bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single cell transcriptomic profiling of neurodegeneration mediated by tau in a novel 3D neuron‐astrocyte coculture model
Authors: Rickner Hannah , Jiang Lulu , Hong Rui , Wolozin Benjamin , Cheng Christine 
Published: December 2021

AbstractBackgroundResearch into neurodegeneration has been hampered by a lack of systems that rapidly and accurately recapitulate neurodegenerative processes. We report development of a model combining human iPSC derived neurons (hiNCs) and astrocytes (hiACs) in self‐aggregating 3D organoids that reproducibly develop a robust range of tau pathology and neurodegeneration. This system is a scalable and highly manipulatable model of neurodegeneration and critical understudied glial responses. Additionally, the model induces pathology without reliance on genetic overexpression. Our system represents an important technological advance in modeling Alzheimer’s Disease (AD), and is a promising tool for identifying disease modifying treatments.MethodsThe system was developed by combining advances in 3D cell modeling and tau propagation. We perform directed differentiation of wild‐type iPSC to hiNCs and hiACs, and hiNCs are selectively exposed to toxic aggregations to induce pathology. Cells are combined in microwells to induce self‐aggregation, and pathology develops over the course of three weeks. Tau pathogenesis in the model was correlated with human tauopathy progression by immunopathology and single cell transcriptomics, and the application of a selective inhibitor PU‐H71 demonstrated the efficacy of the model to explore disease modifying treatment.ResultThe model consistently displays a robust range of tau pathology within three weeks, including progressive development of hyperphosphorylated tau at positions T181, S262, and S396/404, misfolded tau (MC1, TOMA2), and fibrillar tau (THIOS). Neurodegeneration (FlouroJadeB, LDH) is accompanied by reactive astrogliosis (GFAP), which single cell transcriptomics reveals to be driven by heat shock proteins (HSPs). The observed tau pathology and transcriptional responses were reduced by treatment with PU‐H71, which eliminates dysfunctional HSP epichaperome. Together this evidence demonstrates a rapid and reversible recapitulation of tau pathogenesis.ConclusionOur novel model consistently recapitulates tau‐induced neurodegeneration in a human system, and allows for the elucidation of neuronal and astrocytic responses. Additionally, we have demonstrated the power to model the reduction of tau pathology by drug treatment. Continued expansion of the model will include integration of microglia. This novel model represents a technological advance that will allow for the rapid recapitulation of neurodegeneration in a manipulatable system that promises to accelerate drug development for AD.
Mortality in FTD: An Australian perspective
Authors: Loi Samantha M , Chen Ben , Tsoukra Paraskevi , Eratne Dhamidhu , Wibawa Pierre , Farrand Sarah , Kelso Wendy , Evans Andrew H , Walterfang Mark , Velakoulis Dennis 
Published: December 2021

AbstractTHEME: Clinical manifestationsTOPIC: Neuropsychiatry & beh neurologySUBTOPIC: NeuropsychiatryBackgroundSurvival duration in frontotemporal dementia (FTD) remains inconsistent, depending on the clinical phenotype with different risk factors identified. Risk factors to mortality include the FTD‐MND presentation, a genetic predisposition (Agarwal S et al. 2019), deficits in neuropsychological tests, imaging changes (Agarwal et al. 2019; Hodges et al. 2003) and non‐tau pathology (Roberson et al. 2005; Hodges et al. 2003). We aimed to identify survival duration and cause of death in this group.MethodAll inpatients admitted to Neuropsychiatry, based at the Royal Melbourne Hospital, in metropolitan Australia from 1992 – 2014, who were diagnosed with probably FTD of any subtype were included. Linkage data was obtained by the Australian Institute of Health and Welfare (AIHW). We reviewed their clinical information including demographics, age of symptom onset, type of presenting symptom, neuroimaging and diagnosis.ResultOf the 528 individual inpatients identified with a dementia, there were n=100 who had a diagnosis of probable FTD. There were n=76 who had a behavioural‐variant FTD (bv‐FTD), n=14 who had a language‐variant FTD (lang‐FTD) and n=10 who had FTD‐MND. 67% of the group had died. Overall median duration of survival was 10.5 years (95% CI 7.9, 12.2). There were no differences in age of death nor age onset between the three FTD‐subtypes (p=0.479, p=0.289, respectively). As expected, there were significant differences in the median survival duration of the three FTD subtypes, with FTD‐MND having the shortest duration (p=0.004). Causes of death based on ICD‐10 were predominantly dementia‐related (26.3% Other degenerative diseases of nervous system; 17.5% unspecified dementia) but also included acute myocardial infarction (7%) and alcohol‐related (7%). Standardised mortality ratios (SMRs) revealed that compared to population norms, people with FTD had 8x mortality rate.ConclusionNot unsurprisingly, FTD‐MND had the shortest duration compared to the other subtypes of FTD. The duration of survival was comparable to other studies. Causes of death revealed that a dementia was identified in almost half of cases. High SMRs suggest that FTD is a particularly “fatal” type of dementia in younger people. Investigation into risk factors to death is required.
Investigating the non‐cell autonomous role of glial chaperones in Alzheimer’s disease
Authors: Sung Katherine , Yang Fangjia , Noble Wendy , Jimenez‐Sanchez Maria 
Published: December 2021

AbstractBackgroundAstrocytes are vital in the onset and progression of Alzheimer’s disease (AD). Accumulation of reactive astrocytes, together with tau phosphorylation, correlates very strongly with cognitive decline.Molecular chaperones are essential for maintaining protein homeostasis. One family of chaperones are the small heat shock proteins (sHSPs), which include HSPB1 and CRYAB. Expression of these sHSPs seems to be restricted to glial cells, and levels are found to increase in those astrocytes found in AD brains. The role that sHSP play in astrocytes in AD is still not known. Emerging evidence suggests vital interplay between different cell types during neurodegenerative diseases. We therefore aim to investigate the non‐cell autonomous role of astrocytic sHSPs in AD.MethodWe are using primary mouse neurons and organotypic brain slice cultures in conjunction with the recombinant adeno‐associated viral system (rAAV). These systems will allow us to replicate the tau pathology found in AD, investigate neuron‐astrocyte interactions and determine whether either can be altered by overexpression of our sHSPs.Using immunofluorescence, confocal microscopy and western blotting we are characterising expression and localization of sHSPs in post‐mortem human AD brain tissue and brain slice cultures.ResultOur data shows that HSPB1 is specifically expressed in astrocytes in both human brain tissue and slice cultures. Interestingly, HSPB1 levels in the human brain increase in GFAP‐positive astrocytes surrounding amyloid plaques. When organotypic brain slices are treated with cytokines or Aβ oligomers, reactive astrocytes are induced and levels of HSPB1 and CRYAB are also increased, similar to what we observe in human AD brain.ConclusionOur results in human AD brain highlight the importance of astrocytic HSPB1 in AD, and we provide evidence to suggest not only that organotypic brain slices are a good model to replicate and study the function of sHSPs in AD, but that HSPB1 and CRYAB play an important role in the response to AD‐relevant pathology.Using rAAVs, we aim to manipulate astrocytic sHSPs levels in organotypic brain slices to investigate whether astrocytic sHSPs could modulate neuronal health and tau pathology in a non‐cell autonomous manner.
Astrocytic BMAL1 regulates protein aggregation in mouse models of alpha‐synuclein and tau pathology
Authors: Sheehan Patrick W. , Kanan Michael , Benitez Bruno A. , Harari Oscar , Davis Albert A , Musiek Erik S. 
Published: December 2021

AbstractBackgroundThe circadian clock regulates inflammatory responses in the peripheral immune system, though its function in neuroinflammation is poorly understood. Deletion of the master circadian clock transcription factor BMAL1 abrogates cellular circadian clock function and can be used to probe cell‐type specific functions of the clock. Our lab has previously shown that Bmal1 deletion induces oxidative stress, astrocyte activation, and increased β‐amyloid plaque deposition in mice. We hypothesized that deletion of Bmal1 would increase pathology in other protein aggregation models.MethodsWe generated global inducible Bmal1 knock out mice expressing human P301S mutant tau. Pathology, aggregation state, and gliosis were quantified at nine months of age. We induced synuclein aggregation in global Bmal1 knock out mice using an alpha‐synuclein preformed fibril injection (PFF) model. Three months post‐PFF injection, mice were analyzed for synuclein pathology and gliosis. To determine a cell‐type specific effect, we generated astrocyte‐ and microglia‐specific Bmal1 knock out mice and used these for PFF injections. Pathology and gliosis were analyzed from these mice three months post‐PFF injection. We then generated astrocyte‐specific Bmal1 knock out mice expressing human P301S mutant tau to test the effect of Bmal1 deletion in astrocytes on tau aggregation.ResultsGlobal Bmal1 deletion in the P301S model resulted in a significant decrease in aggregated tau and microglia activation. Global Bmal1 knock out mice injected with PFFs had significantly decreased synuclein pathology and a decrease in microgliosis. Bmal1 deletion specifically in astrocytes was sufficient to reduce both tau and synuclein pathology. Using bioinformatics methods, we discovered an astrocytic candidate gene, Bag3, which may play a role in reducing pathology in our models. We used an in vitro PFF uptake assay and found that Bmal1 knockdown resulted in increased PFF uptake, which was reduced to baseline after simultaneous knockdown of Bag3.Conclusion
Bmal1 deletion in astrocytes is sufficient to reduce tau and synuclein pathologies and attenuate microglia activation. This effect may be driven by the upregulation of the macroautophagy chaperone protein, Bag3. Our data suggests that targeting astrocytic protein degradation machinery may be a therapeutic strategy for reducing intra‐neuronal protein aggregates, such as tau and synuclein.
Meaning from tragedy: exploring attitudes toward dementia patient participation in research
Authors: Bhardwaj Twisha , Santulli Robert B 
Published: December 2021

AbstractBackgroundSeveral prominent bioethics committees currently restrict dementia patient participation in research to projects that are low risk or offer potential benefit to the participant (Bernat). While these barriers were crafted to protect persons living with dementia, they may prevent them from contributing to non‐therapeutic research, a meaningful and rewarding effort that might not improve their own illness but could help future patients. One avenue toward preserving patient autonomy would be a dementia‐specific advance directive which would outline wishes for research participation in the event of cognitive impairment. However, there remains the question of whether it should include options for specific procedures (e.g., MRI, blood tests, lumbar puncture) or merely list broad categories of study risk (e.g., low, moderate, high) to which patients could consent. Before implementing novel legal measures, it is critical to examine attitudes of older individuals toward advance planning for research participation.MethodsThe current project will rely on semi‐structured telephone interviews with cognitively intact seniors to investigate attitudes toward dementia patient participation in research. Broadly, subjects will be prompted to reflect upon (i) their willingness to participate in therapeutic and/or non‐therapeutic research should they develop dementia, (ii) the role of an advance directive and surrogate‐decision maker in the context of research participation, and (iii) the preferred format for a research addendum to a dementia‐specific supplement. Notes will be taken during interviews and analyzed quantitatively and qualitatively for salient themes.ResultsThis study has been approved by the Dartmouth Committee for the Protection of Human Subjects. Interviews will begin in the Fall of 2021.ConclusionScientific research is the strongest weapon in the ongoing fight against dementia. Cognitively impaired individuals could be vital members of this effort. By exploring attitudes of older individuals toward advance planning for research participation, this project frames lived experiences within neuroethics and law. Such real‐world opinions will ultimately inform the creation of policy and legal measures to best serve this unique population. Reference: James L. Bernat: Ethical Issues in Neurology, 3rd Philadelphia: Lippincott Williams & Wilkins, 2008, pp. 374‐376.
Applying a deep learning approach focusing on spatiotemporal features in early diagnosis of Alzheimer's disease
Authors: Babatope Eyitomilayo Yemisi , Acosta‐Franco Jesus Alejandro , García‐Vázquez Mireya Saraí , Ramírez‐Acosta Alejandro Álvaro , Citedi‐IPN APIM Laboratory 
Published: December 2021

AbstractBackgroundAlzheimer’s disease is a neurodegenerative disorder (Vally & Kathrada, 2019), the most common type of dementia in the elderly population (Kim, 2020) and is a great challenge in the geriatric field. Cognitive impairment is one of the features shown by Alzheimer’s dementia patients, and instrumental activities of daily living (IADL) are predictors of cognitive impairment as proven by several research works. Over the past few years, deep learning has had a tremendous improvement effect on diverse science areas, inclusive of healthcare (Farouk & Rady, 2020). This study aims to explore a non‐invasive and novel approach with the use of deep learning towards the early diagnosis of Alzheimer’s disease.MethodTo measure cognitive impairment, IADL are objectively recorded, capturing data from egocentric videos using wearable cameras that are attached to a glass frame of each participant, mainly focusing on hands use while performing these activities. Obtained images are analyzed based on human‐object interaction and human‐environment interaction. To make precise analysis while performing these activities, we propose the use and relationship of the anatomical planes (coronal, sagittal and transverse planes) and healthy human functional patterns [Martínez‐Velilla, 2018], in a quantitative way using deep learning. In the coronal plane, patterns involving displacement movements and object manipulation were identified with an accuracy of 87%. The information from the sagittal and transverse planes is developed with a deep learning model, which provides the required depth data to link the IADL's quality. By analyzing these planes, we can get more information about the distance of the hand and body motion while performing these activities.ResultFrom our work, we obtained an accuracy of 87% recognizing movement patterns of displacement and object manipulation, and a good prediction of the depth of the anatomical planes.ConclusionOur model serves as a tool for proactive prediction of Alzheimer’s dementia and support in clinical decision‐making.
Effect of taurine and camel milk on amyloid beta peptide concentration and oxidative stress changes in aluminium chloride‐induced Alzheimer's disease rats
Authors: Abdulkadir Teslim S , Isa Ahmed Sherif , Dawud Fatima A , Ayo Joseph O , Mohammed Mohammed D 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease characterized by brain accumulation of amyloid‐beta peptide, and oxidative stress (Huang et al., 2016). The study evaluated effects of taurine and camel milk (CM) on amyloid‐beta peptide and malondialdehyde concentrations and haemolysis in AlCl3‐model of Alzheimer’s disease in rats.MethodThirty‐five female Wistar rats were divided into seven groups (n=5); Normal saline (0.2 mL/mg body weight); AlCl3 (100 mg/kg); CM (33 mL/kg) (Khatoon et al., 2016); Taurine (50 mg/kg) (Cetiner et al., 2005); AlCl3 (100 mg/kg) + CM (33 mL/kg); AlCl3 (100 mg/kg) + Taurine (50 mg/kg) and AlCl3 (100 mg/kg) + CM (33 mL/kg) + Taurine (50 mg/kg). The administration via oral gavage, lasted for eight weeks. Rats were sacrificed, brain (hippocampal) and blood samples were collected for determination of amyloid‐beta peptide 1‐42 (Aβ) and malondialdehyde concentrations and haemolysis changes.ResultThe concentration of Aβ peptide decreased (P < 0.05) in AD + CM (7.46 ± 0.31 ng/L) and AD + CM + Taurine (9.20 ± 0.43 ng/L), when compared to controls. Malonaldehyde concentration in AD + Taurine decreased (P < 0.05) and superoxide dismutase activity increased (P < 0.05) in AD + CM and AD + CM + Taurine groups compared to controls. At 0.5 % NaCl, percentage haemolysis in AD rats (45.50 ± 1.19 %) was lower (P < 0.05) than in AD + Tau (49.75 ± 3.25 %), AD + CM (51.50 ± 3.00 %) and AD + CM + Tau (52.00 ± 1.70 %) rats. The haemolysis at 0.4 % NaCl was lowest (P < 0.05) in AD (66.00 ± 2.12 %) rats, compared to AD + Tau (71.00 ± 4.40 %), AD + CM (74.25 ± 3.70 %) and AD + CM + Tau (73.50 ± 3.00 %) rats.Percentage haemolysis at 0.5% NaCl concentration increased (P < 0.05) in AD + CM (53.60 ± 2.96 %) and AD + CM + Taurine (51.20 ± 1.53 %) when compared to the controls.ConclusionTaurine and camel milk reduced the accumulation of Aβ peptide and ameliorated the oxidative stress damage by decreasing malondialdehyde concentrations and percentage haemolysis.
Systematic validation of variants of unknown significance in PSEN1
Authors: Burgute Bhagyashri , Renton Alan E. , Ziegemeier Ellen , Cruchaga Carlos , Goate Alison M. , McDade Eric , Llibre‐Guerra Jorge J , Karch Celeste M. 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease that is characterized by extracellular amyloid plaques, intracellular neurofibrillary tangles, and progressive cognitive decline. More than 200 mutations in APP, PSEN1, and PSEN2 cause autosomal dominant AD (ADAD). However, common and rare variants also exist within these genes that may be risk factors, protective factors or non‐pathogenic polymorphisms.MethodTo distinguish polymorphisms from pathogenic mutations, we have developed an algorithm for determining ADAD pathogenicity that weighs genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. Here, we evaluated 5 novel variants in PSEN1 identified in densely affected AD families in Latin America: p.Val103_Ser104delinsGly, K395I, P264T, A275T and I414T. PSEN1 p.Val103_Ser104delinsGly, K395I, and P264T produced a significant increase in the extracellular A42/40 ratio.ResultPSEN1 p.Val103_Ser104delinsGly, K395I, and P264T produced a significant increase in the extracellular A42/40 ratio. PSEN1 A275T produced a significant increase in A42 and A40 levels, without altering the ratio. PSEN1 I141I, however, failed to significantly alter A levels in a manner consistent with known pathogenic mutations.ConclusionThus, we propose that PSEN1 I414T is a risk factor or non‐pathogenic polymorphism, and PSEN1 p.Val103_Ser104delinsGly, K395I, and P264T represent novel likely pathogenic mutations.
A Two‐Clone approach to study signaling interactions among neuronal cells in a pre‐clinical Alzheimer’s Disease model
Authors: Yeates Catherine , Sarkar Ankita , Deshpande Prajakta , Kango‐Singh Madhuri , Singh Amit 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is a debilitating neurodegenerative disorder with no cure and few treatments. AD causes profound cognitive deficits and memory impairments. Accumulation of the peptide amyloid beta plaque is one of the characteristics of the disease. To understand the progression of Alzheimer’s disease, studies often rely on ectopic expression of amyloid‐beta 42 (Aβ42) throughout an entire tissue. Uniform ectopic expression of Aβ42 may obscure cell‐cell interactions that contribute to the progression of the disease.MethodWe developed a two‐clone system to study the signaling cross talk between GFP‐labeled clones of Aβ42‐expressing neurons and wild‐type neurons simultaneously generated from the same progenitor cell by a single recombination event.ResultSurprisingly, wild‐type clones are reduced in size as compared with Aβ42‐producing clones. We found that wildtype cells are eliminated by the induction of cell death. Furthermore, aberrant activation of c‐Jun‐N‐terminal kinase (JNK) signaling in Aβ42‐expressing neurons sensitizes neighboring wild‐type cells to undergo progressive neurodegeneration. Blocking JNK signaling in Aβ42‐producing clones restores the size of wildtype clones.ConclusionHere we present evidence that JNK signaling between Aβ42‐ expressing cells and adjacent wild‐type cells mediate neurodegeneration.
TSPO and P2X7 discriminate between amyloid‐ and tau‐induced glial responses
Authors: Gomez‐Gutierrez Ruben , Fujita Masahiro , Jankowsky Joanna L 
Published: December 2021

AbstractBackgroundCurrent clinical PET imaging relies on translocator protein (TSPO) to detect neuroinflammation in brain disorders including degenerative conditions such as AD, however this marker lacks cell type‐specificity and offers no information on what type of insult is causing the reaction. An ideal PET tracer would detect both the rise in pro‐inflammatory and loss of anti‐inflammatory glial responses and would discriminate cellular responses to amyloid‐beta from tau. We investigated whether a pair of glial purinergic receptors would provide a better measure of inflammatory status in mouse models of AD than the current standard TSPO.MethodWe studied the expression of P2X7, P2Y12, and TSPO in 5xFAD and PS19 transgenic mice at early and late stages of pathology using quantitative immunohistochemistry. Co‐staining with microglial (Iba1) and astroglial (GFAP) markers was used to identify cell types expressing each receptor.ResultExpression of P2Y12 decreased significantly with the onset of both Aβ and tau pathology. TSPO increased in 5xFAD mice with amyloid pathology, but not in PS19 mice with tau pathology. We observed the opposite pattern in P2X7 signal, which increased in PS19 mice with tau pathology, but less in 5xFAD mice with amyloid plaques.ConclusionOur findings suggest there may be distinct neuroinflammatory responses to Aβ and tau with increased TSPO around amyloid but not tau, and a reciprocal increase in P2X7 around tau but not amyloid. We found that P2Y12 and P2X7 serve as complementary markers reflecting the loss of homeostatic microglia and the rise of a reactive phenotype. Our results support continued investigation of P2Y12 and P2X7 as potential biomarkers of distinct neuroinflammatory responses which may be used in conjunction with TSPO to distinguish AD pathologies in clinical settings.