bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi‐modal sequencing analysis of astrocytes in human and mouse reveals strategically positioned novel reactive sub‐states
Authors: Hasel Philip , O'Dea Michael , Sadick Jessica S , Liddelow Shane A. 
Published: December 2022

AbstractBackgroundAstrocytes can have helpful or harmful effects on neuron health and brain function in disease. While they normally provide trophic support to neurons during development and normal functioning, in response to many stimuli their heterogeneous ‘reactive’ responses can alter these functions drastically. Changes in astrocyte function depends on their ‘reactive’ sub‐state. Understanding when and where sub‐states of reactive astrocytes occur, and how these altered functions contribute to disease will pave the way for novel strategies to protect neurons.MethodWe performed combined 10x genomics single cell and spatial transcriptomics in wildtype and Alzheimer’s disease (AD) model mice, combined with single nuclei RNA sequencing of human postmortem non‐symptomatic and AD patient brains.ResultsWith improved capture rates and subsequent powering of astrocyte sequencing we highlight lowly abundant, biologically important, reactive astrocyte sub‐states that are positioned in strategic locations throughout the brain – namely at sites of entry for peripheral immune cells (e.g. adjacent to penetrating vessels in layer I of the cortex, and around the ventricles). Further, we integrate our datasets with previously published scRNAseq and snRNAseq datasets to confirm these small populations exist in other patient populations. Most surprising was that interferon‐responsive reactive astrocytes were present early progression of pathology in the 5xFAD mouse AD model, but not at later time points – suggesting important early (possibly protective) roles for astrocytes early in AD. Additionally, when comparing mouse and human datasets we find most disease pathology‐associated reactive astrocytes are located around strategic points of entry to the brain, and express many inflammation‐responsive transcripts. Probing for ‘modules’ of genes associated with inflammation‐response and reactive sub‐states of microglia and other immune cells highlights putative interactions likely integral for feedback between these two cell types.ConclusionOptimization of astrocyte capture for single cell/nuclei sequencing combined with integration of previously published datasets increased the size of datasets for analysis and power of our analysis. Our data highlight several novel reactive astrocyte sub‐states that warrant additional functional characterization and further investigation.
Astrocytes mediate neuronal network hyperactivity in early AD
Authors: Shah Disha , Gsell Willy , Wahis Jérôme , Luckett Emma S. , Jamoulle Tarik , Preman Pranav , Moechars Daan , Craessaerts Katleen , Horré Katrien , Hendrickx Véronique , Jaspers Tom , Wolfs Leen , Vermaercke Ben , Fiers Mark , Holt Matthew , Vegh Zsuzsanna , Thal Dietmar Rudolf , D'Hooge Rudi , Vandenberghe Rik , Himmelreich Uwe , Bonin Vincent , de Strooper Bart 
Published: December 2022

AbstractBackgroundDysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown.MethodWe analyzed resting‐state functional MRI data from a prospective cohort of patients and from the APP NLF knock‐in mouse model, with the aim to define which regions show early disruptions of functional connectivity (FC) before the presence of amyloid plaques. Next we used in‐vivo two photon calcium imaging to assess activity of astrocytes and neurons. Finally, we modulated calcium activity in astrocytes and assessed the effects on neuronal activity, FC and clinically relevant behavior readouts, i.e. seizure susceptibility and day/night activity.ResultWe found that, prior to amyloid accumulation, the human brain shows increased functional connectivity (FC) of the anterior cingulate cortex. Moreover, early increases of cingulate FC showed a positive correlation to amyloid load several years later in the human brain. Interestingly, we found the same FC deficit in the cingulate cortex of the APP NLF knock‐in mouse model, before amyloid deposition. We demonstrate that these FC deficits coincide with decreased calcium activity of astrocytes and increased neuronal activity. Recovery of the early astrocyte calcium deficits resulted in normalization of neuronal hyperactivity, increased FC as well as seizure susceptibility and day/night behavior disruptions.ConclusionIn conclusion, we show for the first time that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.
Identification of cis‐regulatory elements associated with MAPT expression in human induced pluripotent stem cell derived neural cells.
Authors: Rogers Brianne B. , Lauzon Shelby N. , Davis M. Natalie , Anderson Ashlyn G , Rizzardi Lindsay F. , Cooper Sara J. , Myers Richard M. , Cochran J. Nicholas 
Published: December 2022

AbstractBackgroundTau is encoded by MAPT and abnormal aggregates of tau are a hallmark of many neurodegenerative diseases. MAPT is highly expressed in neurons but much more lowly expressed in other cell types, including neural precursor cells (NPCs), suggesting that its expression may be controlled by neuron‐specific transcription factors and cis‐regulatory elements. Tau reduction, even of endogenous tau, is a current therapeutic strategy in both model systems and humans; therefore, understanding MAPT regulation may point to new strategies to achieve tau reduction. Additionally, genome sequencing studies continue to identify disease‐associated variants in non‐coding regions of the genome. These variants are likely located in regulatory regions and affect the expression of target genes whose function contributes to neurodegeneration. Therefore, an additional benefit of this study is that high confidence regulatory regions for MAPT may provide a way to identify important non‐coding variants associated with disease.MethodsThree‐dimensional chromatin conformation capture (Capture‐C), single‐cell multiomics (RNAseq + ATACseq), and chromatin marks including H3K27ac, H3K4me1, and DNase hypersensitivity were used to identify candidate enhancers of MAPT in human NPCs, NPCs differentiated to neurons, and pure inhibitory or excitatory neuron cultures (all lines were H1/H1). Approaches included nomination of elements with signals specific to neurons or neuronal subtypes. The nominated regions were then assessed using luciferase assays to test sufficiency for regulatory activity as well as CRISPR‐dCas9‐KRAB to assess the effect of nominated elements on MAPT expression.ResultsWe identified both proximal and distal regulatory elements for MAPT with function confirmed by up to four orthogonal approaches (chromatin capture, single cell multiomics, a reporter assay, and element inhibition using dCas9‐KRAB). Several of these elements were specific to neurons. One particularly important region was centromeric to MAPT beyond the H2 inversion breakpoint.ConclusionsOverall, these results indicate that MAPT regulation is likely controlled by neuron‐specific cis‐regulatory elements, including both proximal and distal elements. Next steps include study of the effect of trans‐regulatory elements (i.e., transcription factors) that may control recruitment of these cis‐regulatory elements for expression of MAPT and assessment of the effects of the disease‐associated genetic variation on cis‐regulatory element function and expression of MAPT.
Possible role for blood‐brain barrier disruption in patients with Alzheimer’s disease spectrum and non‐Alzheimer’s disease pathological changes
Authors: Moon Yeonsil , Jeon Hong Jun , Han Seol‐Heui , Noh Min‐Young , Kim Hee‐Jin , Kwon Kyoung JA , Moon Won‐Jin , Kim Seung Hyun 
Published: December 2022

AbstractBackgroundThe blood‐brain barrier (BBB) breakdown has been suggested as an early marker for Alzheimer’s disease (AD); yet the relationship between BBB breakdown and AD‐specific biomarkers based on the amyloid/tau/neurodegeneration (ATN) framework, is not clear. This study aimed to investigate the relationship between BBB permeability, AD‐specific biomarkers, and cognition in patients with cognitive decline.MethodIn this prospective observational study, we enrolled 62 participants with mild cognitive impairment or dementia between January 2019 and October 2020. All participants were assessed cognitive tests, amyloid PET, dynamic contrast enhanced MRI for BBB permeability (Ktrans), CSF studies for Aβ42/40 ratio, CSF phosphorylated tau Thr181 protein (p‐tau), CSF total tau protein (t‐tau), and structural MRI for neurodegeneration.ResultCompared with the Aβ‐G, the Aβ+G had a higher median Ktrans in the frontal cortices (P = 0.049). In Aβ‐G, Ktrans was positively correlated with CSF p‐tau level in the cerebral cortex (all p < 0.05 except for the occipital cortex). In Aβ+G, Ktrans of occipital cortices was related with CSF Aβ42/40 (rho = 0.403, p = 0.027), and CSF t‐tau level (rho = ‐0.404, p = 0.027), whereas, Ktrans of frontal (rho = ‐0.610, p<0.001), insular (r = ‐0.400, p = 0.028), parietal (rho = ‐0.446, p = 0.013) and temporal cortices (rho = ‐ 0.435, p = 0.016) was negatively related with hippocampal volume. When adjusting age and education, neither BBB permeability nor CSF biomarkers predict cognition.ConclusionOur results suggest that the relationship between BBB permeability and ATN biomarkers is evident, more interestingly, this relationship varies with the presence of Aβ plaque accumulation.
Treatment of Alzheimer’s disease by modulation of microglial neuroinflammation by nasal anti‐CD3 mAb
Authors: Weiner Howard L , Lopes Juliana , Zhang Xiaoming , Baufeld Caroline , Rezende Rafael , Selkoe Dennis J , Butovsky Oleg 
Published: December 2022

AbstractBackgroundNeuroinflammation and microglial activation play a role in AD as shown pathologically and by microglial PET imaging (Zhou et al, Front Immunol 2021). We found that nasal anti‐CD3 mAb induced IL‐10‐secreting T cells in the cervical lymph node that migrate to the brain, suppress microglial inflammation and ameliorate disease in a model of progressive MS (Mayo et a,l Brain 2016). In humans we found that nasal anti‐CD3 (Foralumab) decreased inflammation and accelerated resolution of lung inflammation in patients with mild COVID‐19 (Moreira et al, Front Immunol 2021) and modulated microglial activation in progressive MS as measured by microglial PET imaging (Chitnis et al, unpublished). We thus tested nasal anti‐CD3 in animal models of AD.MethodWe treated AD mice (3xTg and APP/PS1) with nasal anti‐CD3, isotype control antibody or PBS 3x/week for 6 months (3xTg) or 3x/week for 2 months (APP/PS1) and investigated cognitive behavior (Morris water maze and Y‐maze), microglia gene profile using a Nanostring myeloid codeset and T cell infiltration in the brain by immunofluorescence.ResultWe found that microglia lose their homeostatic (M0) signature and acquire a neurodegenerative (MGnD) signature in animal models of AD. In 3xTg mice, we found that nasal anti‐CD3 restored the M0 signature by increasing the expression of Cx3cr1, Mafb, and Jun, and lessened the MGnD signature by decreasing the expression of Trem2, Nos2 and Ccl5. Nasal anti‐CD3 improved cognition in 3xTg mice as measured by the Y‐maze and Morris water maze tests and in APP/PS1 mice as measured by the Y‐maze test. Nasal anti‐CD3 induced migration of T cells to the brain which interacted with microglia.ConclusionNasal anti‐CD3 restores the microglial M0 signature and improves behavior in animal models of AD. Based on these results and the successful administration of nasal anti‐CD3 to subjects with progressive MS and COVID‐19, phase 1 trials of nasal Foralumab are planned in subjects with mild AD to assess safety, clinical effects and microglial activation as measured by microglial PET imaging. Nasal anti‐CD3 is a novel approach to treat AD by targeting microglial inflammation.
Amyloid‐β activates NLRP3 inflammasomes by affecting microglial immunometabolism through the Syk‐AMPK pathway
Authors: Jung Eun Sun , Suh Kyujin , Han Jihui , Kim Heyyoung , Kang Hyung‐Sik , Choi Won‐Seok , Mook‐Jung Inhee 
Published: December 2022

AbstractBackgroundNeuroinflammation is considered one of major factors in the pathogenesis of Alzheimer’s disease (AD). In particular, inflammasome activation, including NLRP3 inflammasome in microglia, is regarded as fundamental for the pro‐inflammatory response of immune cells (Hanslik & Ulland, 2020). Aβ functions to primarily activate microglia in AD and reports have been made that Aβ can activate NLRP3 inflammasome(Halle et al., 2008). However, the precise molecular mechanism through which the NLRP3 inflammasome is associated with AD pathologies remains unclear.MethodPrimary microglia were treated with LPS and Aβ, and the induced signaling pathway were examined by RT‐PCR, western blot and immunostaining. Effect of flufenamic acid (FA) were examined and various inhibitors of Syk, AMPK and NLRP3 were used for the verification of the hypothesis. AD mouse model expressing Aβ and tau pathology were intraperitoneally treated with FA. After behavior tests, their brains were obtained for western blot and immunostaining.ResultAβ activates the NLRP3 inflammasome in microglia by activating Syk and inhibiting AMPK. Deactivated AMPK induces metabolic dysregulation, mitochondrial fragmentation and reactive oxygen species formation, leading to the activation of the NLRP3 inflammasome. In addition, flufenamic acid (FA), a member of non‐steroid anti‐inflammatory drugs, was found to effectively inhibit activation of the microglial NLRP3 inflammasome by regulating Syk and AMPK. Importantly, FA has marked therapeutic effects on major AD pathologies including amyloid plaque formation, tau phosphorylation, gliosis and memory dysfunction in vivo in microglia‐dependent way.ConclusionThe molecular mechanism of microglial NLRP3 inflammasome activation by Aβ was demonstrated to be Syk‐AMPK pathway. Also, FA can be repurposed for inhibiting microglial activation of the NLRP3 inflammasome, which is a potential treatment for AD.*ReferencesHanslik, K. L., & Ulland, T. K. (2020). The Role of Microglia and the Nlrp3 Inflammasome in Alzheimer’s Disease. Frontiers in Neurology, 11.Halle, A., Hornung, V., Petzold, G. C., Stewart, C. R., Monks, B. G., Reinheckel, T., Fitzgerald, K. A., Latz, E., Moore, K. J., & Golenbock, D. T. (2008). The NALP3 inflammasome is involved in the innate immune response to amyloid‐β. Nature immunology, 9(8), 857.
Findings from a National Consensus Conference: Interdisciplinary Action Steps to Enhance Support for Dementia Family Caregivers
Authors: Brody Lilla A , Falzarano Francesca , Riffin Catherine 
Published: December 2022

AbstractBackgroundIn 2021, loved ones of individuals with Alzheimer’s disease and related dementias (ADRD) provided an estimated $271 billion worth of unpaid care (Alzheimer’s Association, 2022). While there is mounting consensus for the need to support caregivers, interdisciplinary collaborations are necessary to facilitate the translation of evidence‐based programs into real‐world solutions (Gitlin et al., 2015).MethodsWith funding from the National Institute on Aging, Weill Cornell Medicine hosted “The 2021 Conference on Engaging Family and Other Unpaid Caregivers of People with Dementia in Healthcare Delivery.” The hybrid (virtual/in‐person) event convened interdisciplinary experts from across the nation to establish a policy‐ and practice‐ aligned research agenda aimed at advancing the science of ADRD caregiving. These experts consisted of caregivers of people with ADRD, healthcare providers, researchers, health plan providers, and non‐profit organizations. The conference involved expert panels on caregiving‐related topics (e.g., public policies, intervention research), small group breakout sessions to identify major recommendations, and prioritization of the recommendations through voting.ResultsThe resulting recommendations centered on five topic areas: caregiver identification and assessment, caregiver training, provider training, provider reimbursement, and technology. Two cross‐cutting themes—the need for implementation science and leveraging frameworks of intersectionality— permeated throughout all recommendations. The committee recommended actionable next steps to address the need for training and support across the care continuum, acknowledging that a one‐size‐fits‐all approach is inadequate in addressing the needs of a group as diverse as ADRD caregivers (Alzheimer’s Association, 2022). The group advocated for the development of training programs tailored to the care recipient’s disease stage and caregiver’s preferences.ConclusionThe Alzheimer’s Association and similar organizations are uniquely positioned to support work in the area of caregiver training. These organizations could collaborate with researchers to develop or expand opportunities to aid ADRD caregivers in medical treatment protocols, financial planning, and end‐of‐life preparation. Medical practices could then implement referral protocols connecting ADRD caregivers with local Alzheimer’s Association Chapters, providing much‐needed support. Bridging the gap between training and support could lead to positive outcomes for caregivers, their care recipients, and society at large (Nichols et al., 2017; Rowe et al., 2016; Guterman et al., 2019).
Mid‐to‐Late Life Healthy Lifestyle Modifies Genetic Risk for Longitudinal Cognitive Aging among Asymptomatic Individuals from the Wisconsin Registry for Alzheimer’s Prevention
Authors: Xu Yuexuan , Koscik Rebecca Langhough , Jonaitis Erin M. , Lu Qiongshi , Johnson Sterling C. , Engelman Corinne D. 
Published: December 2022

AbstractBackgroundGenetic and lifestyle factors contribute to an individual’s risk for developing Alzheimer’s disease (AD). A better understanding of interactions between these factors may help design targeted interventions. In this study, we investigated whether number of long‐term healthy lifestyles modified the effect of genetic predisposition to AD on cognitive decline during the preclinical stage of AD.MethodsWe evaluated longitudinal associations of cognitive aging with a healthy lifestyle composite score, which included physical activity, diet, smoking, cognitive activity, and alcohol consumption, and the interaction of the healthy lifestyle composite score with APOE ε4 carrier status and a non‐APOE polygenic risk score (PRS) in a sample of 848 individuals from the Wisconsin Registry for Alzheimer’s Prevention (Table 1). The primary outcome was a multi‐domain cognitive composite (PACC3); secondary outcomes were immediate/delayed memory and executive function composites. We fitted all analyses using a linear mixed effects model and adjusted for within‐individual and within‐family correlation.ResultsFavorable lifestyles can marginally modify the age dependent influence of APOE on PACC3 (p = 0.1) and executive function (p = 0.14), and significantly mitigate the adverse effect of APOE ε4 on delayed recall as people aging (p < 0.01, Figure 1). However, we observed no statistically significant interactions between non‐APOE PRS, combined lifestyle factors, and age for all the assessed cognitive outcomes (Figure 2). When we further stratify the sample by the APOE ε4 carrier status, we found the interaction between non‐APOE PRS, age, and healthy lifestyle is statistically significant for PACC3 (p = 0.02) and delayed recall (p < 0.01) and marginally significant for immediate learning (p = 0.06) among APOE ε4 carriers (Figure 3). Among APOE ε4 noncarriers, combined lifestyle factors can only modify the age‐dependent adverse genetic influence of non‐APOE PRS on PACC3 (p = 0.01), but the protective effect is more evident at a younger age (Figure 4). These results are robust to multiple sensitivity analyses.ConclusionA favorable lifestyle can mitigate the genetic risk caused by both APOE ε4 and non‐APOE PRS, but the protective effect against non‐APOE PRS is more evident among APOE ε4 carriers.
COVID‐19 related life changes for family caregivers of persons with Lewy body disease
Authors: Stacy Kelly E , Miller Elaine , Shatz Rhonna , Bakas Tamilyn 
Published: December 2022

AbstractBackgroundCoronavirus disease 2019 (COVID‐19) affected individuals’ physical and mental health. Protective measures such as closures, social‐distancing, masking, and isolation resulted in increased feelings of loneliness and isolation. This study aimed to investigate life changes associated with COVID‐19 for family caregivers of persons with Lewy body disease (LBD).MethodData were analyzed from an existing LBD caregiver needs and concerns study that took place between January 2021 and February 2021. A mixed methods approach was used to describe how 20 caregivers’ lives changed as a result of the COVID‐19 pandemic. Items from the Bakas Caregiving Outcomes Scale (BCOS) were adapted for COVID‐19 and rated on a response scale ranging from 1 = changed for the worst to 7 = changed for the best, with 4 = did not change. Qualitative data were collected as participants expanded upon their responses to the scale itemsResultCaregivers experienced both positive and negative life changes as a result of COVID‐19. On average, positive changes included increased use of the internet to order items (Mean = 4.35), videoconferencing to connect with others (Mean = 4.55), and improved financial well‐being (Mean = 4.35). Negative changes included reduced social (Mean = 1.7) and family (Mean = 2.05) activities and decreased ability to cope with stress (Mean = 2.60). Most responses ranged from 1 to 4, with some items having wider ranges from 1 to 7 showing that individual caregivers were impacted differently by the COVID‐19 pandemic. Qualitative comments were consistent with quantitative responses. Some caregivers expressed concerns that limited family and social contact contributed to a more rapid decline in the person with LBD. Caregiver health and well‐being were negatively affected as well, with caregivers noting decreased level of energy and worsened physical health.ConclusionFamily caregivers of persons with LBD experienced both positive and negative life changes as a result of COVID‐19. Responses indicated that caregivers were affected in a variety of ways and an individualized approach is recommended in dealing with caregiver life changes resulting from the COVID‐19 pandemic.