and progression of Alzheimer’s disease and other neurodegenerative diseases are poorly understood. The current COVID‐19 pandemic has brought a surge of severe viral illness and highlights the importance of understanding the impact of acute infections on cognition and the manifestation of neurodegenerative disease in survivors. A wealth of observational and clinical data suggests major short‐ and long‐term effects of severe infections on cognition, but detailed and systematic analyses of neuropathological changes after acute infections are scarce. In order to bridge this gap and to provide insight into the cellular and molecular effects of severe systemic inflammation on hallmarks of neurodegenerative diseases, we performed immune profiling on the brains of recovered COVID‐19 patients and of patients without a history of severe systemic infection.MethodImmunohistochemical profiling of microglial, astrocytic, and oligodendrocytic morphological biomarkers was performed in human post‐mortem tissue sourced from various brain regions. Glial coverage was directly quantified using immunohistochemical analysis software QuPath with custom parameters designed to adapt the program for detecting the different cell types. Multiplexed gene expression analysis of immune and neuroglia‐related genes in human post‐mortem tissue was performed using the Nanostring nCounter platform.ResultImmunohistochemical profiling of glial cells in COVID‐19 patients revealed a subtle but distinct difference in microglial activation, as well as differences in coverage of other glial sub‐types, as compared to non‐COVID patients, while no significant differences in disease‐associated protein pathologies were observed. Multiplexed gene expression analysis corroborated these findings and also revealed significant shifts in oligodendrocyte and myelination‐related transcriptomic profiles in COVID patients. A spatial component of COVID‐19 was also observed, with a difference in severity of glial population shifts existing between brain regions.ConclusionThese findings demonstrate a subtle, but distinct and long‐lasting effect of severe systemic infections on the brain’s innate immune system which may impact the onset and progression of neurodegenerative diseases. Gene expression analyses of patients suffering from COVID‐19 also indicate significant alterations in the transcriptome of oligodendrocytes, and further investigation into the cross‐talk between these cells and microglia should be performed.