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| Open AccessCSF proteome profiling reveals biomarkers to discriminate dementia with Lewy bodies from Alzheimer´s disease
This study characterizes the CSF proteome changes underlying Dementia with Lewy Bodies (DLB) and identifies pathophysiological and diagnostic leads associated to this cause of dementia. Findings have been translated into a biomarker panel that could identify DLB patients with high accuracy across different cohorts.
- Marta del Campo
- , Lisa Vermunt
- & Charlotte E. Teunissen
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Article
| Open AccessSingle nucleus transcriptomics of ventral midbrain identifies glial activation associated with chronic opioid use disorder
The cellular signatures of the opioid exposed human midbrain remain unexplored. Here, authors show by single nuclei transcriptomics activation of the glial immune response and dysregulation of synaptic signaling in opioid exposed individuals
- Julong Wei
- , Tova Y. Lambert
- & Schahram Akbarian
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Article
| Open AccessSingle-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD
Hexanucleotide repeat expansion in the C9ORF72 gene produces toxic dipeptide repeat (DPR) in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here the authors apply single-molecule methods to study the translation dynamics of C9ORF72 expanded repeat in different frames showing that multiple translation steps contribute to the final toxic dipeptide production.
- Malgorzata J. Latallo
- , Shaopeng Wang
- & Bin Wu
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Article
| Open AccessUnraveling the mechanisms of deep-brain stimulation of the internal capsule in a mouse model
The mechanisms of deep-brain stimulation for psychiatric disorders remain insufficiently understood. Here, the authors identified recruitment of cortico-striatal regions, in particular the medial orbitofrontal cortex, as a mechanism to treat compulsivity.
- Bastijn J. G. van den Boom
- , Alfredo Elhazaz-Fernandez
- & Ingo Willuhn
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Article
| Open AccessReversal of cell, circuit and seizure phenotypes in a mouse model of DNM1 epileptic encephalopathy
One third of all epilepsies are treatment-resistant. Here, the authors show in a genetic model of epilepsy that a repurposed drug can correct cell defects, brain circuits and seizure-like events by accelerating endocytosis.
- Katherine Bonnycastle
- , Katharine L. Dobson
- & Michael A. Cousin
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Article
| Open AccessTranslocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
TSPO PET imaging is widely used to quantify microglial activation. Here, the authors show that TSPO expression increases in activated rodent but not human microglia, implying that in humans TSPO informs on microglial density rather than activation status.
- Erik Nutma
- , Nurun Fancy
- & David R. Owen
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Article
| Open AccessMicroglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice
The circadian clock protein REV-ERBα has been implicated in neuroinflammation but mechanisms are poorly understood. Here, the authors show that microglial REV-ERBα regulates inflammatory signaling and lipid droplet formation to exert sex-specific effects on tau pathology in mice.
- Jiyeon Lee
- , Julie M. Dimitry
- & Erik S. Musiek
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Article
| Open AccessHuman forebrain organoid-based multi-omics analyses of PCCB as a schizophrenia associated gene linked to GABAergic pathways
Identifying schizophrenia risk genes is essential for illuminating the disease etiology. Here, authors prioritized Propionyl-CoA Carboxylase Subunit Beta (PCCB) as a schizophrenia-associated gene, and linked PCCB to GABAergic pathways using human forebrain organoids-based transcriptomic and metabolomic analysis.
- Wendiao Zhang
- , Ming Zhang
- & Qingtuan Meng
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Article
| Open AccessEffect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease
PSEN1 E280A carriers develop dementia by midlife, but there is variability in disease trajectory. Cognitive decline is accelerated in E280A carriers who also have an APOE e4 allele. Educational attainment moderates the effect of APOE on cognition.
- Stephanie Langella
- , N. Gil Barksdale
- & Yakeel T. Quiroz
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Article
| Open AccessReactivated endogenous retroviruses promote protein aggregate spreading
Endogenous retroviruses, or genomic relics of ancient viral infection, have been associated with certain neurodegenerative diseases. Here, Liu et al. report a pathway by which reactivated viral gene products contribute to intercellular protein aggregate spreading.
- Shu Liu
- , Stefanie-Elisabeth Heumüller
- & Ina M. Vorberg
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Article
| Open AccessA brainstem to circadian system circuit links Tau pathology to sundowning-related disturbances in an Alzheimer’s disease mouse model
Sundowning in Alzheimer’s disease (AD) patients is characterized by agitation and aggression during their afternoon-to-evening transition and a phase delay in circadian rhythms. Here, the authors show that AD model mice develop a phase delay and increased aggression around their active-to-rest transition with Tau pathology in brainstem neurons that target the circadian system.
- Andrew E. Warfield
- , Pooja Gupta
- & William D. Todd
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Article
| Open AccessWhole genome deconvolution unveils Alzheimer’s resilient epigenetic signature
The authors present a deep learning method that deconvolutes ATAC-seq samples into cell type-specific chromatin accessibility profiles. Applied on 191 samples, the method unveils cell type-specific pathways and nominates potential epigenetic mediators underlying resilience to Alzheimer’s disease.
- Eloise Berson
- , Anjali Sreenivas
- & Thomas J. Montine
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Article
| Open AccessAnxious individuals shift emotion control from lateral frontal pole to dorsolateral prefrontal cortex
Why anxious individuals fail to control emotional behaviour is not well understood. Here, the authors show that highly anxious individuals have a more excitable lateral frontopolar cortex, and fail to recruit this region during emotional action control.
- Bob Bramson
- , Sjoerd Meijer
- & Karin Roelofs
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Article
| Open AccessSingle-cell analysis reveals region-heterogeneous responses in rhesus monkey spinal cord with complete injury
The cellular responses below the lesion remain unclear after spinal cord injury (SCI). Here, authors show region-heterogeneous responses in the SCI monkey by single-cell transcriptomics analysis and uncover the mechanism of scaffold-based SCI repair.
- Yongheng Fan
- , Xianming Wu
- & Jianwu Dai
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Article
| Open AccessProfiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex
Opioid use disorder (OUD) is influenced by genetic and environmental factors. Here, authors use a multi-omics approach to reveal DNA hydroxymethylation as an important gene regulatory mechanism for OUD in the human brain.
- Gregory Rompala
- , Sheila T. Nagamatsu
- & Janitza L. Montalvo-Ortiz
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Article
| Open AccessEffects of oxidative stress on hepatic encephalopathy pathogenesis in mice
Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE). Here, authors show that the chemogenetic inhibition of GAD2 population in the SNr region, or the targeted overexpression of mitochondrial UCP2 in such population, or systemic application of a mitochondrial-targeting antioxidant drug Mito-Q could effectively ameliorate HE.
- Yunhu Bai
- , Kenan Li
- & Yanling Yang
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Article
| Open AccessCharacterising the RNA-binding protein atlas of the mammalian brain uncovers RBM5 misregulation in mouse models of Huntington’s disease
RNA-Binding Proteins (RBPs) are critical regulators of RNA biology. Here, the authors describe the Brain-pCLAP methodology, uncover the RBP atlas of the mouse brain and demonstrate the differential binding of the splicing factor RBM5 to Huntington’s disease relevant transcripts in R6/2 mice.
- Meeli Mullari
- , Nicolas Fossat
- & Michael L. Nielsen
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Article
| Open AccessAn optimized Nurr1 agonist provides disease-modifying effects in Parkinson’s disease models
An optimized agonist of Nurr1, 4A7C-301, protects dopamine neurons against environmental and genetic risk factors of Parkinson’s disease (PD) in vitro, and improves both motor and non-motor deficits in male rodent models of PD.
- Woori Kim
- , Mohit Tripathi
- & Kwang-Soo Kim
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Article
| Open AccessParsing altered gray matter morphology of depression using a framework integrating the normative model and non-negative matrix factorization
The neuroanatomical heterogeneity of depression is not well understood. Here, the authors identify four latent factors which characterise different patterns of gray matter morphology and are related to clinical symptoms.
- Shaoqiang Han
- , Qian Cui
- & Yong Zhang
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Article
| Open AccessGenome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity
Huntington’s disease is caused by mutation in the HTT gene. Here, the authors screen for suppressors of mutant HTT-induced toxicity, identifying Mtf1. Mtf1 reduced oxidative stress and cell death in stem cells, and motor defects and protein aggregates in mouse models.
- Giorgia Maria Ferlazzo
- , Anna Maria Gambetta
- & Graziano Martello
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Article
| Open AccessClosed-loop brain stimulation augments fear extinction in male rats
Whether fear memories can be attenuated through on demand electrical stimulation remains unclear. Here, the authors demonstrate that fear extinction can be augmented through closed-loop stimulation of the reward system, guided by hippocampal SWRs.
- Rodrigo Ordoñez Sierra
- , Lizeth Katherine Pedraza
- & Antal Berényi
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Article
| Open AccessBlood transcriptomic signatures associated with molecular changes in the brain and clinical outcomes in Parkinson’s disease
Understanding molecular processes behind variable clinical features of Parkinson’s disease is valuable. Distinct molecular patterns in the brains, reflected in the blood, reveal mechanisms linked to clinical diversity in cognitive and motor decline.
- Krithi Irmady
- , Caryn R. Hale
- & Robert B. Darnell
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| Open AccessCNS-associated macrophages shape the inflammatory response in a mouse model of Parkinson’s disease
In an alpha-synuclein (α-syn) model of Parkinson’s disease (PD), Schonhoff and colleagues have shown that central nervous system (CNS)-associated macrophages (CAMs), but not microglia, potentially orchestrate CD4+ T cell recruitment and mediate an α-syn-induced inflammatory makeup.
- Maximilian Frosch
- , Lukas Amann
- & Marco Prinz
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Article
| Open AccessBorder-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease
Neuroinflammatory mechanisms are implicated in Parkinson disease. Here we identify border-associated macrophages (BAMs), as essential for the α-synuclein-mediated neuroinflammatory response via class II antigen presentation, and T cell infiltration.
- A. M. Schonhoff
- , D. A. Figge
- & A. S. Harms
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Article
| Open AccessElevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway
MAP1B is bound and regulated by fragile X protein FMRP. Here, the authors show that elevated levels of MAP1B reduce the morphological and physiological maturation of human neurons and impair social behavior in mice.
- Yu Guo
- , Minjie Shen
- & Xinyu Zhao
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Article
| Open AccessSchizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids
Copy number deletions in 2p16.3 locus (NRXN1) in individuals significantly increase risk for schizophrenia. Here, authors show, at single cell level, genetic background-specific effects that culminate in synaptic dysfunction using iPSC-derived brain organoid model.
- Rebecca Sebastian
- , Kang Jin
- & ChangHui Pak
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Article
| Open AccessSpecific post-translational modifications of soluble tau protein distinguishes Alzheimer’s disease and primary tauopathies
Post-translational modifications on tau protein in the brain could distinguish primary tauopathies. Here, the authors assess insoluble and soluble tau extracted from post mortem human tauopathy brains and show 4R/3R tau isoform ratio in aggregates is associated with specific modifications on soluble tau protein.
- Nathalie Kyalu Ngoie Zola
- , Clémence Balty
- & Bernard J. Hanseeuw
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Article
| Open AccessGalectin-3 activates spinal microglia to induce inflammatory nociception in wild type but not in mice modelling Alzheimer’s disease
In inflammatory arthritis, pain neurons communicate with spinal cord microglia to establish nociception. Here, the authors show that this communication is mediated by pain neurons releasing galectin-3, which activates microglia through TLR4. In a mouse model of Alzheimer’s disease, pain is attenuated because microglia lack expression of TLR4.
- George Sideris-Lampretsas
- , Silvia Oggero
- & Marzia Malcangio
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Article
| Open AccessThe contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson’s disease
Astrocytes are implicated in the maintenance of the blood-brain barrier (BBB). This study established a microfluidic BBB chip and found that astrocytes may play a role in cerebrovascular dysfunction in people with Parkinson’s disease.
- A. de Rus Jacquet
- , M. Alpaugh
- & F. Cicchetti
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Article
| Open AccessLeveraging football accelerometer data to quantify associations between repetitive head impacts and chronic traumatic encephalopathy in males
The relationship between the components of repetitive head impacts and chronic traumatic encephalopathy (CTE) remains unclear. Here, the authors use American football helmet sensor data to show that duration of play, cumulative head impacts and linear and rotational accelerations are significantly associated with CTE pathology.
- Daniel H. Daneshvar
- , Evan S. Nair
- & Jesse Mez
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Article
| Open AccessNeural correlates of hierarchical predictive processes in autistic adults
It remains unclear whether autism spectrum disorder is characterized by changes in predictive mechanisms. Here, the authors show that, in both neurotypical and autistic adults, priors influence percepts at the behavioral and neural levels and are hierarchically encoded in the brain.
- Laurie-Anne Sapey-Triomphe
- , Lauren Pattyn
- & Johan Wagemans
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Article
| Open AccessKv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice
Seizures can occur in autism spectrum disorders (ASD). Here, the authors report that mice lacking the ASD related Ank2 gene show abnormal behaviours, and juvenile seizure related death, through impaired Kv7 potassium channel function.
- Hyoseon Oh
- , Suho Lee
- & Eunjoon Kim
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Article
| Open AccessBalanced SET levels favor the correct enhancer repertoire during cell fate acquisition
The usage of specific distal regulatory regions within the genome is critical for fate specification and cell maturation. Here, the authors show that the accumulation of the oncoprotein SET, as occurring in the rare Schinzel-Giedion syndrome, and associated histone hypo-acetylation interfere with normal enhancer repertoire employed during brain development.
- Mattia Zaghi
- , Federica Banfi
- & Alessandro Sessa
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Article
| Open AccessTherapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice
The WNT/b-catenin pathway is essential for bloodbrain barrier (BBB) and blood-retina barrier (BRB) function. A bioengineered FZD4-selective WNT surrogate demonstrated systemic efficacy during BRB and ischemic stroke BBB dysfunction in mice.
- Jie Ding
- , Sung-Jin Lee
- & Calvin J. Kuo
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Article
| Open AccessStacked binding of a PET ligand to Alzheimer’s tau paired helical filaments
Understanding the mode of small-molecule binding to amyloid filaments is critical for diagnosing and treating neurodegeneration. The authors use cryo-EM to reveal a stacked binding motif which may hasten design of diagnostics and therapeutics.
- Gregory E. Merz
- , Matthew J. Chalkley
- & Daniel R. Southworth
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Article
| Open AccessA pilot study of closed-loop neuromodulation for treatment-resistant post-traumatic stress disorder
Neurostimulation has been proposed as a potential approach for treatment-resistant PTSD. Here in a pilot study the authors show that amygdala theta activity is heightened during aversive and symptomatic experiences in patients with treatment-resistant post-traumatic stress disorder, and reduced following significant clinical improvement associated with closed-loop stimulation.
- Jay L. Gill
- , Julia A. Schneiders
- & Jean-Philippe Langevin
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Article
| Open AccessNear-lifespan longitudinal tracking of brain microvascular morphology, topology, and flow in male mice
Brain vascular impairment may occur early in diseases such as Alzheimer’s disease. Here the authors longitudinally study brain vascular dynamics in mice using advanced optical coherence tomography and deep learning algorithms, which enables tracking of slow vascular decline in aging and models of disease.
- Konrad W. Walek
- , Sabina Stefan
- & Jonghwan Lee
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Article
| Open AccessCell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes
Sex differences in brain transcriptomics have unknown cell type specificity. Here, authors show concordant cortical transcriptomic patterns in depression within individual cell types between sexes, but distinctly affected top cell types and genes.
- Malosree Maitra
- , Haruka Mitsuhashi
- & Corina Nagy
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Article
| Open AccessAllnighter pseudokinase-mediated feedback links proteostasis and sleep in Drosophila
For homeostatic plasticity, neuronal circuits rely on poorly understood retrograde signals. Here, the authors identify a visual activity-dependent feedback loop mediated by the secreted Allnighter pseudokinase with effects on brain-wide proteostasis and sleep.
- Shashank Shekhar
- , Andrew T. Moehlman
- & Helmut Krämer
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Article
| Open AccessThe in-tissue molecular architecture of β-amyloid pathology in the mammalian brain
In this work the authors reveal in-situ cryoET characterization of β-amyloid plaques in the brain of a mouse model of Alzheimer’s disease.
- Conny Leistner
- , Martin Wilkinson
- & René A. W. Frank
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Article
| Open AccessA pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides
Parkinson’s disease (PD) is linked to environmental factors. Through quantitative epidemiology, this study ties 53 pesticides to PD. An innovative human stem cell platform revealed that 10 of these were directly toxic to human dopamine neurons.
- Kimberly C. Paul
- , Richard C. Krolewski
- & Beate Ritz
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Article
| Open AccessIn situ continuous Dopa supply by responsive artificial enzyme for the treatment of Parkinson’s disease
Oral dihydroxyphenylalanine (Dopa) administration to replenish neuronal dopamine is a treatment for Parkinson’s disease but induces fluctuations in plasma Dopa levels. Here the authors report a nucleic acid-based responsive artificial enzyme (FNA-Fe3O4) for in situ continuous Dopa production.
- Xiao Fang
- , Meng Yuan
- & Huanghao Yang
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Article
| Open AccessSingle-cell analysis reveals inflammatory interactions driving macular degeneration
Single-nucleus RNA-seq was used to profile 11 retinas with varying stages of age-related macular degeneration and 6 control retinas. The authors identified shared glial states across neurodegeneration, indicating that the retina provides a human system for investigating therapeutic approaches in neurodegeneration.
- Manik Kuchroo
- , Marcello DiStasio
- & Brian P. Hafler
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Article
| Open AccessA randomized trial of Trendelenburg position for acute moderate ischemic stroke
The effect of head positioning in acute stroke is controversial. Here, the authors report the results of a clinical trial suggesting that the procedure, initiated within 24 hours of onset, is safe and feasible, but does not improve functional outcome in acute moderate stroke patients with large artery atherosclerosis.
- Hui-Sheng Chen
- , Nan-Nan Zhang
- & Thanh N. Nguyen
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Article
| Open AccessRe-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states
Glioblastoma (GBM) cells can infiltrate into the tumour microenvironment (TME) and contribute to recurrence. Here, the authors analyse primary and recurrent GBMs and their TME using single-nucleus and spatial transcriptomics, revealing tissue states defined by the combinations of neoplastic and non-neoplastic cells, which could be therapeutic targets.
- Osama Al-Dalahmah
- , Michael G. Argenziano
- & Peter Canoll
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Article
| Open AccessGut microbiome dysbiosis across early Parkinson’s disease, REM sleep behavior disorder and their first-degree relatives
Microbiota-gut-brain axis may play an important role in Parkinson’s disease (PD). Here, the authors assess gut microbiota in early PD, REM sleep behaviour disorder (RBD) and first-degree relatives of RBD and show PD-like gut dysbiosis occurs in RBD and their first-degree relatives.
- Bei Huang
- , Steven W. H. Chau
- & Yun Kwok Wing
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Article
| Open AccessA computational analysis of mouse behavior in the sucrose preference test
The sucrose preference test is one of the most widely used paradigms in behavioral neuroscience. Here, authors identify previously unrecognized behavioral subcomponents that can influence how it is interpreted.
- Jeroen P. H. Verharen
- , Johannes W. de Jong
- & Stephan Lammel
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Article
| Open AccessSoluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy
Brain microvascular dysfunction occurs in Alzheimer’s disease and other taupathies. Here the authors show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy, and that it contributes to vascular deficits in these mice.
- Stacy A. Hussong
- , Andy Q. Banh
- & Veronica Galvan
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Article
| Open AccessSingle-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers
Mutations in amyloid precursor protein (APP) and presenilin 1 (PSEN1) cause autosomal dominant AD (ADAD). Here, the authors perform single-nucleus RNA-sequencing of ADAD and other disease risk modifying variant carriers and report altered expression states of specific brain cell types.
- Logan Brase
- , Shih-Feng You
- & Oscar Harari
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