Featured
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Article
| Open AccessTDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression
Amyotrophic Lateral Sclerosis is characterized by TDP-43 proteinopathy in the brain. Here, the authors find TDP-43 aggregation might be mediated by the loss of Asparaginase-like 1, an enzyme that degrades detrimental isoaspartates and is downregulated by the endogenous retrovirus HML-2.
- Marta Garcia-Montojo
- , Saeed Fathi
- & Avindra Nath
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Article
| Open AccessCell-mediated cytotoxicity within CSF and brain parenchyma in spinal muscular atrophy unaltered by nusinersen treatment
Cell-mediated cytotoxicity observed in untreated SMA patients’ CSF and brain parenchyma. Spatial transcriptomic and multiplex immunohistochemistry linked cytotoxicity near affected motoneurons. Nusinersen treatment showed no impact on this profile.
- I-Na Lu
- , Phyllis Fung-Yi Cheung
- & Gerd Meyer zu Horste
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Article
| Open AccessShared EEG correlates between non-REM parasomnia experiences and dreams
Sleepwalking and related parasomnias are associated with partial awakenings out of non-rapid eye movement sleep. Here the authors show that when sleepwalkers have dream-like experiences during their episodes, they display brain activity patterns that resemble those previously described for dreams.
- Jacinthe Cataldi
- , Aurélie M. Stephan
- & Francesca Siclari
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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 AccessSleep fragmentation exacerbates myocardial ischemia‒reperfusion injury by promoting copper overload in cardiomyocytes
Sleep disorders increase the risk and mortality of heart disease. Here, the authors show that sleep fragmentation results in elevated copper levels in the male mouse heart and exacerbates myocardial ischemia–reperfusion injury with increased myocardial cuproptosis and apoptosis.
- Na Chen
- , Lizhe Guo
- & E. Wang
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Article
| Open AccessMetabolic phenotyping reveals an emerging role of ammonia abnormality in Alzheimer’s disease
Metabolic implications in AD are unclear. Here, authors found significant correlations between cognitive impairment and metabolic features in a Chinese aging cohort (n = 1397). The study highlights ammonia disturbance as a potential therapeutic target for AD.
- Tianlu Chen
- , Fengfeng Pan
- & Wei Jia
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Article
| Open AccessCerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases
CSF biomarker concentrations may be influenced by non-disease related interindividual variability. Here, the authors show that reference proteins can capture this variability and enhance the accuracy of Alzheimer’s disease biomarkers.
- Linda Karlsson
- , Jacob Vogel
- & Oskar Hansson
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Article
| Open AccessProtein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson’s phenotypes
The aggregation of the neuronal protein α-Synuclein is associated with the onset of Parkinson’s disease. Here the authors report a two-dimensional Fragment Assisted Structure-based technique to find antagonists of α-Synuclein aggregation and show its promise for identifying lead therapeutics for Parkinson’s disease.
- Nicholas H. Stillman
- , Johnson A. Joseph
- & Sunil Kumar
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Article
| Open AccessMitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease
Idiopathic Parkinson’s disease can be stratified according to the severity of neuronal respiratory complex I deficiency. The emerging disease subtypes show distinct molecular and clinical profiles.
- Irene H. Flønes
- , Lilah Toker
- & Charalampos Tzoulis
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Article
| Open AccessDiphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects
Rare disease DEDSSH1-associated DPH1 mutations impair eEF2 diphthamide modification that leads to eEF2 as a transcriptional coactivator for p53 to enhance expression of the cell proliferation inhibitor p21, resulting in birth defects.
- Yu Shi
- , Daochao Huang
- & Weihong Song
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Article
| Open AccessStructural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A
SV2A is a receptor for botulinum neurotoxin (BoNT) and new generation antiepileptic drugs (AEDs). Here the authors report cryo-EM structures of SV2A in complex with BoNT receptor binding domain and AEDs highlighting the difference in the binding affinity between AEDs.
- Atsushi Yamagata
- , Kaori Ito
- & Mikako Shirouzu
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Article
| Open AccessMechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2
The biogenesis of iron-sulfur proteins in eukaryotes is initiated by the mitochondrial core ISC complex. Here, the authors provide structural, biochemical and spectroscopic data to characterize sulfur transfer intermediates in the core ISC complex.
- Vinzent Schulz
- , Ralf Steinhilper
- & Roland Lill
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Article
| Open AccessSubthalamic stimulation modulates context-dependent effects of beta bursts during fine motor control
How movement speed is neurally modulated remains poorly understood. Here, the authors recorded invasive brain signals in Parkinson’s disease patients during drawing and deep brain stimulation, showing a context-dependent relationship between reductions of movement acceleration and dynamic activity of the basal ganglia.
- Manuel Bange
- , Gabriel Gonzalez-Escamilla
- & Sergiu Groppa
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Article
| Open AccessSplice modulators target PMS1 to reduce somatic expansion of the Huntington’s disease-associated CAG repeat
Somatic expansion of a CAG repeat in HTT drives onset of Huntington’s disease. Using a human cell line model and splice modulators, here the authors show that PMS1 is an enhancer of CAG repeat expansion, making it a target for therapeutic intervention.
- Zachariah L. McLean
- , Dadi Gao
- & James F. Gusella
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Article
| Open AccessMultisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges
Repetitive audio-visual stimulation, or sensory flicker, can modulate oscillations in a non-invasive manner. Here the authors demonstrate the potential of flicker in individuals with epilepsy undergoing intracranial seizure monitoring.
- Lou T. Blanpain
- , Eric R. Cole
- & Annabelle C. Singer
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Article
| Open AccessPlasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer’s disease
The authors investigated associations of brain-derived-tau (BD-tau) with Aβ pathology, changes in cognition and MRI signatures. Staging Aβ-pathology according to neurodegeneration, using BD-tau, identifies individuals at risk of near-term cognitive decline and atrophy.
- Fernando Gonzalez-Ortiz
- , Bjørn-Eivind Kirsebom
- & Kaj Blennow
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Article
| Open AccessIntrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial
In the CELLTOP Phase I trial, stem cells were harvested from patients with spinal cord injury and injected into their central nervous system after processing. The procedure was safe, with no reported serious adverse events during the 2-year follow-up period.
- Mohamad Bydon
- , Wenchun Qu
- & Allan B. Dietz
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Article
| Open AccessDiverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases
Controlling copper levels is essential for life, causing disease when impaired. Here, structures of a copper transporter sheds light on the function of its metal binding domains and unifies previous theories on the details of copper transport.
- Zongxin Guo
- , Fredrik Orädd
- & Pontus Gourdon
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Article
| Open AccessPhosphorylation 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
| Open AccessThe effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease
A network of brain regions degenerates earlier in aging. Here the authors show that, this network is most vulnerable to diabetes, traffic-related pollution and alcohol consumption in terms of risk factors for dementia, and associated with the XG blood group genes.
- Jordi Manuello
- , Joosung Min
- & Gwenaëlle Douaud
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Article
| Open AccessUsing rare genetic mutations to revisit structural brain asymmetry
Asymmetry is a key organising principle of the brain. Here the authors leveraged rare genetic mutations to revisit structural brain asymmetry showing the planum temporale is susceptible to deletions & duplications of specific gene sets.
- Jakub Kopal
- , Kuldeep Kumar
- & Danilo Bzdok
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Article
| Open AccessParechovirus infection in human brain organoids: host innate inflammatory response and not neuro-infectivity correlates to neurologic disease
In comparison to PeV-A1, infection with PeV-A3 is associated with neurological illness in infants. Here, using brain organoids, the authors suggest that the innate inflammatory response as the underlying reason, and not replication kinetics.
- Pamela E. Capendale
- , Inés García-Rodríguez
- & Katja C. Wolthers
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Article
| Open AccessA 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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Article
| Open AccessBiallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
Most individuals with primary familial brain calcification (PFBC) remain genetically unsolved. Here the authors show that NAA60 biallelic variants cause PFBC, likely via reduced N-terminal acetylation and SLC20A2 levels with impaired phosphate uptake.
- Viorica Chelban
- , Henriette Aksnes
- & Henry Houlden
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Article
| Open AccessIdentification of four biotypes in temporal lobe epilepsy via machine learning on brain images
Brain imaging-based disease progression modelling is a promising technique for disease stratification. Here the authors characterize distinct ‘trajectories’ of brain atrophy in temporal lobe epilepsy and identify four subtypes with distinct neuroanatomical signatures.
- Yuchao Jiang
- , Wei Li
- & Dongmei An
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Article
| Open AccessInhibition of urease-mediated ammonia production by 2-octynohydroxamic acid in hepatic encephalopathy
Hepatic encephalopathy is a severe complication of liver disease with a growing prevalence. Here, the authors present a hydroxamate-based urease inhibitor to target the production of intestinal ammonia, one of the contributors to the pathogenesis of hepatic encephalopathy.
- Diana Evstafeva
- , Filip Ilievski
- & Jean-Christophe Leroux
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Article
| Open AccessA single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease
Vascular pathology may play important early role in Alzheimer’s disease (AD). Here, the authors show that β-amyloid induces transcriptomic signatures associated with accelerated apoptosis, impaired function and AD risk in human brain microvasculature.
- Stergios Tsartsalis
- , Hannah Sleven
- & Paul M. Matthews
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Article
| Open AccessNumerosity estimation of virtual humans as a digital-robotic marker for hallucinations in Parkinson’s disease
Virtual reality, robotics and digital online technologies reveal heightened visual overestimation when estimating the number of humans, indexing presence hallucinations in healthy participants and patients with Parkinson’s disease.
- Louis Albert
- , Jevita Potheegadoo
- & Olaf Blanke
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Article
| Open AccessIdentification of the growth cone as a probe and driver of neuronal migration in the injured brain
Structure and functions of the tip of migratory neurons remain elusive. Here, the authors show that the PTPσ-expressing growth cone senses extracellular matrix changes and drives neuronal migration in the injured brain, leading to the functional recovery.
- Chikako Nakajima
- , Masato Sawada
- & Kazunobu Sawamoto
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Article
| Open AccessKdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons
Kdm1a is a histone demethylase implicated in intellectual disability. Here, the authors show that removing Kdm1a in neurons of the adult mouse forebrain disrupts silencing of nonneuronal genes and chromatin organization, emphasizing its role in preserving neuronal genome integrity.
- Beatriz del Blanco
- , Sergio Niñerola
- & Ángel Barco
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Review Article
| Open AccessDiagnosis and management of subarachnoid haemorrhage
Aneurysmal subarachnoid haemorrhage, with its multisystem effects, presents a substantial challenge to clinicians. Here, the authors show the necessity for comprehensive multidisciplinary care and the urgent need for largescale studies to validate standardised treatment protocols for improved outcomes.
- Suneesh Thilak
- , Poppy Brown
- & Tonny Veenith
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Article
| Open AccessApplying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis
People who experience optic neuritis, a cause of potentially serious sudden vision loss, have up to a 50% chance of ultimately being diagnosed with multiple sclerosis. Here, the authors find that genetic information combined with age and sex helps predict risk of future diagnosis of multiple sclerosis.
- Pavel Loginovic
- , Feiyi Wang
- & Tasanee Braithwaite
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Article
| Open AccessMulti-night cortico-basal recordings reveal mechanisms of NREM slow-wave suppression and spontaneous awakenings in Parkinson’s disease
Using at-home intracranial DBS recordings in PD participants, the authors found subcortical beta has an inverse effect on cortical slow-wave in NREM sleep, rises before awakenings and found >88% accuracy in NREM vs Wake classification in brief 5 s epochs.
- Md Fahim Anjum
- , Clay Smyth
- & Simon Little
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Article
| Open AccessBicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury
The acid–base balance regulates cellular responses, but little has been known about its molecular mechanism. Here, the authors unveil a bicarbonate-sensing GPCR, GPR30, that underlies cerebral ischemia–reperfusion injury by regulating blood flow recovery.
- Airi Jo-Watanabe
- , Toshiki Inaba
- & Takehiko Yokomizo
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Article
| Open AccessSNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation
SNURPORTIN-1, encoded by the SNUPN gene, plays a key role in the nuclear import of spliceosomal small nuclear ribonucleoproteins, however its physiological function remains unclear. Here the authors report that recessive SNUPN mutations cause a distinct subtype of childhood muscular dystrophy and reveal SNURPORTIN-1’s role in muscle homeostasis, offering insights for new therapeutic strategies.
- Marwan Nashabat
- , Nasrinsadat Nabavizadeh
- & Nathalie Escande-Beillard
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Article
| Open AccessNAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice
Circulating monocytes contribute to the transition to pain chronicity but the molecular events that cause their deployment are still unclear. Using a mouse model of hyperalgesic priming, here the authors show that blood monocytes contribute to the emergence of chronic pain via a mechanism that requires a transient disruption of NAAA-regulated lipid signaling.
- Yannick Fotio
- , Alex Mabou Tagne
- & Daniele Piomelli
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Article
| Open AccessNoncanonical function of folate through folate receptor 1 during neural tube formation
Neural tube defects are common birth defects that have been shown to be reduced through periconceptional folate supplementation, though the mechanism for this effect is unclear. Here they show that FOLR1 is necessary for neural tube formation in human neural organoids and Xenopus laevis embryos, and that this role is independent of its folate transport function.
- Olga A. Balashova
- , Alexios A. Panoutsopoulos
- & Laura N. Borodinsky
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Article
| Open AccessDeep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome
Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined and the pathophysiology unknown. Here, the authors conduct deep phenotyping of a cohort of PI-ME/CFS patients.
- Brian Walitt
- , Komudi Singh
- & Avindra Nath
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Article
| Open AccessFunctional plasticity of glutamatergic neurons of medullary reticular nuclei after spinal cord injury in mice
Spinal cord injury disrupts the descending command from the brain necessary for locomotion. Here, the authors show the functional plasticity of glutamatergic reticulospinal neurons and how their recruitment can enhance spontaneous motor recovery.
- Maxime Lemieux
- , Narges Karimi
- & Frederic Bretzner
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Article
| Open AccessA mutational atlas for Parkin proteostasis
Gene variants can affect folding and stability of the encoded protein. Here, the authors apply deep mutational scanning to provide genotype-phenotype information for 99% of the possible PRKN variants and reveal mechanistic details on how some variants cause loss-of-function and Parkinsons disease.
- Lene Clausen
- , Vasileios Voutsinos
- & Rasmus Hartmann-Petersen
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Article
| Open AccessRegulation of stress granule formation in human oligodendrocytes
Oligodendrocyte (OL) injury and loss is a pathologic hallmark of multiple sclerosis. Here, the authors show the presence of stress granules in OLs in multiple sclerosis lesions, and their in vitro studies in human OLs indicate that stress granules formation is a response to a combination of metabolic stress and pro-inflammatory conditions.
- Florian Pernin
- , Qiao-Ling Cui
- & Jack P. Antel
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Article
| Open AccessA SPLICS reporter reveals \({{{{{\boldsymbol{\alpha }}}}}}\)-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation
Mitochondria-lysosome interactions are fundamental to cellular physiology. Here, the authors describe a genetically-encoded SPLICS reporter to study short- and long-juxtapositions between mitochondria and lysosomes.
- Flavia Giamogante
- , Lucia Barazzuol
- & Marisa Brini
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Article
| Open AccessThe structure of tyrosine-10 favors ionic conductance of Alzheimer’s disease-associated full-length amyloid-β channels
The structural basis of membrane permeabilization by Alzheimer’s disease-related amyloid β (Aβ) peptides is elucidated. Membrane insertion of tyrosine-10 supports the most effective ionic conductance of the full-length Aβ1-42 compared to other isoforms.
- Abhijith G. Karkisaval
- , Rowan Hassan
- & Suren A. Tatulian
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Article
| Open AccessCompromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment
THOC2 is an essential subunit of Transcription mRNA Export complex of eukaryotic cells and its compromise causes adverse (neuro)development. Using mouse model and patient cells the authors unravel molecular pathology of the syndrome, from R-loops dysregulation, to altered transcriptome and DNA damage triggered cell death.
- Rudrarup Bhattacharjee
- , Lachlan A. Jolly
- & Jozef Gecz
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Article
| Open AccessEfficacy and safety of using auditory-motor entrainment to improve walking after stroke: a multi-site randomized controlled trial of InTandemTM
Post-stroke walking impairment is a significant public health concern. Here, the authors perform an interventional, randomized controlled trial evaluating the efficacy and safety of InTandem™, an autonomous neurorehabilitation system utilizing auditory-motor entrainment to improve walking after stroke.
- Louis N. Awad
- , Arun Jayaraman
- & Sabrina R. Taylor
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Article
| Open AccessLocal 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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Article
| Open AccessEarly 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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Article
| Open AccessIdentification 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
| Open AccessA 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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