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Article
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Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures
Here, the authors use cryo-EM to show that phosphorylating or O-GlcNAcylating α-synuclein on serine 87 leads to the formation of two distinct fibril structures. Both structures display reduced neurotoxicity and propagation activity.
- Jinjian Hu
- , Wencheng Xia
- & Yan-Mei Li
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Article
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A blood-based biomarker workflow for optimal tau-PET referral in memory clinic settings
A screening strategy with plasma p-tau217, evaluated in two independent cohorts from Sweden and Canada, showed that this biomarker may effectively streamline tau-PET referrals in memory clinic settings, optimizing the prognostic work-up of Alzheimer’s disease.
- Wagner S. Brum
- , Nicholas C. Cullen
- & Oskar Hansson
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Local structural preferences in shaping tau amyloid polymorphism
In this work, using a combination of Cryo-EM, in-cell experiments and biophysical analysis, the authors decoded the aggregation propensity of tau, revealing 5 central hot spots in its primary sequence and identify PAM4 as short segment that determines both the structure, as well as the cellular propagation of tau aggregates extracted from Alzheimer’s disease, corticobasal degeneration, and progressive supranuclear palsy patients.
- Nikolaos Louros
- , Martin Wilkinson
- & Joost Schymkowitz
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Early onset diagnosis in Alzheimer’s disease patients via amyloid-β oligomers-sensing probe in cerebrospinal fluid
In this work, the authors characterize a small molecule fluorescent probe pioneering early diagnosis of Alzheimer’s disease through identification of amyloid-β oligomers in patients’ cerebrospinal fluid, demonstrating potential for clinical application.
- Jusung An
- , Kyeonghwan Kim
- & Jong Seung Kim
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Identification of potential aggregation hotspots on Aβ42 fibrils blocked by the anti-amyloid chaperone-like BRICHOS domain
This study identifies potential aggregation hotspots on the fibril surface of Alzheimer’s disease associated Aβ42 fibrils, which are blocked by the anti-amyloid chaperone-like domain BRICHOS.
- Rakesh Kumar
- , Tanguy Le Marchand
- & Axel Abelein
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Article
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A one-two punch targeting reactive oxygen species and fibril for rescuing Alzheimer’s disease
Toxic amyloid-beta plaque and harmful inflammation are two leading hallmarks of Alzheimer’s disease (AD), and precise AD therapy is elusive due to the lack of dual-targeting therapy function, limited blood-brain barrier penetration, and low imaging sensitivity. Here, the authors address these issues by designing a near-infrared-II aggregation-induced emission nanotheranostic for precise AD therapy.
- Jiefei Wang
- , Ping Shangguan
- & Ben Zhong Tang
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Endothelial leakiness elicited by amyloid protein aggregation
This study reports endothelial leakiness in vitro, in silico and in vivo, where adherens junctions are disrupted by their exposure to the anionic oligomers and seeds of Alzheimer’s amyloid beta, preceding proinflammatory and pro-oxidative events.
- Yuhuan Li
- , Nengyi Ni
- & Pu Chun Ke
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Death Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer’s disease and aging
Events that cause neurons to die in Alzheimer’s disease (AD) are poorly understood. Here, the authors provide evidence for a role of RNA interference in AD. Short RNAs causing neurotoxicity and DNA damage are seen in AD and aged brains, and are counteracted by nontoxic RNAs.
- Bidur Paudel
- , Si-Yeon Jeong
- & Marcus E. Peter
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Upregulated pexophagy limits the capacity of selective autophagy
An accumulation of one substrate of selective autophagy can lead to autophagic degradation deficiencies. Here, the authors show that a pathogenic increase in a single autophagy pathway restricts another by consuming the cell’s autophagy capacity.
- Kyla Germain
- , Raphaella W. L. So
- & Peter K. Kim
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Gene-SGAN: discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering
Many diseases can display distinct brain imaging phenotypes across individuals, potentially reflecting disease subtypes. However, biological interpretability is limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Here, the authors describe a deep-learning method that links imaging phenotypes with genetic factors, thereby conferring genetic correlations to the disease subtypes.
- Zhijian Yang
- , Junhao Wen
- & Christos Davatzikos
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Article
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Elevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease
Trans-synaptic tau spread drives neurodegeneration in Alzheimer’s disease. This study shows that GAP-43, a marker of synaptic abnormality, is linked to faster tau spread, showing that synaptic changes may contribute to tau spreading in Alzheimer’s disease.
- Nicolai Franzmeier
- , Amir Dehsarvi
- & Michael Schöll
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Article
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ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells
LRP1 plays a key role in the clearance of Aβ peptides across the blood-brain barrier. Here, the authors report that ANKS1A promotes the LRP1-mediated Aβ clearance in brain endothelium, providing insights into the pathology of Alzheimer’s disease.
- Jiyeon Lee
- , Haeryung Lee
- & Soochul Park
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Synaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration
Translational neurodegeneration needs characterisation of the downstream consequences of synaptic loss. A multimodal imaging approach reveals that synaptic loss affects clinical severity via reduced connectivity in frontotemporal lobar degeneration.
- David J. Whiteside
- , Negin Holland
- & James B. Rowe
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Fatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer’s disease
A 79-year-old woman received three doses of lecanemab, an experimental drug for Alzheimer’s disease, and suffered a seizure and cerebral edema. Neuropathological evaluation showed severe cerebral amyloid angiopathy, arteritis and microhemorrhages.
- Elena Solopova
- , Wilber Romero-Fernandez
- & Matthew Schrag
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Resting-state global brain activity affects early β-amyloid accumulation in default mode network
Why β-amyloid plaque initially accumulates in the default mode network of the cortex before Alzheimer’s disease diagnosis is not known. Here, the authors show that this accumulation is associated with a reduction of global brain activity in these regions.
- Feng Han
- , Xufu Liu
- & Xiao Liu
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Article
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The α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases
A PET tracer for α-synuclein would help diagnosis and treatment of α-syn-related diseases. Here the authors show that ACI-12589 shows an uptake in the cerebellar white matter in patients with multiple-system atrophy.
- Ruben Smith
- , Francesca Capotosti
- & Oskar Hansson
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Article
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Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer’s disease
In this study, the authors found that sTREM2 attenuates tau hyperphosphorylation by activating transgelin-2. They developed an active peptide that mimics the protective effect of sTREM2, which may be an innovative therapeutic intervention for AD.
- Xingyu Zhang
- , Li Tang
- & Zhentao Zhang
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Histidine modulates amyloid-like assembly of peptide nanomaterials and confers enzyme-like activity
In this work, the authors report that Histidine residues play a critical role in modulating amyloid-like assembly and building active sites for Fmoc–F–F and Aβ aggregates. Aβ1-42 filaments were found to perform peroxidase-like activity to enhance oxidative stress, which might also be ascribed to the interaction mode of His and F-F.
- Ye Yuan
- , Lei Chen
- & Lizeng Gao
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Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease
Dopamine neurons control movements while pyramidal neurons regulate memory and language. Here the authors show that circular RNAs production in these neurons appears tailored to neuron identity and genetically linked to neuropsychiatric disease such as Parkinson’s and Alzheimer’s disease.
- Xianjun Dong
- , Yunfei Bai
- & Clemens R. Scherzer
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Bacteroides Fragilis in the gut microbiomes of Alzheimer’s disease activates microglia and triggers pathogenesis in neuronal C/EBPβ transgenic mice
Gut dysbiosis contributes to Alzheimer’s disease (AD) pathogenesis, and Bacteroides strains are commonly enriched in AD gut microbiota. Here, the authors show that Bacteroides fragilis and its metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) can mediate activation of microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice.
- Yiyuan Xia
- , Yifan Xiao
- & Keqiang Ye
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Article
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Expanded vacuum-stable gels for multiplexed high-resolution spatial histopathology
Emerging high-plex imaging technologies are limited in resolving subcellular biomolecular features. Here, the authors propose a spatial histopathology tool that allows for high-plex protein staining and physical expansion, while retaining the lateral tissue expansion.
- Yunhao Bai
- , Bokai Zhu
- & Sizun Jiang
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Article
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Leveraging 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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Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer’s disease
Resilience to Alzheimer’s disease (RAD) is an uncommon combination of high disease burden without dementia. The authors perform proteomic analysis of RAD brains and show lower isocortical and hippocampal soluble Aβ levels, actin filament-based processes, cellular detoxification, and wound healing are significant features.
- Zhi Huang
- , Gennifer E. Merrihew
- & Thomas J. Montine
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N-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer’s disease mouse model
Obesity and aging increase Alzheimer’s disease (AD) risk. Here, using an AD mouse model and high-fat diet, we suggest that immune exhaustion links the two risk factors, and identify a metabolite that can hasten immune dysfunction and memory deficit.
- Stefano Suzzi
- , Tommaso Croese
- & Michal Schwartz
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Article
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Gut microbiome dysbiosis drives metabolic dysfunction in Familial dysautonomia
Familial dysautonomia is a rare genetic disease caused in part by neurodegeneration. Here, the authors show that the gut-metabolism axis is altered in both patients and transgenic mice and that disease pathology is ameliorated by controlling microbiome divergence.
- Alexandra M. Cheney
- , Stephanann M. Costello
- & Seth T. Walk
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DNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types
Here the authors identify differences in cortical DNA methylation associated with Alzheimer’s disease pathology, and profiling nuclei from specific cell-types, find that most of these differences reflect variation occurring in non-neuronal cells.
- Gemma Shireby
- , Emma L. Dempster
- & Jonathan Mill
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Article
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Stress induced TDP-43 mobility loss independent of stress granules
Amyotrophic Lateral Sclerosis related TDP-43 protein translocates to stress granules with a concomitant reduction in mobility. Here, the authors use single molecule tracking and find a stress-induced reduction in TDP-43 mobility also in the cytoplasm potentially relevant for TDP-43 aggregation.
- Lisa Streit
- , Timo Kuhn
- & Karin M. Danzer
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Article
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Cross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease
DNA methylation differences in Alzheimer’s disease have been previously reported, although the interpretation of the differences is unclear. Here, the authors performed epigenome-wide meta-analyses of DNA methylation in blood and brain, and developed a methylation-based risk prediction model for AD.
- Tiago C. Silva
- , Juan I. Young
- & Lily Wang
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Article
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Primary cilia and SHH signaling impairments in human and mouse models of Parkinson’s disease
Here, the authors reveal using single-cell RNA sequencing that Parkinson’s disease (PD) patient-derived neuronal cells show altered primary cilia morphology and signaling suggesting cilia dysfunction may underlie PD pathogenesis.
- Sebastian Schmidt
- , Malte D. Luecken
- & Wolfgang Wurst
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Article
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Shared mechanisms across the major psychiatric and neurodegenerative diseases
Studying the shared genetic etiology of disease can help improve diagnosis and treatment. Here, the authors find evidence for shared genetic and molecular pathophysiology between several common psychiatric and neurodegenerative diseases using results of 25 GWAS and large-scale human brain transcriptomic and proteomic sequencing.
- Thomas S. Wingo
- , Yue Liu
- & Aliza P. Wingo
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NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility
ALS and FTLD are both characterized by insoluble cytoplasmic depositions of TDP43. Here the authors show that the nucleopore protein NUP62 is mislocalized in C9orf72 and sporadic ALS/FTLD and propose that it interacts with TDP-43 to promote its insolubility.
- Amanda M. Gleixner
- , Brandie Morris Verdone
- & Christopher J. Donnelly
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Article
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Pantothenate 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
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Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy
Wang et al show that microglial NF-κB activation is essential for tau spreading and tau-mediated spatial learning and memory deficits in tauopathy mice. Inactivation of NF-κB reversed tau associated microglial states and rescued autophagy deficits.
- Chao Wang
- , Li Fan
- & Li Gan
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Article
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Spelling interface using intracortical signals in a completely locked-in patient enabled via auditory neurofeedback training
The authors record neural firing rates in a patient with ALS in completely locked-in state and show that the patient can modulate neural firing rates based on auditory feedback to select letters to form words and phrases to communicate his needs and experiences.
- Ujwal Chaudhary
- , Ioannis Vlachos
- & Niels Birbaumer
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Article
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Nuclear export and translation of circular repeat-containing intronic RNA in C9ORF72-ALS/FTD
Hexanucleotide repeat expansion in the intron 1 of the C9ORF72 gene can cause amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). Here the authors use single molecule imaging to show nuclear export and translation of circular repeat-containing C9ORF72 intronic RNA.
- Shaopeng Wang
- , Malgorzata J. Latallo
- & Shuying Sun
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Article
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Endo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting
Aβ oligomers (AβO) are thought to represent the main toxic species in Alzheimer’s disease but very high Aβ concentrations are required to study them in vitro and it remains unknown what role these off-pathway oligomers play in vivo. Here, the authors use a dimeric variant of Aβ termed dimAβ, where two Aβ40 units are linked, which facilitates to study AβO formation kinetics and they observe that Aβ off-pathway oligomer formation is strongly accelerated at endo-lysosomal pH, while amyloid fibril formation is delayed. Furthermore, the authors demonstrate that dimAβ is a disease-relevant model construct for pathogenic AβO formation by showing that dimAβ AβOs target dendritic spines and induce AD-like somatodendritic Tau missorting.
- Marie P. Schützmann
- , Filip Hasecke
- & Wolfgang Hoyer
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Article
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Identifying individuals with high risk of Alzheimer’s disease using polygenic risk scores
While polygenic risk scores have been shown to be correlated with disease risk, there is little agreement on how the score should be calculated. Here the authors investigate risk scores for Alzheimer’s disease, finding that the most effective approach includes an APOE score and a polygenic score excluding APOE.
- Ganna Leonenko
- , Emily Baker
- & Valentina Escott-Price
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Article
| Open Access
SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome
Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome characterized by severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here the authors introduce a human SGS model that displays disease-relevant phenotypes to demonstrate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.
- Federica Banfi
- , Alicia Rubio
- & Alessandro Sessa
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Article
| Open Access
KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease
The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.
- Julia Neitzel
- , Nicolai Franzmeier
- & Michael Ewers
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Article
| Open Access
A 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 Access
UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation
Hyperphosphorylated Tau accumulation promotes neurodegeneration in Alzheimer’s disease. Here, the authors screen a miRNA library in Drosophila and identify a conserved ubiquitin ligase that directs Tau for autophagic degradation, uncovering a potential target to treat Tau-mediated neurodegeneration.
- Manivannan Subramanian
- , Seung Jae Hyeon
- & Kweon Yu
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Article
| Open Access
Cryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) patients have brain deposits with amyloid-like aggregates from large C-terminal fragments of the transactive response DNA-binding protein of 43 kDa (TDP-43). Here, the authors present the cryo-EM structure of amyloid fibrils generated from the complete C-terminal TDP-43 low complexity domain and they discuss the effects of disease-causing mutations and phosphorylation of specific Ser residues.
- Qiuye Li
- , W. Michael Babinchak
- & Witold K. Surewicz
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Article
| Open Access
Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats
Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disease caused by toxic RNA containing expanded CGG repeats. Here, the authors show that synthetic oligonucleotides targeting the RNA repeats decrease the pleiotropic effect of this toxic molecule in cellular and animal models of the disease.
- Magdalena Derbis
- , Emre Kul
- & Krzysztof Sobczak
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Article
| Open Access
Machine learning identifies candidates for drug repurposing in Alzheimer’s disease
Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have provided largely negative results, so far. Here, the authors present a machine learning framework that quantifies potential associations between the pathology of AD severity and gene-based molecular mechanisms to enable drug repurposing.
- Steve Rodriguez
- , Clemens Hug
- & Artem Sokolov
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Article
| Open Access
The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition
α-Synuclein is a presynaptic protein whose aberrant aggregation is associated with Parkinson’s disease. Here, the authors show how αSynuclein-induced docking of synaptic vesicles is modulated by the lipid composition changes typically observed in neurodegeneration using an in vitro system.
- Wing K. Man
- , Bogachan Tahirbegi
- & Giuliana Fusco
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Perspective
| Open Access
Increasing the reproducibility of fluid biomarker studies in neurodegenerative studies
Many fluid biomarker findings have had low reproducibility despite initially promising results. Here, the authors review possible sources for low reproducibility of studies on fluid biomarkers for neurodegenerative diseases and suggest guidelines for the biomarker community to agree on and implement.
- Niklas Mattsson-Carlgren
- , Sebastian Palmqvist
- & Oskar Hansson
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Article
| Open Access
RNA-binding proteins Musashi and tau soluble aggregates initiate nuclear dysfunction
The Musashi family of RNA binding proteins are found in an oligomeric state in the brains of patients with Alzheimer’s disease. Here the authors show that Mushashi1 and Musashi2 interact with tau protein in patient tissue and in models of tauopathy.
- Mauro Montalbano
- , Salome McAllen
- & Rakez Kayed
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Article
| Open Access
Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity
In Parkinson’s disease (PD) the monomeric protein alpha-synuclein (aSyn) misfolds and aggregates into insoluble fibrils. Here the authors use NMR measurements and hydrogen–deuterium exchange mass spectrometry and find that the more solvent exposed the N-terminus of aSyn is, the more aggregation prone its conformation becomes, and further show how PD mutations and post translational modifications influence the extent of the N-terminus solvent exposure.
- Amberley D. Stephens
- , Maria Zacharopoulou
- & Gabriele S. Kaminski Schierle
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Article
| Open Access
Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease
Calvo-Rodriguez et al. show elevated calcium levels in neuronal mitochondria in a mouse model of cerebral β-amyloidosis after plaque deposition, which precede rare neuron death events in this model. The mechanism involves toxic extracellular Aβ oligomers and the mitochondrial calcium uniporter.
- Maria Calvo-Rodriguez
- , Steven S. Hou
- & Brian J. Bacskai
Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2