Featured
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Identification of senescent, TREM2-expressing microglia in aging and Alzheimer’s disease model mouse brain
Neuroinflammation and microglia significantly contribute to Alzheimer’s disease pathology, depending on their activation state. We found that TREM2-expressing microglia are a heterogenous population spanning activated to senescent cells.
- Noa Rachmian
- , Sedi Medina
- & Michal Schwartz
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Article
| Open Access
Messenger RNA transport on lysosomal vesicles maintains axonal mitochondrial homeostasis and prevents axonal degeneration
Using human iPSC-derived and mouse neurons, this study demonstrates that mRNA transport on lysosome-related vesicles is critical for the maintenance of axonal homeostasis and that its failure causes axonal degeneration.
- Raffaella De Pace
- , Saikat Ghosh
- & Juan S. Bonifacino
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Research Briefing |
Synapses shape oligodendrocyte precursor cell development and predict myelination location
Using in vivo imaging in zebrafish, we unveiled critical components (PSD-95, gephyrin and neuroligin-3) and dynamic properties of synapses between neurons and oligodendrocyte precursor cells (OPC). Furthermore, we showed that neuron–OPC synapses have a pivotal role in regulating OPC development and CNS myelination.
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Article |
Aerobic glycolysis is the predominant means of glucose metabolism in neuronal somata, which protects against oxidative damage
Neuronal somata perform higher levels of aerobic glycolysis and lower levels of OXPHOS than terminals, which safeguards against oxidative damage.
- Yao Wei
- , QianQian Miao
- & Gang Hu
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Article |
Adaptor protein AP-3 produces synaptic vesicles that release at high frequency by recruiting phospholipid flippase ATP8A1
Release of glutamate at high frequency involves a distinct subset of synaptic vesicles made by adaptor protein AP-3. Sorting of the phospholipid flippase ATP8A1 by AP-3 confers release at high frequency by recruiting synapsin to synaptic vesicles.
- Hongfei Xu
- , Juan A. Oses-Prieto
- & Robert H. Edwards
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Article |
Integrating spatial and single-nucleus transcriptomic data elucidates microglial-specific responses in female cynomolgus macaques with depressive-like behaviors
The cellular and molecular mechanisms underlying major depressive disorder are unclear. Here, the authors report cell type- and cortical layer-specific gene expression changes and identify one microglia subpopulation associated with depressive-like behavior in female non-human primates.
- Jing Wu
- , Yifan Li
- & Peng Xie
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Article
| Open Access
Heart failure-induced cognitive dysfunction is mediated by intracellular Ca2+ leak through ryanodine receptor type 2
Dridi et al. identified a mechanism for cognitive dysfunction after heart failure in which hyper-adrenergic signaling and transforming growth factor-beta activation induced Ca2+ leak by RyR2 channels in hippocampal neurons.
- Haikel Dridi
- , Yang Liu
- & Andrew R. Marks
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Article
| Open Access
Perivascular cells induce microglial phagocytic states and
synaptic engulfment via SPP1 in mouse models of Alzheimer’s
disease
Microglia mediate aberrant synapse engulfment in Alzheimer’s disease (AD), but the underlying mechanisms are poorly understood. Here the authors show a perivascular cells-to-microglia crosstalk that induces microglia phagocytic state resulting in synapse engulfment in two mouse models of AD.
- Sebastiaan De Schepper
- , Judy Z. Ge
- & Soyon Hong
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Article
| Open Access
Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration
Iron-laden microglia assume a disease-relevant, ferroptosis-associated signature and cause neurotoxicity. CRISPR screen uncovered regulators of ferroptosis in microglia. This ferroptosis–microglia–neurodegeneration axis could be targeted therapeutically.
- Sean K. Ryan
- , Matija Zelic
- & Timothy R. Hammond
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Article |
Age-related Huntington’s disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy
Oh et al. modeled age-dependent onset of Huntington’s disease by comparing reprogrammed neurons from pre-symptomatic and symptomatic patients. They found that an age-associated miRNA led to autophagy impairment and neurodegeneration.
- Young Mi Oh
- , Seong Won Lee
- & Andrew S. Yoo
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Article
| Open Access
Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity
This study tracked the initial self-assembly, oligomerization and structural conversion of α-synuclein inside neurons. Early seeding events occur on mitochondrial membranes, where oligomerization induces mitochondrial dysfunction and neuronal loss.
- Minee L. Choi
- , Alexandre Chappard
- & Sonia Gandhi
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Article |
Ptchd1 mediates opioid tolerance via cholesterol-dependent effects on μ-opioid receptor trafficking
Using forward genetics, the authors identified the cholesterol regulator Ptchd1, which controls opioid tolerance by affecting desensitization and trafficking of opioid receptors.
- Nycole Maza
- , Dandan Wang
- & Kirill A. Martemyanov
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Article
| Open Access
Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques
Interrogation of neuronal autophagy in vivo in Alzheimerʼs disease mouse models identified deficient autolysosome acidification as the basis for extreme autophagic stress, yielding β-amyloid accumulation within intact neurons, which are the main source of senile plaques.
- Ju-Hyun Lee
- , Dun-Sheng Yang
- & Ralph A. Nixon
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Article |
Distinct nuclear compartment-associated genome architecture in the developing mammalian brain
In the nucleus, specific stretches of DNA are ‘anchored’ to distinct membrane-less compartments that harbor gene regulatory function. Using GO-CaRT, the authors discovered unique aspects of genome architecture in neural precursors in vivo, providing new insights into brain development and disease.
- Sajad Hamid Ahanger
- , Ryan N. Delgado
- & Daniel A. Lim
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Resource |
Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis
Tian et al. conducted a genome-wide CRISPRi/CRISPRa screen in human neurons and uncovered a neuron-specific link among prosaposin, lipofuscin and ferroptosis. The CRISPRbrain data commons enables comparison of gene function across human cell types.
- Ruilin Tian
- , Anthony Abarientos
- & Martin Kampmann
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Article |
Oligodendrocyte precursor cell specification is regulated by bidirectional neural progenitor–endothelial cell crosstalk
Paredes et al. identify bidirectional crosstalk between the neural and the vascular compartment in the developing CNS required for oligodendrocyte precursor cell specification and mediated by an angiopoietin1–Tie2–TGFß1 signaling axis.
- Isidora Paredes
- , José Ricardo Vieira
- & Carmen Ruiz de Almodóvar
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Article |
Vector trace cells in the subiculum of the hippocampal formation
Poulter et al. report on vector trace cells (VTCs) in the hippocampal subiculum. VTCs support vector coding for previously encountered, now absent, objects and boundaries, potentially facilitating navigation to remembered goals.
- Steven Poulter
- , Sang Ah Lee
- & Colin Lever
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News & Views |
Natural killers of cognition
One of the mechanisms driving aging and neurodegenerative diseases is the accumulation of senescent cells, while their elimination mitigates age-related decline. A new report details how, with aging, changes in the dentate gyrus microenvironment lead to natural-killer-cell-mediated clearance of neurogenic senescent cells, resulting in cognitive decline.
- Nurit Papismadov
- & Valery Krizhanovsky
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Article |
Mesophasic organization of GABAA receptors in hippocampal inhibitory synapses
Using cryo-electron tomography to detect individual GABAA receptors in hippocampal synapses, we discovered a hierarchical and mesophasic organization of inhibitory postsynaptic density proteins that enables efficient synaptic transmission.
- Yun-Tao Liu
- , Chang-Lu Tao
- & Guo-Qiang Bi
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Article |
Synaptic vesicles transiently dock to refill release sites
Kusick et al. capture snapshots of synaptic vesicle docking and fusion using a new time-resolved electron microscopy technique. They find that vesicles are replaced milliseconds after they fuse, which may contribute to short-term synaptic plasticity.
- Grant F. Kusick
- , Morven Chin
- & Shigeki Watanabe
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Article |
Alzheimer’s-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia
Andreone, Przybyla et al. used induced pluripotent stem cell-derived human microglia to show that TREM2-dependent phagocytosis and lipid metabolism require the Alzheimer’s risk factor PLCγ2, which can also mediate TREM2-independent inflammatory signaling via Toll-like receptors.
- Benjamin J. Andreone
- , Laralynne Przybyla
- & Joseph W. Lewcock
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Article |
Microglia and macrophages promote corralling, wound compaction and recovery after spinal cord injury via Plexin-B2
Zhou et al. unveil a novel role for activated microglia and macrophages during wound healing after CNS injury. Microglia promote corralling and form a protective barrier at the injury penumbra via the axon guidance receptor Plexin-B2.
- Xiang Zhou
- , Shalaka Wahane
- & Hongyan Zou
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News & Views |
Structure of an Arc-ane virus-like capsid
Recent findings unveil a viral-like mechanism for the transmission of synaptic plasticity signals involving the activity-regulated cytoskeleton-associated protein (Arc). Arc forms capsid-like particles that package RNA and are transported across synapses. Here Erlendsson et al. present a high-resolution structural representation of Arc capsids, enabling deeper analysis of their function.
- Vivian Budnik
- & Travis Thomson
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Review Article |
The influence of environment and origin on brain resident macrophages and implications for therapy
Framed around the potential use of microglia as new cellular therapies for brain disease, Bennett and Bennett review new discoveries about the effects of developmental origin and environmental signals on brain macrophage identity and function.
- Mariko L. Bennett
- & F. Chris Bennett
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Article |
Exome sequencing in amyotrophic lateral sclerosis implicates a novel gene, DNAJC7, encoding a heat-shock protein
DNA sequencing of 3,864 individuals with ALS and 7,839 controls identified a novel disease gene, DNAJC7, which encodes a heat-shock protein. As DNAJC7 is an essential part of cell maintenance, mutations in DNAJC7 may lead to neurodegeneration.
- Sali M. K. Farhan
- , Daniel P. Howrigan
- & Benjamin M. Neale
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Review Article |
Emerging intersections between neuroscience and glioma biology
Malignant gliomas recapitulate steps in neurodevelopment to form organ-like structures. Jung et al. review how neuroscience can provide novel insights into glioma biology, and how these insights might be used for future therapeutic approaches.
- Erik Jung
- , Julieta Alfonso
- & Frank Winkler
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Article |
Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence
Chow et al. show that high blood levels of insulin in prediabetic conditions are linked to saturated insulin levels in the brain. Chronic insulin exposure leads to insulin resistance, cell cycle reentry and premature aging, corresponding to senescence-like pathological changes in neurons.
- Hei-Man Chow
- , Meng Shi
- & Karl Herrup
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Resource |
Epigenomic signatures underpin the axonal regenerative ability of dorsal root ganglia sensory neurons
This manuscript describes the systematic investigation of epigenomic signatures discriminating between regenerative success and failure in dorsal root ganglia sensory neurons following axonal injury. This epigenomic map offers a tool to design novel approaches for neuronal repair.
- Ilaria Palmisano
- , Matt C. Danzi
- & Simone Di Giovanni
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Resource |
Single-cell transcriptomic profiling of the aging mouse brain
A single-cell transcriptomic atlas of the aging mouse brain reveals coordinated and cell-type-specific aging signatures across multiple cell populations. Catalogs of aging-related genes, pathways and ligand–receptor interactions are reported.
- Methodios Ximerakis
- , Scott L. Lipnick
- & Lee L. Rubin
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Technical Report |
Cell-type-specific profiling of brain mitochondria reveals functional and molecular diversity
Fecher et al. devise an approach to isolate cell-type-specific mitochondria from the mouse CNS. They demonstrate proteomic diversity of cerebellar mitochondria covering bioenergetics, calcium handling and organelle contact sites.
- Caroline Fecher
- , Laura Trovò
- & Thomas Misgeld
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Obituary |
“For Paul”
On April 13, the neuroscience community lost a remarkable scientist and true humanitarian. Paul Greengard, co-recipient of the Nobel Prize in Physiology or Medicine in 2000, Vincent Astor Professor and head of the Laboratory of Molecular and Cellular Neuroscience at the Rockefeller University in New York City, died of an apparent heart attack at age 93. Paul will be remembered for his seminal contributions to neuroscience, for pioneering the field of neuronal signal transduction and for training hundreds of neuroscientists. For anyone who knew Paul it will come as no surprise that up until a few hours before his death, Paul was doing what he liked the best: working on a scientific manuscript.
- Helen S. Bateup
- , Myriam Heiman
- & Anne Schaefer
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Article |
Loss of nuclear UBE3A causes electrophysiological and behavioral deficits in mice and is associated with Angelman syndrome
This paper elucidates the mechanism regulating the subcellular localization of UBE3A and demonstrates that abrogation of UBE3A nuclear localization leads to electrophysiological and behavioral impairments in mice and to Angelman syndrome in humans.
- Rossella Avagliano Trezza
- , Monica Sonzogni
- & Ype Elgersma
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Article |
L3MBTL1 regulates ALS/FTD-associated proteotoxicity and quality control
Lu et al. report a pathway that reprograms protein quality control under stress. Identified in a Caenorhabditis elegans screen and characterized in mammalian systems, L3MBTL1 and its partner SETD8 modulate proteotoxicity and are deregulated in patients with ALS/FTD.
- Jiayin Lu
- , Goran Periz
- & Jiou Wang
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News & Views |
Astrocytes usurp neurons as a disease focus
Astrocytes are emerging as causal or modulating factors in diverse neurological disorders. Two papers published in Nature Neuroscience in 2007 revealed astrocytes as causally contributing to motor neuron loss in amyotrophic lateral sclerosis, thereby challenging the longstanding neuron-centric view of neurodegenerative disease.
- Shane A. Liddelow
- & Michael V. Sofroniew
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Article |
Microvascular endothelial cells engulf myelin debris and promote macrophage recruitment and fibrosis after neural injury
Blood vessels help macrophage entry. Zhou et al. show that activated microvessels serve as critical portals for macrophage entry to boost inflammation after spinal cord injury.
- Tian Zhou
- , Yiming Zheng
- & Yi Ren
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Article |
Invasion of white matter tracts by glioma stem cells is regulated by a NOTCH1–SOX2 positive-feedback loop
CD133 and Notch1 double-positive GSCs were preferentially located along Jagged1-expressing white matter tracts, which exhibited a demyelinated phenotype. The NOTCH1–SOX9–SOX2 positive-feedback loop controls GSC invasion along white matter tracts.
- Jun Wang
- , Sen-Lin Xu
- & Shi-Cang Yu
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Review Article |
Converging pathways in neurodegeneration, from genetics to mechanisms
Neurodegenerative diseases cause progressive loss of brain functions associated with aging. Here we review intricate genotype–phenotype relationships, shared pathogenic mechanisms, and emerging therapeutic opportunities and challenges.
- Li Gan
- , Mark R. Cookson
- & Albert R. La Spada
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News & Views |
FRETting over postsynaptic PKC signaling
Protein kinases are key regulators of excitatory synapse plasticity. In this issue, using novel optical reporters of protein kinase C (PKC) activity, Colgan et al. identify PKCα as critical for integrating NMDA receptor and neurotrophin signaling to control dendritic spine structural plasticity, synaptic potentiation, and learning and memory.
- Mark L. Dell’Acqua
- & Kevin M. Woolfrey
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News & Views |
Nuclear pores: the gate to neurodegeneration
Compromised compartmentalization of nucleus and cytoplasm has emerged as a central feature of aging and neurodegenerative diseases. Nucleocytoplasmic transport is disrupted, with widespread mislocalization of nuclear pore proteins, in TDP-43 proteinopathies such as, amyotrophic lateral sclerosis and frontotemporal dementia.
- Nan Li
- & Clotilde Lagier-Tourenne
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Article
| Open Access
TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD
Pathological TDP-43 protein aggregates are a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 pathology alters the morphology of nuclear pore complexes and cause deficits in nucleocytoplasmic transport.
- Ching-Chieh Chou
- , Yi Zhang
- & Wilfried Rossoll
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News & Views |
Munc13 marks the spot
Super-resolution optical imaging of presynaptic terminals shows that a protein essential to all known forms of neurotransmitter release is clustered in small assemblies that likely correspond to release sites for synaptic vesicle fusion.
- Timothy A. Ryan
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Article |
Synaptic weight set by Munc13-1 supramolecular assemblies
The authors show that Munc13-1 molecules form multiple supramolecular self-assemblies that serve as vesicular release sites. Having multiple Munc13-1 assemblies affords a stable synaptic weight, which confers robustness of synaptic computation.
- Hirokazu Sakamoto
- , Tetsuroh Ariyoshi
- & Kenzo Hirose
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Brief Communication |
Regulation of developing myelin sheath elongation by oligodendrocyte calcium transients in vivo
Myelin formed by oligodendrocytes enables rapid, energy-efficient information transmission in CNS, but its development is unclear. The authors show that the rate of intracellular calcium transients regulates elongation of developing myelin sheaths.
- Anna M. Krasnow
- , Marc C. Ford
- & David Attwell
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Article |
Astrocytes control synaptic strength by two distinct v-SNARE-dependent release pathways
The mechanisms of gliotransmitter release and their impact on neuronal signaling have remained largely elusive. The authors describe two functionally non-overlapping v-SNARE-dependent astrocytic release pathways that oppositely control synaptic strength at presynaptic sites. Thus, astrocytes are able to fine-tune fast glutamatergic neurotransmission and control fundamental processes of synaptic communication.
- Yvonne Schwarz
- , Na Zhao
- & Dieter Bruns
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Article |
Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects
Antipsychotic treatment in patients with schizophrenia often reduces hallucinations and delusions, but cognitive deficits that impair performance of everyday activities may persist or worsen. Our findings reveal a mechanism by which increased NF-κB activity leads to increased HDAC2 levels, impairing synaptic plasticity and memory during prolonged antipsychotic treatment.
- Daisuke Ibi
- , Mario de la Fuente Revenga
- & Javier González-Maeso
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News & Views |
Helping EGFR inhibition to block cancer
Effectiveness of EGFR treatment is impaired through an early adaptive response. TNF–JNK–Axl–ERK signaling contributes to this primary resistance to EGFR inhibition and might serve as novel target to improve EGFR inhibition.
- Rolf Warta
- & Christel Herold-Mende
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Article |
C9orf72 expansion disrupts ATM-mediated chromosomal break repair
An expanded repetition of a DNA sequence within the C9orf72 gene is the most common genetic cause for motor neuron disease and frontotemporal dementia. In this study, the authors show that this expansion causes increased genomic breaks and reduces the cell's ability to repair the breaks, ultimately leading to neuronal cell death.
- Callum Walker
- , Saul Herranz-Martin
- & Sherif F El-Khamisy
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