bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dementia‐linked TDP‐43 dysregulation in astrocytes impairs memory, antiviral signaling, and chemokine‐mediated astrocytic‐neuronal interactions
Authors: Murava Avital Licht , Meadows Samantha , Palaguachi Fernando , Song Soomin C. , Bram Yaron , Zhou Constance , Schwartz Robert E. , Froemke Robert C. , Orr Adam L. , Orr Anna G. 
Published: December 2021

AbstractBackgroundTDP‐43 pathology is linked to cognitive deficits in diverse neurodegenerative disorders, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). The effects of TDP‐43 pathology in different cell types, including astrocytes, are not clear.MethodIn this study, we used postmortem human brain samples, extensive behavioral testing in numerous cohorts of doubly transgenic mice, gene profiling in different isolated brain regions and cells, glial‐neuronal co‐culture assays and physiology, and biochemical assays to identify specific signaling cascades linked to TDP‐43.ResultOur results show that astrocytic TDP‐43 is mislocalized in postmortem human hippocampal tissue from AD cases. To assess the effects of widespread or hippocampus specific dysregulation of astrocytic TDP‐43 in complementary systems, we generated three novel astrocyte specific mouse models of TDP‐43 dysfunction. Consistently, these mouse models indicated that astrocytic TDP‐43 dysfunction causes progressive hippocampus‐dependent memory loss, but not motor deficits. Manipulation of astrocytic TDP‐43 also increased hippocampal levels of interferon ‐inducible chemokines CXCL9 and CXCL10, and altered cell‐autonomous antiviral signaling and defense against viral pathogens. Moreover, expression of CXCR3, the shared receptor for CXCL9 and CXCL10, was increased selectively in hippocampal presynaptic terminals. Acute or chronic stimulation of presynaptic CXCR3 modulated neuronal activities and presynaptic vesicles.ConclusionOverall, our findings shed new light on TDP‐43 dysregulation in astrocytes and its potential contributions to disease‐related impairments in cognitive and immune‐related functions. We report a novel chemokine‐mediated astrocytic‐neuronal pathway that is likely downstream of aberrant antiviral immune signaling in astrocytes that affects presynaptic release and neuronal activities. Together, these results implicate astrocytic TDP‐43 dysregulation in the pathogenesis of dementia and point to chemokine signaling and CXCR3 as potential therapeutic targets for alleviating cognitive decline.
The Drosophila K+‐dependent Na+/Ca2+ exchanger Nckx30C is implicated in temperature sensitive paralysis and age‐dependent neurodegeneration
Authors: Majlish Al Nahian Khan , Lye Shu Hui , Cytron Emilia , Bolus Harris , Marotto Kathleen , Chtarbanova Stanislava 
Published: December 2021

AbstractBackgroundIncreasing evidence links epileptic seizures to neurodegenerative disorders such as Alzheimer’s disease (AD) although the mechanisms underlying this relationship are not fully understood. Ion channels are crucial to the maintenance of intracellular calcium (Ca2+) signaling in the nervous system, and a perturbation in their structure and function could result in both neuropathology and seizures. Moreover, perturbed cellular Ca2+ homeostasis is known to be implicated in AD pathogenesis. Previous studies in the model organism Drosophila have established a connection between mutations linked to temperature‐sensitive (TS) paralysis, which is reminiscent of vertebrate epileptiform behavior, and neurodegeneration. Thus, Drosophila could serve as an excellent model to investigate the molecular mechanisms relating these two conditions.MethodWe performed an unbiased genetic screen to identify mutants that exhibit paralytic behavior at 38°C. We used gene mapping, and DNA sequencing to locate the mutation in the Nckx30C gene. We carried out TS paralysis assays, lifespan analysis, climbing assay and brain histology to look for neurodegeneration, as well as immunohistochemistry to examine synaptic morphology at the larval neuromuscular junction (NMJ). Knockdown using RNAi established the cell‐type specific basis of the TS‐paralytic and neurodegenerative phenotypes.ResultMutant line 426 exhibited TS paralysis and progressive neurodegeneration in comparison to controls. We mapped the mutation to the Nckx30C locus, in the region encoding the predicted ion‐binding domain. In comparison to wild type, 426 flies showed reduced lifespan, impaired climbing and changes in NMJ morphology, indicative of synaptic dysfunction. We found lifespan reduction and early‐onset neurodegeneration in flies carrying two other Nckx30C alleles. Neuron‐ but not glia‐specific knockdown of Nckx30C recapitulates the TS‐paralytic phenotype of 426 flies. Knockdown of Nckx30C in glia and neurons led to early onset climbing defects.ConclusionThe Drosophila Nckx30C gene encodes for a K+‐dependent Na+/Ca2+ exchanger with enriched expression in brain tissue. Nckx30C is homologous to mammalian Solute Carrier Family 24 (SLC24) proteins of which pathophysiological involvement and function in the brain is poorly understood. Our studies of Nckx30C in flies could help to decipher the function of SLC24 proteins in both seizures and neurodegenerative conditions such as AD.
Regenerating spiral ganglion neurons employing the cochlear implant
Authors: Huynh Quy‐Susan , Holsinger R. M. Damian 
Published: December 2021

AbstractBackgroundSensorineural hearing loss is treated using cochlear implants. The electrodes in the implants directly stimulate spiral ganglion neurons (SGNs). However, SGNs continually degenerate and are difficult to access behind the bony modiolar wall of the cochlea. The electrode‐tissue interface needs to be improved to enhance hearing for users.Implanting the electrode closer to the SGNs, requires a greater insertion depth and increases the amount of scar tissue that forms around the electrode. The introduction of neurotrophic factors has the potential to improve neural regeneration. However, currently there are a lack of methods to deliver neurotrophic factors locally and sustainably into the cochlea.We propose a neural electrode system utilising electrical stimulation (ES) to increase the expression of brain‐derived neurotrophic factor (BDNF) and guide SGNs and their neurites towards the electrode. Additionally, the electrode system would utilise an electrospun nanofiber scaffold surrounding the electrode to act as a mechanical support to the cells and their projections.MethodNanofiber scaffolds were electrospun onto wires and glass coverslips and cultured with human SH‐SY5Y neuroblastoma and rat Schwann cells. Immunohistochemistry and scanning electron microscopy were used to characterise the scaffolds and biocompatibility.Platinum electrodes were used to stimulate both rat Schwann cells and SH‐SY5Y cells for 3 hours using a 100mV/mm DC electric field. Following 20 hours of incubation, the cells were immunostained to measure changes in BDNF expression.ResultWe discovered that not only were the scaffolds biocompatible, but the cells aligned along the nanofibers, forming networks on the scaffolds. We observed statistically significant increases in BDNF expression in Schwann cells, as well as a limited BDNF increase in SH‐SY5Y cells that may be a result of the incubation period used in our experiment and is currently under investigation.ConclusionThese results suggest the feasibility of the system and have the potential to improve cochlear implants.
Alzheimer’s disease associated AKAP9 I2558M mutation alters posttranslational modification and interactome of tau and cellular functions in CRISPR‐edited human neuronal cells
Authors: Hersh Samuel Walter , You Yang , Aslebagh Roshanak , Shaffer Scott A , Ikezu Seiko , Mez Jesse , Lunetta Kathryn L , Logue Mark W. , Farrer Lindsay A. , Ikezu Tsuneya 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is a pervasive neurodegeneration disease with high heritability. Whole exome sequencing study identified two rare African American (AA)‐specific variants in AKAP9, a kinase anchor protein 9, (rs144662445 and rs149979685), that increased the odds of AD more than 2.75‐fold. However, the functional impact of the AKAP9 rs144662445 (I2558M) mutation in the central nervous system and the underlying mechanism in AD remain unclear.MethodAKAP9 I2558M mutation was introduced by CRISPR‐mediated knock‐in and validated by Sanger sequence in SH‐SY5Y cells stably expressing P301L Tau (SH‐SY5Y P301L cells), which was further differentiated into neuronal cells. Tau phosphorylated level between AKAP9 WT and I2558M cells was evaluated by immunocytochemistry and ELISA assay. Moreover, we analyzed the tau interactome in AKAP9 I2558M cells by affinity purification‐mass spectrometry. In silico analysis was performed to compare the differences between AKAP9 WT and mutation in tau‐interacting proteins. The protein synthesis and oxidative activity in SH‐SY5Y P301L neurons with and without I2558M were measured by using the Click‐iT protein synthesis kit and CellRox dye, respectively.ResultNo difference in the neuronal cell morphology was observed between differentiated WT and mutant SH‐SY5Y P301L cells. The AD‐associated AKAP9 I2558M mutation resulted in a significant increase in phosphorylated tau protein at residues S396 and S404 site in a differentiated SH‐SY5Y P301L cell line. The presence of this mutation altered the composition of tau‐interacting proteins, by increasing interaction of proteins associated with translation, RNA localization and oxidative activity. Importantly, functional studies showed a significant reduction in protein synthesis activity and excessive oxidative stress in AKAP9 mutant compared to wild type cells.ConclusionOur results demonstrated specific effects of rs14462445 on mis‐processing of tau and suggest a potential role of AKAP9 in AD pathogenesis.
p‐Coumaric acid protects against D‐galactose induced neurotoxicity by attenuating neuroinflammation and apoptosis in mice brain
Authors: Daroi Pratibha Atul 
Published: December 2021

AbstractBackgroundD‐galactose (D‐gal) induced senescence in rodents is a widely used Alzheimer’s model. Chronic administration of D‐gal causes neuroinflammation leading to cognitive deficit and memory impairment.MethodPresent study investigated the neuroprotective effects of the natural phenol, p‐Coumaric acid (PCA) and its underlying mechanism against the chronic D‐gal induced senescence in Swiss albino mice. D‐gal (150 mg/kg) was administration s.c.ly to mice for 42 consecutive days.ResultD‐gal produced cognitive impairment as observed in Morris water maize (MWM) and Y maze test, which was ameliorated by concurrent treatment with PCA (80 mg/kg, and 100 mg/kg, p.o.). Importantly, PCA treatment attenuated the D‐gal induced oxidative stress and significantly inhibited acetylcholinesterase (AChE) activity in mice brain. Furthermore, PCA treatment significantly lowered levels of inflammatory marker nuclear factor kappa B (NFκB) and reduced levels of proapoptotic enzyme caspase 3. We also observed that PCA treatment exhibited β‐secretase enzyme (BACE1) inhibitory effect. However, PCA treatment failed to decrease the level of advanced glycation end products (AGE) both in vitro and in vivo.ConclusionCurrent study demonstrated the significant neuroprotective effect of PCA against D‐galactose induced neuroinflammation, cognitive impairment and apoptosis.
Circulating klotho is elevated in cerebrospinal fluid, but not serum, among KLOTHO KL‐VS allele carriers at risk for Alzheimer’s disease
Authors: Gaitán Julian M. , Dubal Dena B. , Okonkwo Ozioma C. 
Published: December 2021

AbstractBackgroundThe klotho protein supports brain health and is encoded by the KLOTHO gene. The KL‐VS allele modulates klotho protein secretion and function, but it is unknown how KL‐VS genotype affects circulating klotho levels in blood and cerebrospinal fluid (CSF) among people at risk for AD.Methods1112 cognitively intact participants from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center underwent genotyping for KLOTHO KL‐VS (non‐carrier: KL‐VSNC; heterozygote: KL‐VSHET; homozygote: KL‐VSHOM) and APOE4 alleles. 1098 participants underwent venipuncture and 183 underwent lumbar puncture. Circulating klotho was measured by ELISA in serum and/or CSF. Linear regression adjusted for age and sex tested the effect of KL‐VS genotype on klotho in serum or CSF. In a subset of 169 participants with both serum and CSF data, linear regression adjusted for time between specimen collections tested the effect of specimen source on klotho level.ResultsVisual inspection for outliers excluded four high serum klotho values (range 2461.5–4171.3 pg/mL; two KL‐VSNC, one KL‐VSHET, one KL‐VSHOM); no CSF values were excluded. The mean participant age was 62.4 ± 6.6 and education was 15.8 ± 2.7 years. The majority were female (69.4%), White (92.6%), and had family history of dementia (72.6%), and 38.1% were APOE4 carriers. KL‐VS genotype distribution was 73.1% KL‐VSNC, 25.2% KL‐VSHET, and 1.7% KL‐VSHOM. Mean serum klotho in KL‐VSNC was 800.8 ± 252.8 pg/mL and was not different in KL‐VSHET (b=17.7, SE=17.5, p=.31) or KL‐VSHOM (b=84.0, SE=58.1, p=.15). Mean CSF klotho in KL‐VSNC was 932.2 ± 153.2 pg/mL and was significantly higher in KL‐VSHET (b = 225.8, SE = 25.1, p< .001) and KL‐VSHOM (b=327.8, SE=75.5, p< .001). Mean CSF klotho was significantly higher than serum klotho in the entire subset (b=162.8, SE=25.9), p< .001) and within each KL‐VS genotype (p’s< .05).ConclusionsIn adults at risk for AD, CSF klotho is elevated in heterozygotic and homozygotic carriers of the KLOTHO KL‐VS allele. Serum levels are lower than CSF and did not differ by genotype. Klotho specimen source should be considered in analyses of circulating klotho on brain health.
Home monitoring of daily living activities and prediction of agitation risk in a cohort of people living with dementia
Authors: Fletcher‐Lloyd Nan , Soreq Eyal , Wilson Danielle , Nilforooshan Ramin , Sharp David J , Barnaghi Payam 
Published: December 2021

AbstractBackgroundPeople living with dementia (PLWD) have an increased susceptibility to developing adverse physical and psychological events. Internet of Things (IoT) technologies provides new ways to remotely monitor patients within the comfort of their homes, particularly important for the timely delivery of appropriate healthcare. Presented here is data collated as part of the on‐going UK Dementia Research Institute’s Care Research and Technology Centre cohort and Technology Integrated Health Management (TIHM) study. There are two main aims to this work: first, to investigate the effect of the COVID‐19 quarantine on the performance of daily living activities of PLWD, on which there is currently little research; and second, to create a simple classification model capable of effectively predicting agitation risk in PLWD, allowing for the generation of alerts with actionable information by which to prevent such outcomes.MethodA within‐subject, date‐matched study was conducted on daily living activity data using the first COVID‐19 quarantine as a natural experiment. Supervised machine learning approaches were then applied to combined physiological and environmental data to create two simple classification models: a single marker model trained using ambient temperature as a feature, and a multi‐marker model using ambient temperature, body temperature, movement, and entropy as features.ResultThere are 102 PLWD total included in the dataset, with all patients having an established diagnosis of dementia, but with ranging types and severity. The COVID‐19 study was carried out on a sub‐group of 21 patient households. In 2020, PLWD had a significant increase in daily household activity (p = 1.40e‐08), one‐way repeated measures ANOVA). Moreover, there was a significant interaction between the pandemic quarantine and patient gender on night‐time bed‐occupancy duration (p = 3.00e‐02, two‐way mixed‐effect ANOVA). On evaluating the models using 10‐fold cross validation, both the single and multi‐marker model were shown to balance precision and recall well, having F1‐scores of 0.80 and 0.66, respectively.ConclusionRemote monitoring technologies provide a continuous and reliable way of monitoring patient day‐to‐day wellbeing. The application of statistical analyses and machine learning algorithms to combined physiological and environmental data has huge potential to positively impact the delivery of healthcare for PLWD.
Decreased O‐GlcNAcylation and mitochondrial dysfunction are involving in low glucose induced Alzheimer’s disease‐like phenotype in induced pluripotent stem cell‐derived neurons
Authors: Huang Chia‐Wei , Hart Gerald W. 
Published: December 2021

AbstractBackgroundEvidence supporting that glucose metabolic abnormalities occur prior to Alzheimer’s disease (AD) symptoms. Reduced O‐GlcNAc (OGN) levels likely arise from impaired glucose metabolism or availability and correlates with AD pathogenesis. So far, the mechanism of sAD and the role of OGN in AD pathology remained largely unknown due to a lack of human sAD model.MethodWe generated human cortical neurons from human‐induced pluripotent stem cells and treated neurons with glucose reduction media. FluoroJADE staining and cell viability assays were used to study the effects of low glucose on the degenerative status and cell viability of neurons. Abnormal protein production, phosphorylation, and accumulation were detected by western blotting and immunofluorescence staining using antibody against p‐tau and beta‐amyloid. Neurite and synaptic structure were observed by immunofluorescence staining, while neuronal network activity was detected by multi‐electrode array electrophysiological analyses. Mitochondrial abnormalities, including increased oxidative stress, reduced membrane potential, and mitochondrial dysfunction, were evaluated using CM‐H2DCFDA, JC‐1 and Seahorse, respectively.ResultWe show that lowering glucose level to 2mM leads to dramatic increases of neuron degeneration on day 3 and 5 of treatment and decreased cell viability on day 7. Interestingly, long‐term low glucose treatment induces AD features in neurons, including abnormal hyperphosphorylated tau accumulation and increasing beta‐amyloid production. Besides, glucose deficiency also causes decreased neurite coverage, synapse density, and neuron network activity. Furthermore, we find that O‐GlcNAc levels are significantly reduced soon after low glucose treatment and remain low until the end of experiment. Raising O‐GlcNAc levels by thiamet‐G, inhibitor of O‐GlcNAcase, even in low glucose treated neurons, rescues low glucose‐induced AD phenotypes. Moreover, our data shows that O‐GlcNAc dysregulation causes mitochondrial abnormalities, which occur before any other degenerative phenotype appeared, and may be one of the underlying mechanisms of sAD onset and pathogenesis.ConclusionWe established a human neuron model in which the pathological features are reproduced by glucose deficiency. This platform can serve as a tool for better understanding molecular processes involved in neurodegeneration in sAD. Our results also suggest that dysregulated O‐GlcNAc levels and mitochondrial dysfunction by glucose deficiency are involved in the onset and progression of sAD.
CGG Repeats in the FMR1 Gene as Predictor of Visuospatial Working Memory
Authors: Hickey Alexandra C , Friedman Laura , Klusek Jessica 
Published: December 2021

AbstractBackgroundThe FMR1 premutation, defined by an expansion of 55–200 CGG repeats on the FMR1 gene, occurs in 1 in 150 women in the US. The premutation is related to complications, including risk for neurodegenerative disease (Fragile X‐associated tremor/ataxia syndrome; FXTAS) and broader neurocognitive features occurring outside of the context of FXTAS. Understanding the premutation’s effect on cognition, such as visuospatial working memory (VWM), will provide a more comprehensive understanding of cognitive symptoms associated with the FMR1 premutation genotype. Previous findings demonstrated that premutation males with high CGG repeats perform worse on VWM tasks (Hocking et al., 2012). Few studies examined VWM in female carriers, who typically show milder symptoms. This study examined VWM in female carriers and its relationship with CGG repeat length.MethodsParticipants were 33 premutation carrier women and 22 neurotypical controls aged 27‐59 (M=45) years. Groups did not significantly differ in age (p=.132), education (p=.682), or race (p=.661). Participants completed Spatial Addition test of the WMS‐IV (Weschler, 2009). DNA from buccal swabs was analyzed for CGG repeat length using the Asuragen AmplideX kit.ResultsGiven the incomplete penetrance the FMR1 premutation phenotype, where only a subgroup of women experience symptoms, analyses focused on identifying those who obtained low/at‐risk standard scores (1+SD below the mean), as opposed comparing mean performance across groups. Chi‐squared analyses indicated that premutation carrier women were more likely score 1+ SD below the mean on the Spatial Addition test (30% vs 0% of controls), X
2=8.14, p=.004. Logistic regression indicated that CGG repeat length was a significant predictor of scoring 1+SD below the mean, after controlling for education level, (χ2=‐7.50, p=.032). For every unit increase in CGG repeat length, the odds of scoring 1+SD below the mean increased by a factor of 1.07 (95% CI: 1.00, 1.12).ConclusionsFemale premutation carriers were more likely to show VWM difficulties, which were associated with genetic liability (i.e., CGG repeat length). Future research may explore VWM deficits in relation to FXTAS risk.