bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potential drivers of age‐ and beta‐amyloid‐related neurodegeneration in early and late Alzheimer’s Disease regions in cognitively normal older adults
Authors: Wuestefeld Anika , Berron David , van Westen Danielle , Stomrud Erik , Mattsson‐Carlgren Niklas , Strandberg Olof , Smith Ruben , Palmqvist Sebastian , Glenn Trevor , Hansson Oskar , Wisse Laura 
Published: December 2021

AbstractBackgroundAging, cerebrovascular disease, β‐amyloid (Aβ), and tau pathology are hypothesized to play a role in neurodegeneration, but their interplay is unclear. We investigate associations of these predictors with neurodegeneration, and potential mediating effects on age‐ and Aβ‐related neurodegeneration, in an early Alzheimer’s disease (AD) region (medial temporal lobe (MTL)), and other earlier/later AD neocortical regions in cognitively normal older adults and a low‐Aβ subgroup.Method351 adults (41‐91 years) from the Swedish BioFINDER‐2 study were included (65.5±11.8 years; low‐Aβ: n=232, 63.1±11.9 years). Using the Automated Segmentation for Hippocampal Subfields package for T1‐ and T2‐weighted MRI, volumes (dentate gyrus, subiculum (SUB), cornu ammonis 1) and thickness (entorhinal cortex, Brodmann areas (BA) 35/36, and parahippocampal cortex (PHC)) were obtained. FreeSurfer parcellation was used to obtain thickness of neocortical regions involved earlier/later in AD. [18F]RO948‐ and [18F]flutemetamol‐PET standard uptake value ratios were calculated for local tau (partial‐volume corrected) and global Aβ. White matter lesion volumes (WML) were obtained to estimate cerebrovascular disease. Global Aβ‐PET and cerebrospinal fluid Aβ‐42/40 ratio determined Aβ status.ResultsIn the whole group, negative (partial) correlations of age/local tau‐PET/WML with structure in most examined regions were observed (Table 1). In the MTL, these predictors were mostly associated with SUB/BA35/PHC. Global Aβ‐PET showed consistent negative associations with neocortical thickness. Low‐Aβ group associations were comparable. In the whole group, age‐structure associations were mediated serially via Aβ‐local tau and directly via tau‐PET in regions with early AD pathology (SUB/BA35, precuneus/posterior cingulate (PPC); Fig.1). In a later AD region (inferior parietal cortex (IP)), local tau‐PET mediated Aβ‐IP association. In low‐Aβ individuals, local tau‐PET mediated the age‐PPC association (Fig.2). Global WML mediated age‐structure associations in posterior MTL and parietal regions in the whole (Fig.1) and low‐Aβ group (Fig.2).ConclusionThe role of both Aβ‐ and tau‐PET in mediating age‐structure associations in regions typically linked to either early Aβ or tau, could point to an earlier role of Aβ in the MTL and tau in PPC than expected. WML mediating age‐effects on neurodegeneration, in posterior MTL and parietal regions, indicates a potential vulnerability of the posterior‐medial network to cerebrovascular disease.
Testing the neuroinflammatory role of tau‐induced transposable elements in tauopathy
Authors: Thomas Elizabeth Ochoa , Ramirez Paulino , Hyman Bradley T , Ray William J , Frost Bess 
Published: December 2021

AbstractBackgroundNovel mechanisms through which pathogenic tau leads to neuronal toxicity remain largely unexplored as therapeutic targets for tauopathies. Activation of retrotransposons has been identified as a mechanism by which pathogenic tau contributes to neurotoxicity (Guo et al., 2018; Sun et al., 2018). To mobilize, retrotransposons are transcribed into RNA, reverse transcribed into DNA, and reinserted into the genome in a new location. Control of retrotransposons occurs at two levels, 1) transcriptional control via the location of retrotransposons within highly condensed heterochromatin and 2) by post‐transcriptional silencing mechanisms. While activated retrotransposons can create novel mutations via the “copy‐and‐paste” mechanism, double stranded RNAs (dsRNAs) formed from transposable element transcripts trigger the innate immune response, further contributing to cell toxicity (Cuellar et al., 2017; Kassiotis & Stoye, 2016; Roulois et al., 2015). Elevation of dsRNAs is documented in models of AGS and TDP‐43 proteinopathy, where dsRNA derived from repetitive elements can stimulate an interferon response (Ahmad et al., 2018; LaRocca, et al., 2019; Rodriguez et al., 2021).We are currently testing the hypothesis that transposable element‐derived dsRNAs stimulate the immune response in tauopathy.MethodBioinformatic analysis of bidirectional transcription was completed on RNA‐sequencing data from control and tau transgenic Drosophila. dsRNAs were quantified by J2 anti‐dsRNA antibody via immunofluorescence and ELISA. Analysis of inflammatory markers in Drosophila was completed by RNA‐sequencing and with a custom NanoString Gene Expression codeset.ResultWe find that dsRNAs are elevated in the brains of tau transgenic Drosophila, in the cortex of a mouse model of tauopathy, and in post‐mortem brain tissue from human tauopathy. Based on bioinformatic analysis, we identified retrotransposons that are bidirectionally transcribed in tau transgenic Drosophila. RNA sequencing and NanoString analysis of tau transgenic flies reveals elevated levels of innate immune response gene transcripts. Loss of transposon transcriptional silencing results in similar dsRNA production and immune system activation found in tau transgenic Drosophila.ConclusionOur goal is to determine if RNA intermediates from tau‐induced transposable elements are a therapeutic target for tauopathies. Overall, our findings support a model where dsRNA production induced by loss of transcriptional transposon silencing contributes to inflammation in tauopathy
Identification of state‐specific proteomic characteristics of microglia‐derived exosomes
Authors: Santiago Juliet V , Rayaprolu Sruti , Xiao Hailian , Seyfried Nicholas T. , Rangaraju Srikant 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is the most common neurodegenerative disorder defined by progressive pathological protein aggregation (amyloid‐beta and tau) and deterioration of cognitive function. Microglia‐mediated neuroinflammation is a key pathological component of AD; however, there are critical gaps in our understanding of how microglia perpetuate AD pathology. One proposed mechanism of microglia‐mediated neuroinflammation and neurodegeneration is exosome release because of their critical role in the transport of macromolecules between cells to facilitate intercellular communication. Thus, it is possible that microglia‐derived exosomes transfer pathogenic cargo which could perpetuate AD pathology. The proteomic profiles and influence of different microglia‐derived exosomal populations on AD pathology remain unknown. We hypothesize that different microglia states determine the molecular composition of exosomes.MethodWe treated a murine microglia cell line, BV2 cells, with various cytokines to polarize them and collect their exosomes for downstream mass spectrometry (MS) analyses. Three groups of BV2 cells (n=4/group) were treated with either lipopolysaccharide (LPS) to polarize to a pro‐inflammatory state, interleukin 10 (IL‐10) to polarize to an anti‐inflammatory state, or transforming growth factor beta (TGF‐β) to polarize to a homeostatic state. Untreated BV2 cells served as a control group. Following 72 hours of treatment, BV2 cells were lysed and cell culture media was collected for exosome isolation.ResultTransmission electron microscopy images and western blotting for exosomal marker, CD9, confirmed exosome purification by our isolation method. In MS studies, we identified 533 proteins in exosome fractions and 1,866 proteins in BV2 cell proteomes. We found that known exosome related proteins, Sdcbp and Igsf8, were significantly increased in the exosomal proteome compared to the whole cell proteome. We identified proteins that are differentially expressed across polarization with unique proteins increased in exosomes derived from LPS, IL‐10, and TGF‐β treated BV2 cells. Validation studies of these top hits are ongoing, and studies are underway to replicate these findings in primary microglia.ConclusionOur results indicate that exosomes derived from microglia adopt distinct state‐associated protein profiles which may have differential effects on other cell types. This work will guide future studies concerning the role of exosomal cargo in perpetuating AD pathology.
Evaluation of Metformin and Dehydrozingerone against fluorosis induced neurodevelopmental toxicity in preclinical models
Authors: Ahuja Tejas , Kumar Nitesh , Begum Farmiza , Shenoy Rekha R 
Published: December 2021

AbstractBackgroundInorganic fluoride is widely used in dental practices to treat problems like dental caries and also to prevent bone related issues. It has been reported that exposure to excess amounts of fluoride either through drinking water or other sources impairs vital functions of the body and can prove to be toxic specially for the central nervous system. Many studies have shown that sodium fluoride (NaF) crosses the blood brain barrier in early developmental stages and causes impairments related to learning and memory, anxiety, decreased locomotor ability and in some cases, depression like behaviour specially in children. This study aims at evaluating the neurotoxic effects of chronic exposure of NaF in developmental stages in albino Wistar rats using Pre‐Natal in‐vivo model.MethodIn this model, adult male & female Wistar rats were procured & mated. Once the pregnancy was established in female rats, NaF (100 ppm) was fed via drinking water to the groups. For treatment groups, Metformin (200 mg/kg) & Dehydrozingerone (DHZ) (200 mg/kg) were administered along with NaF. Dosing was continued throughout the gestation and lactation period to the newly born pups via mother. After 21 days, pups were separated from mothers & direct dosing of both NaF & test doses to the rat pups was initiated until the end of experiment. At the end of dosing period, animals were taken for behavioural tests, biochemical estimation & histopathological studies.ResultNaF exposure significantly decreased learning, memory & locomotor ability was able to induce anxiety like behaviour. Levels of AchE & lipid peroxidation was found to be significantly elevated. GSH levels were significantly decreased in hippocampus & frontal cortex in disease group. Histopathology studies showed presence of degenerated neurons in hippocampus of disease group. It was also observed that treatment with Metformin & DHZ was able to ameliorate the cognitive impairment, improve condition of oxidative stress & decrease neuronal degeneration in rat pups (at p<0.05).ConclusionThis study shows that chronic exposure to NaF led to cognitive impairment & results showed that Metformin & DHZ has neuroprotective ability with special emphasis on antioxidant properties.
Identification of Kv1.3 potassium channel interacting proteins in mammalian cells.
Authors: Bowen Christine A , Dowling Tia C , Lin Young , Bagchi Pritha , Nguyen Hai Minh , Wulff Heike , Seyfried Nicholas T. , Rangaraju Srikant 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuronal loss, accumulation of amyloid‐beta(Aβ) plaques, and neuroinflammation. Microglia, the immune cell of the brain, transition to disease associated microglia (DAM) in AD. A subset of DAM, known as proinflammatory DAM, promote neuronal injury and release proinflammatory cytokines. Our lab established that proinflammatory DAM highly express Kv1.3 potassium channel, which consist of a homotetramer of Kv1.3 that interacts with a homotetramer of Kvβ2. Blockade of the Kv1.3 channel reduces microglial immune responses in mouse models. Both Kv1.3 and Kvβ2 contain motifs that interact with immune signaling proteins, however more evidence is needed to support this hypothesis. TurboID is a biotin ligase that biotinylates proteins within a 10nm radius. Split‐TurboID consists of two functionally inactive fragments of TurboID that within proximity of each other, fuse and actively biotinylate proteins within proximity. We will identify molecular interactors of Kv1.3 channels in mammalian cells using proximity labeling.MethodWe fused TurboID or Split‐TurboID to the N‐ or C‐terminal Kv1.3 and Kvβ2 using a 15 amino‐acid inert linker and transfected the constructs into Hek293 cells. TurboID not fused to Kv1.3 and sham transfection acted as controls. Flow cytometry and patch‐clamp electrophysiology confirmed the presence of functional Kv1.3 channels. Biotinylated proteins were streptavidin bead affinity‐enriched from cell lysates and confirmed using western blots.ResultLabel free quantitation mass spectrometry (LFQ‐MS) identified 2,195 biotinylated proteins of which very few were enriched in negative controls. There were 313 proteins as N‐term interactors, 385 as C‐term interactors, and 226 proteins common to both N and C term fusions, representing proteins indirectly associated with Kv1.3 channels. we identified 14 unique N‐term interactors (including metabolic proteins, eg. Naca, Txnl1, Stub1) and 38 unique C‐term interactors (including membrane trafficking proteins, eg. Ank3, Plekha7, Erlec1). Split‐TurboID interactions between Kv1.3 and Kvβ2 indicate that these interacting proteins are largely dependent on the fully functional Kv1.3 with the Kvβ2 subunit present. We packaged these plasmids into lentiviruses to transduce into mouse microglial cell lines.ConclusionOur findings indicate Kv1.3 channels interacting with Kvβ2 are a novel molecular mechanism of immune regulation in mammalian cells.
miR‐277 targets hid to ameliorate Aβ42‐mediated neurodegeneration in Drosophila eye model of Alzheimer’s Disease
Authors: Deshpande Prajakta , Chen Chao‐Yi , Yeates Catherine , Chen Chun‐Hong , Kango‐Singh Madhuri , Singh Amit 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD), an age‐related progressive neurodegenerative disorder, exhibits reduced cognitive functions with no cure to date. One of the reasons for AD is the extracellular accumulation of Amyloid‐beta 42 (Aβ42) plaques. Misexpression of human Aβ42 in the developing retina of Drosophila exhibits AD‐like neuropathology. Accumulation of Aβ42 plaque(s) triggers aberrant signaling resulting in neuronal cell death by unknown mechanism(s).Method: Alzheimer’s disease (AD), an age‐related progressive neurodegenerative disorder, exhibits reduced cognitive functions with no cure to date. One of the reasons for AD is the extracellular accumulation of Amyloid‐beta 42 (Aβ42) plaques. Misexpression of human Aβ42 in the developing retina of Drosophila exhibits AD‐like neuropathology. Accumulation of Aβ42 plaque(s) triggers aberrant signaling resulting in neuronal cell death by unknown mechanism(s).ResultGain‐of‐function of mir‐277 rescues Aβ42 mediated neurodegeneration whereas loss‐of‐function of mir‐277 enhances Aβ42 mediated neurodegeneration. Moreover, misexpression of higher levels of mir‐277 in the GMR>Aβ42 background restores the retinal axonal targeting indicating functional rescue. Furthermore, we have identified head involution defective (hid) as one of the targets of mir‐277. The hid transcript levels are decreased by one third when mir‐277 is misexpressed in the GMR>Aβ42 background in comparison to the GMR>Aβ42 fly model.ConclusionHereby we provide a mechanism of how mir‐277 modulates Aβ42 mediated neurodegeneration by regulating hid transcript levels and demonstrate its neuroprotective role in Aβ42‐mediated neuropathology.
Effect of insulin resistance on the association between cardiorespiratory fitness and cognition in adults at risk for Alzheimer's disease
Authors: McIntyre Clayton Connor , Okonkwo Ozioma C. , Gaitán Julian M. , Bendlin Barbara B , Edmunds Kyle J 
Published: December 2021

AbstractBackgroundCardiorespiratory fitness (CRF) and cognition have been found to be correlated, though it is unclear what mechanisms are responsible for this correlation. CRF and cognition are also closely related to insulin resistance. We investigated whether insulin resistance explains the relationship between CRF and cognition.MethodThis study included 1157 participants, all cognitively unimpaired and without history of diabetes. CRF was estimated using a validated equation that takes age, sex, BMI, resting heart rate, and self‐reported physical activity habits as inputs. Insulin resistance was quantified by the Homeostatic Model Assessment for Insulin Resistance (HOMA‐IR). Composite scores for executive function, immediate learning, delayed recall, and the Preclinical Alzheimer’s Cognitive Composite (PACC3) were calculated from neuropsychological tests administered by trained technicians. For each cognitive score, linear regression models were utilized to test the influence of CRF on cognition. Mediation analyses were performed to determine whether HOMA‐IR contributed to significant associations between CRF and cognition. All analyses controlled for age, sex, years of education, familial history of Alzheimer’s disease, and Apolipoprotein E4 (APOE4) carriage. Bootstrapped confidence intervals were used to estimate the effect of HOMA‐IR on the CRF/cognition relationship.ResultThe sample was comprised of 69.8% females and 38.7% APOE4 carriers with a mean age of 64.5 ± 7.2 years and a mean 16.3 ± 2.8 years of education. CRF was positively associated with executive function (total effect: B=.015, SE=.005, p=.003), but was not associated with immediate learning (p=.920), delayed recall (p=.970), or PACC3 (p=.258). HOMA‐IR was further investigated as a mediator between CRF and executive function. CRF was negatively associated with HOMA‐IR (B=‐.241, SE=.013, p<.001) and HOMA‐IR had a non‐significant negative association with executive function (B=‐.013, SE=.012, p=.264). While adjusting for HOMA‐IR as a mediator, the association of CRF with executive function was positive and significant (direct effect: B=.012, SE=.006 p=.040). The bootstrapped estimate of the effect of HOMA‐IR on the CRF/executive function relationship was insignificant (B=.0031, CI = [‐.0020, .0087]).ConclusionHOMA‐IR did not significantly mediate the relationship between CRF and executive function among individuals at heightened risk for Alzheimer’s disease.
Colocalization of the β amyloid peptide with bacteria in postmortem brain tissue of patients with familial Alzheimer's disease
Authors: Gomez Johana , Villegas‐Lanau Carlos Andrés , Mesa Ana ,   Neuroscience research group
Published: December 2021

AbstractBackgroundβ‐amyloid (βA) is a highly conserved peptide throughout the evolution of species that has been proposed as a participant in vital functions. This peptide has been related to the onset and progression of Alzheimer’s disease (AD). Additionally, recent scientific reports have demonstrated in vitro activity against bacteria, fungi and virus. The aim of this study is to describe the colocalization between βA and bacteria in postmortem brain tissue of patients with familial AD.MethodInitially, we observed bacterial accumulations in brain tissue of two patients with familial Alzheimer's disease and in one case colocalization of βA with bacteria was observed. In order to confirm whether this finding was repeated, shortly after donation and before being fixed with formaldehyde, five cases fresh cerebral samples from five cases with early onset AD were immediately inoculated in vitro with Enterococcus faecalis and Lactobacillus rhamnosus. After different periods of time, both immunostaining for βA detection and Gram staining for bacteria observation were performed on each sample.ResultColocalization of βA and gram positive bacteria were observed in all cases. In those infected in vitro, the phenomenon was observed after a period of 24 h of incubation at 35 °C. In the cases fixed with formaldehyde to 10%, its observed multiples cavitations macroscopic in white substance throughout the brainConclusionThese results suggest that the βA agglutinates the bacteria, then it’s possible a relationship between βA and bacteria, possibly due to the antimicrobial activity that has been attributed to βA. However, it is necessary to carry out studies with a larger number of samples to confirm the phenomenon and to attempt to explicate it from the cellular and molecular points of view.
Fibroblast Growth Factor 21 and Autophagy Modulation Ameliorates Amyloid β‐Induced Alzheimer Disease Pathology in Rats
Authors: Taliyan Rajeev , Kakoty Violina , KC Sarathlal , Kumari Shobha 
Published: December 2021

AbstractBackgroundAlzheimer's disease (AD) is a multifactorial neurodegenerative condition and the most common cause of its initiation is accumulation of oligomeric amyloid beta1‐42 (Aβ1‐42). In recent past, several studies have shown autophagy deficits in AD may resulted accumulation of misfolded protein, Aβ1‐42 and phosphorylated tau (ptau). Fibroblast growth factor 21 (FGF21), a metabolic hormone, has shown strong neuroprotective efficacy via increasing autophagic flux in AD. Therefore, this study was designed to investigate the synergistic neuroprotective efficacy of lentiviral FGF21 gene (LV‐FGF21) delivery and rapamycin‐autophagy modulator in Aβ1‐42 induced AD in rats.MethodLV‐FGF21 was administered 4weeks before inducing AD by oligomeric Aβ1‐42 into the lateral cerebral ventricles. Rats were divided into control, sham group administered with PBS intracerebroventricularly (ICV), ICV‐Aβ1‐42 group, ICV‐Aβ1‐42 group pre‐treated with LV‐FGF21, and pre‐treated LV‐FGF21 group combined with rapamycin. Morris water maze (MWM), ELISA assay for measuring protein levels of Aβ1‐42, ptau, soluble amyloid precursor protein (sAPP) and beta‐site APP cleaving enzyme 1 (BACE1), oxidative stress measurement, mRNA expression and immunofluorescence analysis were performed after treatment completion.ResultAβ1‐42 oligomer formation was confirmed by FESEM analysis. After 14 days, MWM analysis showed that the combination group considerably restored the cognitive ability while attenuated the level of Aβ1‐42, ptau, sAPP, and BACE1. Moreover, oxidative stress parameters considerably improved for the combined treated group as compared with ICV‐Aβ1‐42 group. Also, mRNA expression of main autophagy mediators (beclin‐1, LAMP‐2, LC3, ATF4, p62/SQSTM1) reflected positive outcome for the combination treatment group.ConclusionThe findings of the present study confirmed the neuroprotective potential of FGF21 and rapamycin in debilitating AD pathology in rats.