bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Aerobic Exercise Training on Mood and Cognition in Adults at Risk for Alzheimer’s Disease
Authors: Brach Talia L. , Gaitán Julian M. , Okonkwo Ozioma C. 
Published: December 2021

AbstractBackgroundAerobic exercise is positively associated with mood and cognition, but its effect on protection against decline in mood and cognition in late‐middle aged adults at risk for Alzheimers disease (AD) is unknown.Method23 late‐middle aged adults from a cohort enriched with family history of AD and the APOE4 allele were randomized into Usual or Enhanced Physical Activity (PA) groups. Enhanced PA completed a progressive 26‐week supervised aerobic exercise program at 70‐80% heart rate reserve for 50 minutes, 3 times per week to achieve or exceed public health guidelines. Usual PA only received materials regarding active lifestyle. The Profile of Mood States (POMS) assessed total mood disturbance (TMD), characterized by fatigue, depression, tension, confusion, anger, and vigor. The California Verbal Learning Test II (CVLT‐II) measured verbal learning and memory via the total, short, and long delayed recall, and learning slope. The Delis‐Kaplan Executive Function System (DKEFS) assessed executive function via the trail‐making, color‐word interference (CWI), verbal fluency, and tower subtests. Graded treadmill exercise testing assessed cardiorespiratory fitness (CRF), and triaxial accelerometry measured moderate‐to‐vigorous physical activity (MVPA). Independent samples t‐tests between groups and Pearson’s correlations were conducted on baseline to post‐intervention change scores.ResultFatigue decreased significantly in Enhanced PA compared to Usual PA (‐1.18 ± 4.05 vs 2.92 ± 2.68, p= .009), and the decreases in TMD (‐7.64 ± 17.78 vs 6.00 ± 16.42, p=.07) and tension (‐2.00 ± 4.41 vs 0.67 ± 2.39, p= .08) among Enhanced PA were nearly significant. Changes in other mood subcategories and in cognition were not different between groups (all p’s> .15), except improved executive function on the DKEFS CWI as previously published (Gaitán et al. 2019). Correlations of mood with verbal learning and memory or executive function were not significant (all r’s < .17, all p’s> .44). Correlations of mood or cognition with CRF or MVPA were not significant (p’s> .175), except between DKEFS CWI and CRF as previously published (Gaitán et al. 2019).ConclusionAerobic exercise training may protect against fatigue in adults at risk for AD. However, change in mood was not associated with cognitive changes in this cohort.
Cellular proteomic profiling using proximity labeling by TurboID in microglial and neuronal cell lines
Authors: Sunna Sydney N , Rayaprolu Sruti , Bowen Christine A , Bagchi Pritha , Seyfried Nicholas T. , Rangaraju Srikant 
Published: December 2021

AbstractBackgroundDespite advancements in systems‐level analyses to Alzheimer's disease, global proteomic profiling of brain homogenate cannot resolve molecular changes occurring in distinct cell types. Proximity labeling of proteins by the biotin‐ligase TurboID, coupled with mass spectrometry (MS) analyses of biotinylated proteins, can resolve cell‐type specific proteomes from brain without cell type enrichment. Before in‐vivo applications, it is important to identify proteins preferentially labeled by TurboID in mammalian cells, and directly compare biotinylated proteomes with whole cell proteomes. We determined whether TurboID‐labeled proteomes in microglial (BV2) and neuronal (N2A) cell lines are representative of total cellular proteomes under homeostatic and activated conditions.MethodWe generated N2A and BV2 cell lines that stably express TurboID fused to a nuclear export sequence. Cells incubated in 200μM biotin and 1μg/mL lipopolysaccharide (LPS) for 48hrs to mimic inflammatory stress. Western blotting and label‐free quantitation MS identified biotinylated proteins in whole‐cell‐lysates and streptavidin‐enriched preparations.ResultWestern‐blot confirmed robust biotinylation in TurboID N2A and BV2 cell‐lines. LFQ‐MS quantified >3,000 proteins in inputs and >2,400 proteins in biotinylated proteomes from both cell types. In BV2 and N2A inputs, TurboID expression and biotinylation didn't impact the proteome, evidenced by few differentially‐expressed proteins and absence of cellular respiration measures in mitochondrial stress‐tests, comparing TurboID and non‐TurboID cells. Of all the proteins quantified in BV2 and N2A TurboID inputs, ∼50% were also quantified in the biotinylated proteomes in both cell types. Compared to input proteomes of both cell types, the biotinylated proteome was enriched in vesicular, ribosomal, mitochondrial, cytoplasmic and cytoskeletal proteins. The biotinylated proteome successfully differentiated BV2 and N2A cells. LPS stimulation altered levels of 759 proteins in BV2 cells in the input proteome, of which the top increased (e.g. Irg1, Oasl1, Cyb5a) and decreased (e.g. Mrc1, Mgl2, Arg1) proteins showed concordant changes in the biotinylated BV2 proteome.ConclusionOur analyses show that proteomic labeling by TurboID in microglial and neuronal cell lines doesn't disrupt cellular function. The resulting biotinylated proteomes are reasonably representative of the whole‐cell proteome and captures the most robust alterations induced by immune stimuli in microglia. These foundational data will guide future applications of proximity‐labeling for cell‐type‐specific proteomics in‐vivo.
Alcohol use disorder and mild cognitive impairment: Shared neural signatures during an episodic memory task
Authors: Barlis Katie L , Bustos Nicholas , Warner Graham , Nowling Duncan , Cosentino Emily , Benitez Andreana , Flanagan Julianne , Mintzer Jacobo E , Joseph Jane E 
Published: December 2021

AbstractBackgroundAlcohol Use Disorder (AUD) has previously been identified as a risk factor for Alzheimer’s disease and cognitive impairment. However, the mechanisms underlying the connection between AUD and Alzheimer’s disease remain unclear. Episodic memory is impaired in both AUD and mild cognitive impairment (MCI), and is associated with the transition from MCI to Alzheimer’s disease. This study used functional magnetic resonance imaging (fMRI) to compare activation during encoding of an episodic memory task in mid‐life AUD subjects to subjects with mild cognitive impairment (MCI), a prodromal stage of Alzheimer’s disease.MethodParticipants included 14 AUD subjects age 45 to 65 (M = 56 years), and 14 MCI subjects age 45 to 85 (M = 67 years). Healthy control subjects were matched to AUD and MCI groups by age and sex. Images were acquired on a 3T Siemens Prisma (3 mm3 voxels, TR = 1.1s, TE = 30 ms). During the fMRI task, participants viewed pictures of faces and objects and were instructed to remember these pictures for later. Activation maps were produced through general linear model analysis using cluster correction thresholding (Z>3.3, p = .05) in FSL (version 6.0).ResultsAUD and MCI groups showed reduced extent of BOLD activation during encoding versus baseline (Figure 1). Compared to matched controls, AUD and MCI subjects showed less medial temporal lobe (amygdala), brainstem, and thalamus activation. Additionally, AUD subjects did not exhibit the frontal activation that was present in MCI and matched controls.ConclusionsGiven the small sample sizes, caution should be taken in interpreting these results. Nonetheless, these preliminary findings suggest that mid‐life AUD subjects show similar patterns of reduced activation during episodic encoding to those with MCI. Reduced medial temporal lobe activation may represent vulnerability to Alzheimer’s disease, which is present in both MCI and AUD. Explanations for the differences in frontal activation might include compensatory mechanisms in MCI or executive dysfunction in AUD. Future analyses will aim to disentangle these effects by examining the relationship between BOLD signal activation and behavioral outcomes.
Starvation and activity dependent modulation of salt taste behavior in Drosophila
Authors: Kaushik Shivam , Limas Diego E Rincon , Kain Pinky 
Published: December 2021

AbstractBackgroundSodium present in NaCl is a fundamental nutrient required for many physiological processes but high salt consumption in western world is contributing health risk to all age individuals. Although high salt detection pathways have been studied in great detail, the mechanisms that regulate high salt consumption in animals are largely unknown. To understand how pre‐exposure to high NaCl diet modulates subsequent feeding behavior, we looked into the neural mechanisms of high NaCl consumption in adult Drosophila.MethodWe used Neuro‐Genetics, imaging and behavioral assays to determine how flies respond to high NaCl exposure.ResultWe studied the neural mechanism by which flies modify their acceptance of high salt as a function of diet, where a long‐term high‐salt exposure increases taste sensitivities of pharyngeal LSO (Labral sense organ) neurons and enhances high salt intake. We discovered that exposing flies to high NaCl diet (200mM NaCl in fly food) for three days modify their feeding responses to high levels of salt. High NaCl fed flies show decline in high salt aversion under starvation. Genetic suppression of LSO pharyngeal neurons in high NaCl fed flies inhibits excessive salt intake. We found that this modulation requires functional LSO neurons and starvation state, and that multiple independent taste receptor neurons and pathways are involved in this process. Silencing any one of multiple LSO neuronal types inhibits excessive salt intake.ConclusionOur data support the idea that high dietary salt modulates and reshapes salt and other taste curves to promote over consumption of food in flies. Our study suggest flies can adapt to the amount of salt ingested over several days, indicating the presence of a critical mechanism to reset the salt appetite and related neural circuits. Identification of new molecular sensors for salt and related neural controls such as hormones, neuropeptides, and neurotransmitters may yield insights into the coordination of processes in the nervous system.
Racial considerations of age and white matter hyperintensities
Authors: Misiura Maria , Igwe Kay C , Wharton Whitney , Verble Danielle D , Turner Jessica A , Dotson Vonetta , Brickman Adam M. , Hu William T 
Published: December 2021

AbstractBackgroundWhite matter hyperintensities (WMH) are regions that appear very bright on Fluid‐Attenuated Inversion Recovery (FLAIR) magnetic resonance images (MRI). They are generally attributed to cerebrovascular disease (CVD) and confer a greater risk for Alzheimer’s Disease (AD). Black individuals (BIs) typically have greater WMH burden than their white counterparts and have a two‐fold greater risk of developing AD in their lifetimes. For this project, we wanted to determine whether WMH were related to diagnostic category, and if this relationship differed according to race.MethodCohort 1 included middle‐aged cognitively normal black and white individuals (N=50). Cohort 2 included older black and white individuals on the dementia continuum (NC=47, MCI=10, AD=3). Data collection included a neuropsychological battery and magnetic resonance imaging (MRI). Fluid attenuated inversion recovery (FLAIR) MRI data were analyzed to obtain lobe specific WMH volumes (frontal, temporal, occipital, parietal, cerebellar). Because of age and diagnostic differences, we analyzed each cohort separately. We constructed multivariate linear models for each cohort with WMH volumes as the outcome variable, age, race, gender, and diagnostic category (Cohort 2 only) as independent variables. We included age X race, and race X diagnosis (Cohort 2 only) interaction terms.ResultThere were no racial or diagnostic differences in regional WMH volume. However, in Cohort 1, there was a significant race X age interaction in the parietal lobe such that in BIs, as age increased, WMH volume also increased (B=, t(3,46)=2.07, p =0.04). In Cohort 2, this relationship extended to the temporal (B=0.09, t(3,55)=2.95, p=0.04), and occipital lobes (B=0.09, t(3,55)=2.99, p=0.04). There was no such relationship observed in WIs.ConclusionAge conferred greater WMH volume in BIs than in WIs in cognitively normal individuals and individuals on the dementia spectrum. The relationship we observed between WMH and AD could be seen as additive rather than causative, as we observed only a relationship between age and WMH volume, not diagnostic category. The differential findings across race suggest that age has a greater effect on BIs on CVD and brain health. These findings, although not causal, should encourage AD researchers to collect more diverse samples, and consider underlying CVD in data analyses.
Investigating the mechanisms of brain innate immune activation following bacterial infection in Drosophila
Authors: Mainali Sameekshya , Harper Luren , Bolling Jordan , Berry Kaitlin , Kitchens Elizabeth , Chtarbanova Stanislava 
Published: December 2021

AbstractBackgroundCentral Nervous System (CNS) infections caused by bacteria and resulting immune responses could underlie neurodegenerative diseases such as Alzheimer’s disease (AD). Neuroinflammation is a well‐known component of AD furthering disease pathology and progression. However, the mechanisms by which infectious agents contribute to neuroinflammatory reactions and neurodegeneration are not fully understood. The model organism Drosophila melanogaster shares conserved mechanisms of innate immune activation and neural development with mammals, and thus represents an excellent system for the investigation of pathogen‐associated neurodegeneration. Previous work in flies has shown that bacterial brain injection results in age‐dependent neurodegeneration and impaired locomotor activity. Furthermore, these phenotypes depend on NF‐κB in both glia and neurons, suggesting that long‐term inflammatory processes take place in both cell types. However, a detailed picture of innate immune pathway activation in the Drosophila brain following bacterial infection is lacking. Here, we investigate the activation in the brain of the two Drosophila NF‐ κB pathways, Toll and Immune deficiency (IMD), in response to infection with Gram‐positive and Gram‐negative bacteria, respectively.MethodFly brains are infected by pricking heads with a thin, metal needle, dipped into concentrated pellets of overnight cultured bacterial solutions. Activation of NF‐κB pathways in brain cell types is assayed using immunohistochemistry and confocal microscopy of flies carrying fluorescent NF‐κB reporters. The dependence of canonical NF‐κB pathway components is assayed using quantitative reverse‐transcription PCR (RT‐qPCR) using RNA isolated from dissected brains of control‐injected or bacterially injected flies.ResultOur preliminary results show that brain bacterial injection leads to the activation of GFP reporters for both Toll and IMD pathways in multiple glial subtypes in the fly brain 24h following infection. We have optimized a protocol for brain‐specific gene expression of NF‐κB targets and are currently examining the response to bacterial challenge of multiple mutants for components of the Toll and IMD pathways.ConclusionWe have established a Drosophila model of bacterial brain infection that allows studying the long‐term consequences of pathogen‐mediated neuroinflammatory reactions associated with neurodegeneration. Our system could be used to identify the processes of immediate protection as well as the long‐term effects of brain infection.
Astroglial ER protein Membralin is an essential neuroinflammation regulator
Authors: Jiang LuLin , Li Xiaoguang , Myers Stephanie , Huang Timothy , Kaufman Randal J. 
Published: December 2021

AbstractBackgroundThe endoplasmic reticulum (ER) is the primary organelle for synthesizing membrane proteins, secretory proteins, and lipids. Disturbance of ER homeostasis in peripheral immune cells is associated with inflammatory responses. Glial cells, including astrocytes and microglia, are the immune cells in the brains, becoming reactive/gliosis during the progression of Alzheimer’s disease (AD). However, whether and how glial protein homeostasis mediate the reactive state of glial cells is yet to be investigated. We previously identified a novel ER‐associated degradation component, membralin/TMEM259, as an important mediator in neurodegeneration. Loss of membralin impaired the turnover of nicastrin protein, which increased gamma‐secretase complex formation and activity. Knockdown membralin in the TgCRND8‐AD mice exaggerated beta‐amyloid‐associated neuronal damage. Moreover, selective deletion of membralin in astrocytes decreased excitatory amino acid transporter 2 (EAAT2) expression and induced excitotoxicity. Elevating membralin levels in SOD1 G93A
ALS mouse model can significantly extend the lifespan of the animals.MethodTranscriptomic profiles of the cortex tissues and histology were analyzed in the astrocyte‐conditional membralin knockout animals. Primary astrocyte ER morphology was examined by electron microscopy analysis. We crossed the transgenic membralin animals with 5xFAD animals and assessed the AD pathology.ResultAstroglial membralin knockout animals develop strong neuroinflammation phenotypes. Loss of membralin in astrocytes disrupts ER homeostasis and nuclear envelop integrity, and induces senescence‐like phenotypes. In contrast, the elevation of membralin in astrocytes can alleviate the induction of C3+ astrocytes upon c1q/IL1a/TNFa treatment. Further, elevating membralin levels in 5XFAD mouse model can significantly reduce the AD pathologies.ConclusionMembralin is critical in mediating the reactive states of astrocytes. Modulation of astroglial ER homeostasis can be a promising target to regulate neuroinflammation for AD therapy.
Investigating epigenetic loci implicated in Alzheimer’s disease via the CRISPR‐Cas9 system
Authors: Schrauben Michael , Smith Adam R. , Washer Sam , Dempster Emma , Lunnon Katie 
Published: December 2021

AbstractBackgroundDifferentially methylated positions (DMPs) identified by Epigenome‐wide association studies (EWAS) of Alzheimer’s disease (AD) were modified by the CRISPR‐Cas9 system to investigate the role of epigenetic alterations in AD pathogenesis.MethodCell lines of neuronal phenotype (SH‐SY5Y) and microglial phenotype (IHM‐SV40) were used to explore the functional consequence of loci demethylation, where removal of the methyl groups was achieved by the modified CRISPR‐dCas9 system. Lentiviral delivery of the dCas9‐TET1CD demethylase tool and guide RNA (gRNA) constructs targeting the CpG sites associated with differential expression of ANK1 and BIN1 in AD was validated by fluorescence‐activated cell sorting (FACS). Bisulphite pyrosequencing was applied to confirm the DNA methylation edit.ResultHigh transduction efficiencies were observed during FACS of SH‐SY5Y cells transduced with CRISPR‐dCas9 constructs targeting the BIN1 locus and IHM‐SV40 cells with constructs against the ANK1 locus. Methylation analysis of these target regions in the modified cell lines demonstrated a reduction in methylation when compared to the untreated control cells. This modification was maintained over a three‐week period.ConclusionDelivery and activity of our CRISPR‐dCas9 fusion constructs was demonstrated in cell line models of AD. In the future, we intend to profile the epigenome and transcriptome of these modified cell lines to identify any off‐target effects of the CRISPR‐dCas9 system and determine differences in mRNA transcript variant levels of our target genes.
Assessment of genetic modulators in cerebrospinal fluid levels of YKL‐40, and C‐reactive protein: An association with Alzheimer disease
Authors: Parveen Kayenat 
Published: December 2021

AbstractBackgroundAlzheimer's disease (AD) is one of the most complex progressive neurological diseases that cause memory loss and cognitive deterioration owing to the death of brain cells. Some potential biomarkers have been discovered in cerebrospinal fluid (CSF) which could help in the prediction of AD. These biomarkers are either associated with amyloid pathology or tau pathology. But some of the biomarkers are also associated with neuro‐Inflammation, which is the third potential event associated with AD pathogenesis[i]. The levels of YKL‐40 and C‐Reactive Protein(CRP) in CSF are the biomarkers, which are found to be associated with AD[ii]. In this study, we are investigating more about the roles of these biomarkers in AD pathogenesis.MethodThe analysis was performed on the DELCODE dataset (n=311). The findings were validated in ADNI(n=277) and requested the independent cohort ACE (n=543) to contribute to our study in meta‐analysis. The Z‐score is produced and utilized as a phenotype with sex, age, 3 Principal Component Analysis, and diagnosis as covariates in linear regression. Furtheron, we used DELCODE, ADNI, and ACE summary statistics to run random and fixed‐effect models for the meta‐analysis.ResultFollowing the study, we discovered the genetic variants of YKL‐40, and CRP with genome‐wide significant P‐values (5 x 10‐8) and evidence of connection in all datasets. In these biomarkers, however, including diagnosis as a covariate plays important role. All of the biomarkers' lambda values indicate that there is no inflation in the analysis(λ = 1.0). There was no discernible difference in age or gender. According to the meta‐analysis the genome‐wide significant loci linked with YKL‐40 appear to be in the region of chr1 and chr3; and for CRP in chr6 and chr19.ConclusionOur findings imply that the important SNPs linked to these biomarkers are found in protein‐coding areas and are connected with inflammation. In the CSF of people with AD, levels of YKL40, and CRP are higher than in healthy people. Innate immune responses and neuro‐inflammatory signaling pathways are both affected by these proteins. Taken together, these findings emphasize the importance of comprehending the complexities of AD.
Cerebrospinal fluid levels of fatty acid binding protein 3 associate with brain amyloidosis in cognitively healthy individuals at risk of developing Alzheimer’s disease
Authors: Dhiman Kunal , Martins Ralph N , Gupta Veer Bala 
Published: December 2021

AbstractBackgroundAn accurate diagnosis of preclinical Alzheimer’s disease (AD) can be made by developing classifier algorithms that include biomarkers commensurate with different pathological changes. Amyloid positivity forms the key criterion of identifying cognitively healthy individuals having either preclinical AD pathological change or preclinical AD. Therefore, biomarkers that not only associate with a specific pathophysiology, but also with brain amyloidosis should be included in diagnostic classifiers. Here, we assessed the association of baseline levels of cerebrospinal fluid (CSF) fatty acid binding protein 3 (FABP3) – a biomarker of neurodegeneration associated with disrupted lipid metabolism, with brain amyloidosis at baseline, as well as change in amyloidosis, in cognitively healthy individuals.MethodFatty acid binding protein 3 levels were measured in CSF samples of 142 cognitively healthy participants from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL), using a commercial electrochemiluminescence immunoassay on a Meso Scale Discovery platform. Participants were aged >60 years, and their brain amyloid‐β (Aβ) load was assessed via positron emission tomography (PET) using different tracers.ResultAssociation of CSF FABP3 levels with baseline brain Aβ load as measured by standardized uptake value ratio (SUVR), as well as change in Aβ load at follow‐up was assessed using linear regression analyses. The average follow‐up time interval was 1.7 years. FABP3 levels were positively associated with baseline brain Aβ load as measured by SUVR (standardised β = 0.22, p = 0.009) and also with the change in brain Aβ load i.e., change in SUVR at follow‐up (standardised β = 0.32, p = 0.004).ConclusionResults indicate that changes in amyloid pathology align with changes in lipid metabolism. Since FABP3 is a biomarker of neurodegeneration, indicative of disrupted lipid metabolism and associated with amyloidosis, it can be used to facilitate screening or diagnosis of preclinical AD.