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| Open AccessDistinct and shared functions of ALS-associated proteins TDP-43, FUS and TAF15 revealed by multisystem analyses
Abnormal functions of RNA-binding proteins TAF15, FUS and TDP43 are associated with amyotrophic lateral sclerosis. Here, Kapeli et al. characterize the RNA targets of TAF15 and identify points of convergence and divergence between the targets of TAF15, FUS and TDP43 in several neuronal systems.
- Katannya Kapeli
- , Gabriel A. Pratt
- & Gene W. Yeo
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Article
| Open AccessThe neuritic plaque facilitates pathological conversion of tau in an Alzheimer’s disease mouse model
Alzheimer’s disease (AD) is pathologically characterized by the accumulation of neuritic plaques and neurofibrillary tangles but it is not known whether the neuritic plaque is necessary to drive the conversion of wild-type tau. Here the authors developed a mouse model in which wild-type tau is converted into pathological tau in a neuritic plaque-dependent manner.
- Tong Li
- , Kerstin E. Braunstein
- & Philip C. Wong
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Article
| Open AccessProsaposin is a regulator of progranulin levels and oligomerization
Increasing progranulin (PGRN) levels is a promising approach for treating frontotemporal dementia and other neurodegenerative diseases. Here Nicholson et al.show that the prosaposin (PSAP) locus is associated with plasma PGRN levels and demonstrate that PSAP can alter PGRN levels and its oligomerization.
- Alexandra M. Nicholson
- , NiCole A. Finch
- & Rosa Rademakers
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Article
| Open AccessMicroglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury
Microglia and monocytes contribute to neuropathic pain states, but the precise role of the two cell types is not clear. Here Peng et al.use temporally controlled ablation of monocytes and microglia in mice to show that these cells work together to initiate neuropathic-pain like behaviour, but are less important in the maintenance phase.
- Jiyun Peng
- , Nan Gu
- & Long-Jun Wu
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Article
| Open AccessEarly role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis
Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.
- Y. Iturria-Medina
- , R. C. Sotero
- & Ansgar J. Furst
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Article
| Open AccessEarly synaptic deficits in the APP/PS1 mouse model of Alzheimer’s disease involve neuronal adenosine A2A receptors
Hippocampal synaptic dysfunctions are an early symptom of Alzheimer’s disease. Here, the authors find adenosine A2A receptors are up-regulated in APP/PS1 model mice and that deleting or blocking receptor activity helps alleviate plasticity and memory impairments.
- Silvia Viana da Silva
- , Matthias Georg Haberl
- & Christophe Mulle
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Article
| Open AccessThe Parkinson’s disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway
Mutations in ATP13A2 are associated with lysosomal dysfunction and early onset Parkinson’s disease. Here Bento et al. show that ATP13A2 depletion negatively regulates SYT11, at both transcriptional and post-translational levels, which in turn impairs function of the autophagy-lysosome pathway.
- Carla F. Bento
- , Avraham Ashkenazi
- & David C. Rubinsztein
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Article
| Open AccessUbiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1
Mutations in LRRK2 are linked to Parkinson’s Disease. Here, the authors identify WSB1 as a LRRK2 interacting protein and find that it promotes LRRK2 aggregation in primary neurons and drosophila models via ubiquitin K27 and K29 linkages.
- Frederick C. Nucifora Jr
- , Leslie G. Nucifora
- & Christopher A. Ross
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Article
| Open AccessConvulsive seizures from experimental focal cortical dysplasia occur independently of cell misplacement
The etiology of focal cortical dysplasia (FCD) is not fully understood. Here authors generate an mTORC1 overactivation mouse model that recapitulates hallmarks of type II FCDs, including spontaneous seizures, and suggest that neuronal defects, rather than macrostructural changes, lead to seizures.
- Lawrence S. Hsieh
- , John H. Wen
- & Angelique Bordey
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Article
| Open AccessDesign of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10
Expanded RNA repeats in non-coding region of a gene represent a hallmark of several diseases. Here, the authors identify two small molecules that selectively bind AU repeats and use them to design a compound that targets the pathogenic RNA associated with spinocerebellar ataxia type 10.
- Wang-Yong Yang
- , Rui Gao
- & Matthew D. Disney
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Article
| Open AccessEarly detection of cryptic memory and glucose uptake deficits in pre-pathological APP mice
Identifying early signs of Alzheimer’s disease is important when it comes to diagnosis and treatment. Here, the authors identify subtle memory retrieval deficits and associated brain glucose uptake impairments in very young mouse models of Alzheimer’s, prior to plaque development.
- V. Beglopoulos
- , J. Tulloch
- & R. G. M. Morris
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Article
| Open AccessMutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia
Karin Tuschl, Philippa Mills and colleagues report mutations in the manganese (Mn) transporter gene SLC39A14in childhood-onset parkinsonism-dystonia. Using functional recapitulation, the authors also show that slc39A14 loss-of-function in zebrafish can lead to Mn dysregulation and locomotor impairment.
- Karin Tuschl
- , Esther Meyer
- & Stephen W. Wilson
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Article
| Open AccessATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation
Here, Dirk Lefeber and colleagues identify functional mutations in ATP6AP1 encoding Ac45. The authors show that Ac45 is the functional ortholog of yeast V-ATPase assembly factor Voa1 and provide evidence for tissue-specific Ac45 processing, associated with the clinical phenotype of immunodeficiency, hepatopathy, and neurocognitive abnormalities.
- Eric J. R. Jansen
- , Sharita Timal
- & Dirk J. Lefeber
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Article
| Open AccessKCNQ channel openers reverse depressive symptoms via an active resilience mechanism
Potassium channels in the ventral tegmental area are known to regulate resilience against stress-induced depression. Here, the authors show over expression of KCNQ3 channels in VTA dopaminergic neurons or treatment with KCNQ channel openers normalizes depressive behaviours in mouse models.
- Allyson K. Friedman
- , Barbara Juarez
- & Ming-Hu Han
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Article
| Open AccessGut environment-induced intraepithelial autoreactive CD4+ T cells suppress central nervous system autoimmunity via LAG-3
Experimental autoimmune encephalomyelitis (EAE) involves inflammatory cell infiltration into the central nervous system (CNS) and models the human disease multiple sclerosis. Here the authors show that transferred CD4+ gut intraepithelial lymphocytes can migrate into the CNS and inhibit inflammation in recipient mice with EAE.
- Atsushi Kadowaki
- , Sachiko Miyake
- & Takashi Yamamura
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Article
| Open AccessAltered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism
SHANK3 mutations have been linked to autism spectrum disorders, although the underlying mechanisms remain unclear. Here, the authors generate a complete knockout Shank3 mouse model, identifying ASD-like behaviours associated with impaired mGluR5-Homer scaffolding and abnormal brain connectivity.
- Xiaoming Wang
- , Alexandra L. Bey
- & Yong-hui Jiang
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Article
| Open AccessDeregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer’s disease
F1FO ATP synthase is a critical enzyme for the maintenance of mitochondrial function. Here the authors demonstrate that loss of the F1FO-ATP synthase subunit OSCP and the interaction of OSCP with Aβ peptide in Alzheimer’s disease patients and mouse models lead to F1FO-ATP synthase deregulation and disruption of synaptic mitochondrial function.
- Simon J. Beck
- , Lan Guo
- & Heng Du
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Article
| Open AccessMicroglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke
How microglia contribute to brain injury or repair is unclear. Here combining microglia manipulations and calcium imaging, the authors show that selective elimination of microglia leads to disrupted neuronal calcium dynamics and markedly increased brain injury after cerebral ischemia.
- Gergely Szalay
- , Bernadett Martinecz
- & Ádám Dénes
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Article
| Open AccessUntangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses
Whole tissue RNA profiling can help identify altered molecular pathways underlying neurodegenerative disease, but often masks cell type-specific transcriptional changes. Here, the authors compare transcriptomes of neurons, astrocytes, and microglia from Alzheimer's disease model brains and identify hundreds of cell-type specific changes.
- Karpagam Srinivasan
- , Brad A. Friedman
- & David V. Hansen
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Article
| Open AccessA two decade dementia incidence comparison from the Cognitive Function and Ageing Studies I and II
Future dramatic rises in dementia are widely reported, assuming no change in incidence. Matthews and colleagues report that, in contrast to such statements, age-specific incidence has dropped over 20 years, with overall incidence of dementia remaining stable in a large multi-site population study from England.
- F. E. Matthews
- , B. C. M. Stephan
- & G. Forster
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Article
| Open AccessPhosphorylation modifies the molecular stability of β-amyloid deposits
Protein aggregation plays a crucial role in several neurodegenerative diseases. Here the authors demonstrate that phosphorylation of β-amyloid aggregates—the pathological hallmark of Alzheimer's disease—can change the molecular properties of aggregates, suggesting how phosphorylation contributes to disease progression.
- Nasrollah Rezaei-Ghaleh
- , Mehriar Amininasab
- & Markus Zweckstetter
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Article
| Open AccessReal-time imaging of glutamate clearance reveals normal striatal uptake in Huntington disease mouse models
Huntington disease (HD) has been linked via biochemical uptake assays to impaired glutamate clearance and resultant excitotoxicity. Here, utilizing a fluorescent reporter, the authors measure real-time glutamate dynamics in mouse model HD brain slices and find normal or even accelerated glutamate clearance.
- Matthew P. Parsons
- , Matthieu P. Vanni
- & Lynn A. Raymond
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Article
| Open AccessSpatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma
Diffuse Intrinsic Pontine Gliomas are diagnosed by sampling a small portion of the tumour. Here, using multiple samples from tumours, the authors analyse the spatial and temporal distribution of driver mutations revealing that H3K27M mutations arise first in tumorigenesis followed by a specific invariable sequence of driver mutations, which are homogeneously distributed across the tumour mass.
- Hamid Nikbakht
- , Eshini Panditharatna
- & Javad Nazarian
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Article
| Open AccessCD8+ T-cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing
Rasmussen Encephalitis is a rare neurological disease accompanied by inflammation and T cell infiltration in the brain. Here the authors show that the severity of this disease correlates with clonal CD8 T cell expansion.
- Tilman Schneider-Hohendorf
- , Hema Mohan
- & Nicholas Schwab
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Article
| Open AccessIdentification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration
This study presents gene expression responses of cultured brain cells to hundreds of chemicals found in the environment and in food. The authors identified chemicals that induce transcriptomic profiles that overlap those seen in human brains affected with autism, aging, and neurodegeneration.
- Brandon L. Pearson
- , Jeremy M. Simon
- & Mark J. Zylka
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Article
| Open AccessThe ictal wavefront is the spatiotemporal source of discharges during spontaneous human seizures
Epileptic brains display inhibitory restraint as manifested by the spread of synchronized activities being delayed in timing. Here, Elliot Smith and colleagues show fast-moving traveling wave that originates from the edge of ictal wavefront with subsequent depolarization and multiunit firing in the seizing brain regions in epileptic patients.
- Elliot H. Smith
- , Jyun-you Liou
- & Catherine A. Schevon
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Article
| Open AccessBidirectional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression
BRAG1 mutations are linked to synaptic deficits and X-chromosome linked intellectual disability. Here, the authors show that BRAG1 mediates activity-dependent removal of synaptic AMPA receptors via Arf-GEF activity and PDZ interactions, and is required for maintaining AMPAR-mediated synaptic transmission.
- Joshua C. Brown
- , Amber Petersen
- & Nashaat Z. Gerges
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Article
| Open AccessOptogenetic dissection of ictal propagation in the hippocampal–entorhinal cortex structures
The network mechanism supporting seizure spread in temporal lobe epilepsy (TLE) is only partially understood. Using optogenetic methods, Lu et al.identify a feed-forward propagation pathway of ictal discharges from the dentate gyrus/hilus to the medial entorhinal cortex in a mouse model of TLE.
- Yi Lu
- , Cheng Zhong
- & Liping Wang
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Article
| Open AccessPX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking
The molecular underpinning of autism is unclear. Here the authors show PX-RICS deficient mice exhibit autism-like social behavioural abnormalities and impaired GABAA receptor trafficking, and enhancing inhibitory synaptic transmission with a GABAAreceptor agonist ameliorate the behavioural deficits.
- Tsutomu Nakamura
- , Fumiko Arima-Yoshida
- & Tetsu Akiyama
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Article
| Open AccessThe TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model
Dysregulation of microRNAs has been implicated in neurodevelopmental disorders, including schizophrenia. Here the authors show that the TLX-miR-219 cascade regulates the proliferation of neural stem cells during normal development, and this pathway is dysregulated in a schizophrenia iPSC model.
- Kiyohito Murai
- , Guoqiang Sun
- & Yanhong Shi
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Article
| Open AccessGenome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank
Here, Richa Saxena and colleagues perform a genome-wide association study (GWAS) of self-reported morningness/eveningness preference in the UKBiobank cohort, and identify new genetic loci that contribute to a person's chronotype.
- Jacqueline M. Lane
- , Irma Vlasac
- & Richa Saxena
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Article
| Open AccessIncreased amyloidogenic APP processing in APOE ɛ4-negative individuals with cerebral β-amyloidosis
Autosomal dominant Alzheimer's disease is thought to be caused by increased amyloidogenic APP processing. Mattson et al.show that association between brain Aβ and cerobrospinal fluid Aβ40 levels is stronger in APOE ɛ4 negative people, suggesting that increased processing may also underlie sporadic disease.
- Niklas Mattsson
- , Philip S. Insel
- & Oskar Hansson
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Article
| Open AccessAntibody-based PET imaging of amyloid beta in mouse models of Alzheimer’s disease
Imaging tools for evaluating progression of Alzheimer’s disease have been lacking. Here the authors develop a blood brain barrier-permeable Aß probe based on a radiolabelled, anti-Aß antibody, and report age-dependent brain uptake visualized in vivo with PET in mouse models of the disease.
- Dag Sehlin
- , Xiaotian T. Fang
- & Stina Syvänen
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Article
| Open AccessGene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders
Autism spectrum disorder is approximately 4.5 times more likely to occur in boys than girls. Here, Werling, Geschwind and Parikshak characterized sexually dimorphic gene expression in the non-diseased, post-mortem, adult and prenatal human brain, and show genes expressed at higher levels in males are significantly enriched for genes upregulated in autistic brain.
- Donna M. Werling
- , Neelroop N. Parikshak
- & Daniel H. Geschwind
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Article
| Open AccessMeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome
Post-translational modifications of methyl-CpG-binding protein 2 (MeCP2) are important for its function and dysfunction in Rett syndrome. Here, Tai et al. show a functional interaction between MeCP2 SUMOylation and phosphorylation in rodent behavior and synaptic plasticity.
- Derek J. C. Tai
- , Yen C. Liu
- & Eminy H. Y. Lee
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Article
| Open AccessGenetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum
This genome-wide association study identifies five significant SNPs in two loci which are associated with the epigenetic age of post-mortem cerebellar tissue according to a DNA methylation based biomarker of human aging.
- Ake T. Lu
- , Eilis Hannon
- & Steve Horvath
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Article
| Open AccessRapid endothelial cytoskeletal reorganization enables early blood–brain barrier disruption and long-term ischaemic reperfusion brain injury
Matrix metalloproteinases (MMPs) released from infiltrating immune cells are a major contributor to blood-brain barrier (BBB) breakdown following stroke. Here, the authors identify an early, MMP-independent BBB breakdown mechanism caused by rapid cytoskeletal rearrangements in endothelial cells, which could be inhibited by ADF.
- Yejie Shi
- , Lili Zhang
- & Jun Chen
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Article
| Open AccessIntracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites
α-synuclein is a protein linked to the occurrence of Parkinson's disease. Here, the authors use time-resolved in-cell NMR spectroscopy to study the repair of methionine-oxidized α-synuclein by endogenous cellular enzymes.
- Andres Binolfi
- , Antonio Limatola
- & Philipp Selenko
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Article
| Open AccessImpairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson’s disease
PLA2g6 regulates store-operated Ca2+ entry and is linked to Parkinson’s disease. Here, Zhou et al find faulty PLA2g6-dependent Ca2+signaling in idiopathic PD patients, and show that its impairment triggers autophagic dysfunction and loss of dopaminergic neurons in a new PLA2g6 ex2KO mouse model.
- Qingde Zhou
- , Allen Yen
- & Victoria M. Bolotina
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Article
| Open AccessToxic tau oligomer formation blocked by capping of cysteine residues with 1,2-dihydroxybenzene groups
Aggregation of microtubule associated protein tau is one of cause of neuronal loss in tauopathies including Alzheimer’s disease. Here, the authors show that compounds with a 1,2-dihydroxybenzene skeleton can modify cysteine residues in tau and block toxic tau aggregation.
- Yoshiyuki Soeda
- , Misato Yoshikawa
- & Akihiko Takashima
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Article
| Open AccessBasolateral and central amygdala differentially recruit and maintain dorsolateral striatum-dependent cocaine-seeking habits
Drug seeking behaviour has habitual neural substrates. Here, Murray et al. show that the basolateral amygdala and central nucleus of the amygdala are necessary to recruit and maintain, respectively, the intrastriatal functional transition that underlies cocaine seeking habits.
- Jennifer E. Murray
- , Aude Belin-Rauscent
- & David Belin
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Article
| Open AccessEPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques
Amyloid-beta deposits are a pathological hallmark of Alzheimer’s disease, and have previously been targeted in immunisation therapies. Here, the authors show that oral administration of the small molecule EPPS reduces Aß plaque and oligomer load in APP/PS1 mice and improves learning and memory performance.
- Hye Yun Kim
- , Hyunjin Vincent Kim
- & YoungSoo Kim
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Article
| Open AccessEndogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7
Nav1.7 channels are known to regulate pain perception in humans and mice. Here, the authors provide evidence that Nav1.7 deletion leads to transcriptional upregulation of opioid peptides in sensory neurons, and that treatment with the opioid blocker naloxone helps reverse analgesia in mice and human Nav1.7 nulls.
- Michael S. Minett
- , Vanessa Pereira
- & John N. Wood
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Article
| Open AccessDICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression
DICER1 is required for the maturation of miRNAs which regulate expression of thousands of genes. Here the authors show significantly reduced levels of DICER1in individuals having post-traumatic stress disorder and comorbid depression suggestive of a role in the molecular mechanism of the condition.
- Aliza P. Wingo
- , Lynn M. Almli
- & Kerry J. Ressler
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Article
| Open AccessAβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer’s disease
Understanding how ß-amyloid contributes to synapse loss and dysfunction is a central goal of Alzheimer’s disease research. Here, Leshchyns’ka et al.identify a novel mechanism by which Aß disassembles hippocampal glutamatergic synapses via cleavage of a neural cell adhesion molecule 2 (NCAM2).
- Iryna Leshchyns’ka
- , Heng Tai Liew
- & Vladimir Sytnyk
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Article
| Open AccessTRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production
Attempts to treat Alzheimer's disease by targeting γ-secretase cleavage of APP into Aß have been unsuccessful, partially due to off-target effects. Here, the authors identify TRPC6 as a novel γ-secretase modulator, showing that it interacts with APP to regulate Aß levels while sparing Notch cleavage.
- Junfeng Wang
- , Rui Lu
- & Yizheng Wang
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Article |
The trans-SNARE-regulating function of Munc18-1 is essential to synaptic exocytosis
Munc18-1 binds trans-SNARE complexes and promotes membrane fusion in vitro. Here the authors provide genetic evidence that this trans-SNARE-regulating function plays an essential role in synaptic releases in neurons, and show that this function is disrupted by a disease-causing Munc18-1 mutation.
- Chong Shen
- , Shailendra S. Rathore
- & Jingshi Shen
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Article
| Open AccessDelta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease
Age is the greatest risk factor for Alzheimer’s disease, yet how ageing regulates disease pathology is unclear. Here, the authors find that asparagine endopeptidase expression increases with age and cleaves APP, contributing to ß-amyloid production and cognitive defects in a transgenic mouse model.
- Zhentao Zhang
- , Mingke Song
- & Keqiang Ye
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Article
| Open AccessStructural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug
The leukotriene receptor antagonist montelukast is an anti-asthmatic drug. Here, the authors show that montelukast reduces neuroinflammation, promotes hippocampal neurogenesis and restores learning and memory in old rats suffering from ageing-associated cognitive dysfunction.
- Julia Marschallinger
- , Iris Schäffner
- & Ludwig Aigner
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