Featured
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Article
| Open AccessFluorescent fatty acid conjugates for live cell imaging of peroxisomes
The array of tools to image peroxisome regulation is still limited. Here, the authors develop improved fatty acid-based probes with high peroxisome specificity and bright fluorescence in the red/far-red spectrum, which makes them ideal to study peroxisomes in live cells and whole organisms.
- Daria Korotkova
- , Anya Borisyuk
- & Triana Amen
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Article
| Open AccessEffects of SPI1-mediated transcriptome remodeling on Alzheimer’s disease-related phenotypes in mouse models of Aβ amyloidosis
Although SPI1 gene was identified as a risk factor for Alzheimer’s disease, its role in the disease remains unclear. Here, the authors show that decreasing SPI1 level exacerbates disease symptoms, whereas increasing its level ameliorates phenotypes.
- Byungwook Kim
- , Luke Child Dabin
- & Jungsu Kim
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Article
| Open AccessBacteroidota inhibit microglia clearance of amyloid-beta and promote plaque deposition in Alzheimer’s disease mouse models
The gut microbiota and microglia play critical roles in Alzheimer’s disease (AD). Here, the authors show that Bacteroides fragilis contributes to AD pathogenesis in mouse models by suppressing immune-mediated microglial clearance of amyloid beta.
- Caroline Wasén
- , Leah C. Beauchamp
- & Howard L. Weiner
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Article
| Open AccessStructure of alpha-synuclein fibrils derived from human Lewy body dementia tissue
The accumulation of alpha-synuclein fibrils within neurons is the defining feature of Lewy body dementia (LBD). Here the authors report a method to produce large quantities of alpha-synuclein fibrils that reproduce the complex structure of the fibrils that accumulate in LBD brain tissue.
- Dhruva D. Dhavale
- , Alexander M. Barclay
- & Paul T. Kotzbauer
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Article
| Open AccessUltrastructure of human brain tissue vitrified from autopsy revealed by cryo-ET with cryo-plasma FIB milling
Here the authors report a method for cryogenic electron microscopy imaging of human brain tissue samples directly obtained from autopsy, offering insights into cellular ultrastructure and a tool to study potential pathologic features.
- Benjamin C. Creekmore
- , Kathryn Kixmoeller
- & Yi-Wei Chang
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Review Article
| Open AccessNeuropathogenesis-on-chips for neurodegenerative diseases
This review focuses on recent advances in on-chip platforms for patient-like in vitro modeling of the pathology of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as Amyotrophic lateral sclerosis. The authors advocate for broader usage of these human-relevant models in the academic and pharmaceutical fields.
- Sarnai Amartumur
- , Huong Nguyen
- & Chaejeong Heo
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Article
| Open AccessA Protein Misfolding Shaking Amplification-based method for the spontaneous generation of hundreds of bona fide prions
To study neurodegenerative prion diseases, a method (PMSA) for generating prions spontaneously is presented. Applied to 380+ different prion proteins, their tendency to become pathogenic was ranked, illuminating their formation process.
- Hasier Eraña
- , Cristina Sampedro-Torres-Quevedo
- & Joaquín Castilla
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Article
| Open AccessEfficient generation of a self-organizing neuromuscular junction model from human pluripotent stem cells
Here, Urzi et al. pioneered a 2D self-organizing neuromuscular junction (soNMJ) model from human pluripotent stem cells, with implications for neuromuscular disease modeling and drug screening approaches.
- Alessia Urzi
- , Ines Lahmann
- & Mina Gouti
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Article
| Open AccessLate gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa
Is there a critical period to deliver gene therapies in photoreceptor degeneration? Using a mouse model of retinitis pigmentosa, the authors show that once 70% of rods are lost, gene replacement fails to restore normal retinal output.
- Miranda L. Scalabrino
- , Mishek Thapa
- & Greg D. Field
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Article
| Open AccessDissecting the human leptomeninges at single-cell resolution
The meninges protect the central nervous system at the brain border, and its dysfunction can lead to neural inflammation and cell damage. Here, the authors uncover the gene signatures of diverse cell types in the aged human leptomeninges and highlight their changes in Alzheimer’s Disease.
- Nicola A. Kearns
- , Artemis Iatrou
- & Yanling Wang
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Article
| Open AccessCross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy
Progressive supranuclear palsy is a devastating neurological disorder without treatment. Here, the authors leveraged omics data and model organisms to nominate, prioritize, and validate high-confidence candidate genes as therapeutic targets.
- Yuhao Min
- , Xue Wang
- & Nilüfer Ertekin-Taner
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Article
| Open Accessα-Synuclein aggregates amplified from patient-derived Lewy bodies recapitulate Lewy body diseases in mice
α-Synuclein aggregates in Lewy bodies (LBs) have not been widely used for research due to the limited availability of diseased brains. Here, the authors report a mouse model that recapitulates LB diseases using the LB amplification method.
- Norihito Uemura
- , Nicholas P. Marotta
- & Virginia M.-Y. Lee
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Article
| Open AccessCircadian clock disruption promotes the degeneration of dopaminergic neurons in male Drosophila
Circadian disruptions are frequent comorbidities of neurodegenerative disorders, such as Parkinson’s, marked by dopaminergic neuron loss. Here, the authors reveal circadian clocks dictate the susceptibility of dopamine neurons to oxidative stress.
- Michaëla Majcin Dorcikova
- , Lou C. Duret
- & Emi Nagoshi
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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 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 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 AccessMulti-omic approach characterises the neuroprotective role of retromer in regulating lysosomal health
Daly, Danson and colleagues employ a multi-omic approach in neuroglioma cells to characterise endolysosomal dysfunction caused by perturbation of the evolutionarily conserved Retromer complex, highlighting Retromer’s neuroprotective function.
- James L. Daly
- , Chris M. Danson
- & Peter J. Cullen
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Article
| Open AccessTargeting neuronal lysosomal dysfunction caused by β-glucocerebrosidase deficiency with an enzyme-based brain shuttle construct
Mutations in glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher’s disease and are the most common risk factor for Parkinson’s disease. Using a fusion protein comprising GCase and a transferrin receptor antibody fragment, the authors show that the transferrin receptor pathway can be therapeutically exploited to both pass the blood-brain barrier and efficiently target lysosomal GCase deficiency.
- Alexandra Gehrlein
- , Vinod Udayar
- & Ravi Jagasia
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Article
| Open AccessGlucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism
GBA1 mutations cause Gaucher’s disease and are the strongest risk factor for Parkinson’s disease. Using stable cell lines and patient iPSCs, the authors show mitochondrial localization of GBA1, which may affect neurodegenerative disease risk.
- Pascale Baden
- , Maria Jose Perez
- & Michela Deleidi
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Article
| Open AccessHematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy
Cerebral adrenoleukodystrophy (CALD) is a demyelinating disease caused by loss of ABCD1 gene function. Here the authors investigate white matter structural and microvascular changes in boys with CALD that received gene therapy with autologous hematopoietic stem-cells.
- Arne Lauer
- , Samantha L. Speroni
- & Patricia L. Musolino
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Article
| Open AccessTyrosyl-tRNA synthetase has a noncanonical function in actin bundling
Mutations in tRNA ligases, essential components of the translational machinery, are associated with Charcot-Marie-Tooth peripheral neuropathy, but the mechanistic details are not known. The authors report that the tyrosyl-tRNA synthetase is an evolutionary-conserved F-actin organizer, and dysregulation of this function is associated with the disorder.
- Biljana Ermanoska
- , Bob Asselbergh
- & Albena Jordanova
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Article
| Open AccessLSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice
Here, Prakasam and colleagues show that polyQ-expanded androgen receptor toxicity can be attenuated using artificial miRNAs targeting Lsd1 and Prmt6, two AR-co-activators overexpressed in an androgen-dependent manner specifically in skeletal muscle, thus ameliorating spinal-bulbar muscular atrophy phenotypes in flies and mice.
- Ramachandran Prakasam
- , Angela Bonadiman
- & Maria Pennuto
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Article
| Open AccessCSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model
Tau-mediated neurodegeneration is driven by disease-activated microglia and suppressed by their pharmacological blockade. The authors identified drug dose- and sex-dependent residual microglial phenotypes, neuronal excitotoxicity, and animal survival.
- Noah R. Johnson
- , Peng Yuan
- & Carlo Condello
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Article
| Open AccessHBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids
Complex neuropathologies, like macular degeneration, are common but incompletely understood. Here the authors report a complex human retina pathology organoid model induced by HBEGF-TNF, causing PIEZO1-mediated photoreceptor degeneration by cell extrusion.
- Manuela Völkner
- , Felix Wagner
- & Mike O. Karl
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Article
| Open AccessPrevalence and mechanisms of somatic deletions in single human neurons during normal aging and in DNA repair disorders
DNA damage has been implicated in aging and neurodegeneration. Here, the authors develop a bioinformatic method to detect deletions in single neuron genome sequences and reveal an increased burden of somatic deletions during aging and in DNA repair disorders.
- Junho Kim
- , August Yue Huang
- & Eunjung Alice Lee
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Article
| Open AccessPreclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration
The authors show in an animal model and in a study in patients with dementia with Lewy bodies (DLB) that the drug neflamapimod has potential to treat diseases, such as DLB, associated with loss of neurons that produce the neurotransmitter acetylcholine.
- Ying Jiang
- , John J. Alam
- & Ralph A. Nixon
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Article
| Open AccessRetromer deficiency in Tauopathy models enhances the truncation and toxicity of Tau
Tau and the Retromer complex are both linked to Parkinson’s and Alzheimer’s disease. Using Drosophila neurodegeneration models, this study finds that low retromer activity induces a specific increase of a highly toxic truncated form of human Tau.
- Jamshid Asadzadeh
- , Evelyne Ruchti
- & Brian D. McCabe
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Article
| Open AccessEpigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology
Parkinson’s disease and dementia with Lewy bodies are closely related neurodegenerative disorders, although the epigenetic similarities are not well known. Here, the authors study Lewy pathology and DNA methylation in postmortem human frontal cortex, identifying differentially methylated genomic loci.
- Lasse Pihlstrøm
- , Gemma Shireby
- & Mathias Toft
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Article
| Open Accessα-Synuclein fibril-specific nanobody reduces prion-like α-synuclein spreading in mice
Butler et al. selected disulfide bond-free nanobodies to target α-synuclein fibrils. Nanobody PFFNB2 was shown to disaggregate α-synuclein fibrils in vitro and inhibit α-synuclein pathology development in neuron cultures and mouse models.
- Yemima R. Butler
- , Yuqing Liu
- & Wenjing Wang
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Article
| Open AccessCis- and trans-resveratrol have opposite effects on histone serine-ADP-ribosylation and tyrosine induced neurodegeneration
Here, the authors show that histone serine-ADP-ribosylation is decreased in Alzheimer’s disease brains and increased tyrosine levels deplete tyrosyl-tRNA synthetase levels and cause neuronal damage. Cis-resveratrol was shown to facilitate histone serine-ADP-ribosylation-dependent DNA repair and provides neuroprotection, while trans-resveratrol induces neurodegeneration in rat cortical neurons.
- Megha Jhanji
- , Chintada Nageswara Rao
- & Mathew Sajish
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Article
| Open AccessRNase H2, mutated in Aicardi‐Goutières syndrome, resolves co-transcriptional R-loops to prevent DNA breaks and inflammation
RnaseH2 is mutated in severe neuro-inflammatory disorder Aicardi‐Goutières syndrome. Here the authors reveal that RNase H2 controls cellular R-loop homeostasis to promote transcription, genome integrity and prevent R-loop-associated inflammation.
- Agnese Cristini
- , Michael Tellier
- & Natalia Gromak
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Article
| Open AccessPantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism
PKAN and PD are two distinct diseases with overlapping pathophysiology. Here, authors show that their pathogenic genes PANK2 and PINK1 interact. PANK2 regulates mitophagy via CoA metabolism, while PINK1 supervises PANK2 translation on mitochondria.
- Yunpeng Huang
- , Zhihui Wan
- & Bing Zhou
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Article
| Open AccessDissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease
In Alzheimer’s disease (AD) tau and neurodegeneration have complex regional relationships. Here, the authors show neuronal hypometabolism discordant with tau burden defines functional resilience or susceptibility to Alzheimer’s pathology via limbic/cortical axes. Susceptible groups have faster cognitive decline and evidence of non-Alzheimer’s pathologies.
- Michael Tran Duong
- , Sandhitsu R. Das
- & Ilya M. Nasrallah
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Article
| Open AccessTau deposition patterns are associated with functional connectivity in primary tauopathies
Tau pathology drives neuronal dysfunction in 4- repeat tauopathies. Here, the authors combine tau-PET, resting-state fMRI and histopathology data, to show that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.
- Nicolai Franzmeier
- , Matthias Brendel
- & Michael Ewers
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Article
| Open AccessMapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers
In this work, Louros et al. uncover a rule book for interactions of amyloids with other proteins. This grammar was shown to promote cellular spreading of tau aggregates in cells, but can also be harvested to develop structure-based aggregation blockers.
- Nikolaos Louros
- , Meine Ramakers
- & Joost Schymkowitz
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Article
| Open AccessKansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice
Here the authors show that the Koolen-de Vries syndrome associated gene KANSL1 modulates autophagosome-lysosome fusion via transcriptional regulation of autophagosomal gene Syntaxin17, and that 13-cis retinoic acid can reverses mitophagic defects and neurobehavioural abnormalities of mice lacking Kansl1.
- Ting Li
- , Dingyi Lu
- & Xin Pan
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Article
| Open AccessModulation of dopamine tone induces frequency shifts in cortico-basal ganglia beta oscillations
Dopamine tone modulation generates changes in beta oscillation physiology. Here the authors show beta frequency, and not power, coherence, phase-locking, or PAC is monotonically linked to dopamine tone and is likely the key property of pathological oscillations in cortical and basal ganglia networks.
- L. Iskhakova
- , P. Rappel
- & H. Bergman
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Article
| Open AccessTau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation
Brain inflammation generally accelerates neurodegeneration but the mechanisms of this are not fully characterised. Here the authors show that PQBP1 in microglia is important for sensing extrinsic Tau 3 R/4 R proteins and triggers an innate immune response through cGAS and STING resulting in cognitive impairment.
- Meihua Jin
- , Hiroki Shiwaku
- & Hitoshi Okazawa
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Article
| Open AccessInterferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy
Studies on interferon-driven brain pathology have so far been hampered by the lack of appropriate animal models. Here the authors characterize RNASET2-deficient mice and show that neuroinflammation and brain atrophy are IFNAR1-dependent.
- Matthias Kettwig
- , Katharina Ternka
- & Jutta Gärtner
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Article
| Open AccessHighly efficient intercellular spreading of protein misfolding mediated by viral ligand-receptor interactions
Pathologic protein aggregates associated with neurodegenerative diseases have the ability to transmit to unaffected cells via extracellular vesicles or direct cell-to-cell contact. Here, Liu et al. show that viral glycoproteins can contribute to intercellular proteopathic seed transmission via both routes.
- Shu Liu
- , André Hossinger
- & Ina M. Vorberg
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Article
| Open AccessA C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation
A hexanucleotide repeat expansion of C9orf72 is translated to dipeptide repeat proteins in amyotrophic lateral sclerosis and frontotemporal dementia patients. Here the authors generate a C. elegans model of C9orf72-mediated ALS/FTD and show that translation initiation factor eIF2D regulates the dipeptide repeat protein expression.
- Yoshifumi Sonobe
- , Jihad Aburas
- & Paschalis Kratsios
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Article
| Open AccessAn immune response characterizes early Alzheimer’s disease pathology and subjective cognitive impairment in hydrocephalus biopsies
Specific transcriptional changes in microglia associated with Alzheimer’s disease have been reported. Here, the authors show that transcriptional analysis of human hydrocephalus biopsies identifies changes in immune response genes associated with early AD pathology, including cognitive decline.
- Wenrui Huang
- , Anne Marie Bartosch
- & Andrew F. Teich
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Article
| Open AccessHecw controls oogenesis and neuronal homeostasis by promoting the liquid state of ribonucleoprotein particles
Ribonucleoprotein (RNP) granules are responsible for mRNA transport and local translation required for neuronal and oocyte maturation. Here the authors show that loss of the Drosophila Ub ligase Hecw enlarges RNP granules, leads to a liquid to gel-like transition, and results in defective oogenesis and neuronal loss.
- Valentina Fajner
- , Fabio Giavazzi
- & Simona Polo
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Article
| Open AccessC9orf72-derived arginine-rich poly-dipeptides impede phase modifiers
Nuclear import receptors (NIRs) regulate self-association of RNA-binding proteins as phase modifiers, while C9orf72-derived arginine-rich polydipeptides lead to aberrant phase transitions. Here the authors show in molecular basis how arginine-rich poly-dipeptides impede the ability of NIRs, particularly Kapβ2.
- Hitoki Nanaura
- , Honoka Kawamukai
- & Eiichiro Mori
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Article
| Open AccessGenetically encoded cell-death indicators (GEDI) to detect an early irreversible commitment to neurodegeneration
Cell death is a critical process in health and disease, yet available markers record later stages of cell death once a cell has already begun to decompose. Here the authors show the use of a genetically encoded calcium indicator that demarcates an irreversible stage of cell death earlier than previously possible.
- Jeremy W. Linsley
- , Kevan Shah
- & Steven Finkbeiner
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Article
| Open AccessPhenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons
α-Synuclein aggregation contributes to Parkinson’s disease and related disorders. Here the authors investigate patterns of α-synuclein aggregation in human dopaminergic neurons in response to fibrils derived from individuals with Parkinson’s disease or multiple system atrophy.
- Benedict Tanudjojo
- , Samiha S. Shaikh
- & George K. Tofaris
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Article
| Open AccessPlasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations
Plasma biomarkers of amyloid, tau and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. Here, the authors show plasma ATN biomarkers predict clinical deterioration and cognitive decline and show in a simulated clinical trial combining all three biomarkers reduced the required sample size.
- Nicholas C. Cullen
- , Antoine Leuzy
- & Oskar Hansson
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Article
| Open AccessA molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech
Progressive apraxia of speech (PAOS) is a neurodegenerative syndrome of multiple etiologies which affects spoken communication. Here, the authors characterized the molecular pathology, biochemistry, genetics and longitudinal neuroimaging of 32 autopsy-confirmed patients with PAOS who were followed over 10 years.
- Keith A. Josephs
- , Joseph R. Duffy
- & Jennifer L. Whitwell
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Article
| Open AccessA multicentre validation study of the diagnostic value of plasma neurofilament light
Cerebrospinal fluid neurofilament light (NfL) is a biomarker for neurodegeneration that can also be assessed in blood. Here the authors show in a validation study the potential for plasma NfL as a biomarker for several neurodegenerative diseases.
- Nicholas J. Ashton
- , Shorena Janelidze
- & Oskar Hansson