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| Open AccessBHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer’s disease and other disorders of lipid-rich tissues
Factors regulating lipid and lysosomal clearance in microglia and peripheral macrophage are not known. Here, authors nominate and validate transcription factors BHLHE40 and BHLHE41 as regulators of these processes in health and disease.
- Anna Podleśny-Drabiniok
- , Gloriia Novikova
- & Alison Mary Goate
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Article
| Open AccessProfiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation
Microglia nodules are associated with brain pathology. Here, the authors show demyelination in microglia nodules in multiple sclerosis (MS), likely due to oxidized phospholipid phagocytosis and immune activation, suggesting that nodules could be involved in MS lesion formation.
- Aletta M. R. van den Bosch
- , Marlijn van der Poel
- & Jörg Hamann
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Article
| Open AccessMicroglia govern the extinction of acute stress-induced anxiety-like behaviors in male mice
Stress-related anxiety can gradually become extinct but the underlying mechanisms are unclear. Here, the authors show that microglial engulfment of dendritic spines promotes the extinction of acute stress-induced anxiety-like behaviors in mice.
- Danyang Chen
- , Qianqian Lou
- & Yan Jin
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Article
| Open AccessCell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease
Alzheimer’s disease genetic risk is enriched in glial genes. Here, the authors derive cell-type-specific polygenic risk scores and link astrocytic genes with Aβ, and microglial genes with Aβ, tau, microglial activation, and cognitive decline.
- Hyun-Sik Yang
- , Ling Teng
- & Reisa A. Sperling
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Article
| Open AccessINPP5D regulates inflammasome activation in human microglia
INPP5D/SHIP1 is a microglial-expressed gene that has been associated with Alzheimer’s disease through genetic studies. This study reveals that reduction in INPP5D activity induces activation of the NLRP3-inflammasome in human microglia.
- Vicky Chou
- , Richard V. Pearse II
- & Tracy L. Young-Pearse
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Article
| Open AccessLipofuscin-like autofluorescence within microglia and its impact on studying microglial engulfment
Microglia are brain macrophages that engulf and clear cellular material and protein aggregates. Here, the authors show that lipofuscin-like autofluorescence can confound microglial engulfment analyses, which they can resolve with a photobleaching protocol.
- Jacob M. Stillman
- , Francisco Mendes Lopes
- & Dorothy P. Schafer
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Article
| Open AccessSpecies-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction
The innate immune cells undergo metabolic reprogramming upon inflammation. Here, the authors report that both mouse and human microglia display a metabolic reprogramming in the presence of a TLR4 activation, however species-specific enzymes are responsible for this process.
- Angélica María Sabogal-Guáqueta
- , Alejandro Marmolejo-Garza
- & Amalia Dolga
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Article
| Open AccessFEAST: A flow cytometry-based toolkit for interrogating microglial engulfment of synaptic and myelin proteins
When and how microglia engulf synapses and myelin is still unclear. Here, the authors provide a suite of flow cytometry-based approaches to quantify engulfment, paving the way for high-throughput assessment of microglial function in health and disease.
- Lasse Dissing-Olesen
- , Alec J. Walker
- & Beth Stevens
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Article
| Open AccessC9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9
The role of microglia in amyotrophic lateral sclerosis (ALS) is unclear. Here, the authors show that iPSC microglia from C9orf72-ALS patients are toxic to motor neurons and identify microglial MMP9 as a potential therapeutic target.
- Björn F. Vahsen
- , Sumedha Nalluru
- & Kevin Talbot
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Article
| Open AccessLoss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice
The role of lactate in the control of microglial function remains poorly investigated. Here, the authors show that lactate promotes lysosomal acidification in microglia, and that mice lacking the lactate transporter MCT4 in these cells display defective brain development and anxiety-like behavior.
- Katia Monsorno
- , Kyllian Ginggen
- & Rosa Chiara Paolicelli
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Article
| Open AccessPD-L1 positive astrocytes attenuate inflammatory functions of PD-1 positive microglia in models of autoimmune neuroinflammation
Co-inhibitory signaling controls immune mechanisms in health and disease. The authors here show that in autoimmune neuroinflammation, astrocytic PD-L1 mitigates autoimmune neuroinflammation through interaction with PD1 expressing microglia.
- Mathias Linnerbauer
- , Tobias Beyer
- & Veit Rothhammer
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Article
| Open AccessTranslocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
TSPO PET imaging is widely used to quantify microglial activation. Here, the authors show that TSPO expression increases in activated rodent but not human microglia, implying that in humans TSPO informs on microglial density rather than activation status.
- Erik Nutma
- , Nurun Fancy
- & David R. Owen
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Article
| Open AccessMicroglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice
The circadian clock protein REV-ERBα has been implicated in neuroinflammation but mechanisms are poorly understood. Here, the authors show that microglial REV-ERBα regulates inflammatory signaling and lipid droplet formation to exert sex-specific effects on tau pathology in mice.
- Jiyeon Lee
- , Julie M. Dimitry
- & Erik S. Musiek
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Article
| Open AccessVγ1 and Vγ4 gamma-delta T cells play opposing roles in the immunopathology of traumatic brain injury in males
Traumatic brain injury is not only a neurological but also an immunological condition in which multiple innate and adaptive immune cell types play roles. Here authors show in a mouse model that the Vγ4 subtype of the unconventional gamma-delta T cells promote neuroinflammation, while the Vγ1 subtype ameliorates immunopathology.
- Hadi Abou-El-Hassan
- , Rafael M. Rezende
- & Howard L. Weiner
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Article
| Open AccessSpatial Transcriptomics-correlated Electron Microscopy maps transcriptional and ultrastructural responses to brain injury
To understand complexity of cellular function, multiple phenotypic readouts are needed. Here, authors devised an approach integrating location, transcriptome, ultrastructure, and lipid content to characterize single-cell states after brain injury.
- Peter Androvic
- , Martina Schifferer
- & Ozgun Gokce
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Article
| Open AccessGalectin-3 activates spinal microglia to induce inflammatory nociception in wild type but not in mice modelling Alzheimer’s disease
In inflammatory arthritis, pain neurons communicate with spinal cord microglia to establish nociception. Here, the authors show that this communication is mediated by pain neurons releasing galectin-3, which activates microglia through TLR4. In a mouse model of Alzheimer’s disease, pain is attenuated because microglia lack expression of TLR4.
- George Sideris-Lampretsas
- , Silvia Oggero
- & Marzia Malcangio
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Perspective
| Open AccessAn aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease
In this perspective, the authors hypothesise that glial senescence, requiring senescent microglia burden, perpetuates further aging, Alzheimer’s pathologies, and senescence. Increasing glial senescence is proposed as necessary to drive individuals from healthy cognition into cognitive decline and dementia.
- Victor Lau
- , Leanne Ramer
- & Marie-Ève Tremblay
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Article
| Open AccessCSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model
Tau-mediated neurodegeneration is driven by disease-activated microglia and suppressed by their pharmacological blockade. The authors identified drug dose- and sex-dependent residual microglial phenotypes, neuronal excitotoxicity, and animal survival.
- Noah R. Johnson
- , Peng Yuan
- & Carlo Condello
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Article
| Open AccessMicroglial debris is cleared by astrocytes via C4b-facilitated phagocytosis and degraded via RUBICON-dependent noncanonical autophagy in mice
Microglia are professional phagocytes in the CNS. However, which cells scavenge corpses of microglia is largely neglected. Peng and colleagues found that nonprofessional phagocytes (astrocyte) phagocytose the debris of professional phagocytes (microglia).
- Tian Zhou
- , Yuxin Li
- & Bo Peng
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Article
| Open AccessSleep decreases neuronal activity control of microglial dynamics in mice
Microglia survey the parenchyma, which leads to morphology changes over time. Here the authors show using 2 photon imaging of microglia in vivo that sleep modulates microglial morphodynamics through Cx3cr1 signaling.
- I. Hristovska
- , M. Robert
- & O. Pascual
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Article
| Open AccessBrain milieu induces early microglial maturation through the BAX-Notch axis
The mechanisms by which the brain milieu confers microglial development are not clear. Here, the authors show that the BAX-CaMKII-CREB-Notch signaling axis triggered by the neuronal milieu plays a role in early microglia maturation.
- Fangying Zhao
- , Jiangyong He
- & Li Li
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Article
| Open AccessThe alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury
The neuroimmune interactions driving secondary degeneration in the injured spinal cord remain elusive. Here, the authors reveal that damaged microglia release IL-1α, resulting in neutrophil infiltration and the loss of mature oligodendrocytes through astrocytic and endothelial IL-1R1 in mice.
- Floriane Bretheau
- , Adrian Castellanos-Molina
- & Steve Lacroix
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Article
| Open AccessRejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance
The authors discovered that proinflammatory senescent myeloid cells may recruit peripheral immune cells in the aged mouse brain. Their findings implicate senescent cell clearance as a strategy to counter aged brain inflammation and cognitive decline.
- Xu Zhang
- , Vesselina M. Pearsall
- & Marissa J. Schafer
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Article
| Open AccessChimeric GPCRs mimic distinct signaling pathways and modulate microglia responses
Understanding the function of GPCRs requires stimulation with their specific ligands. Here, the authors design chemogenetic G-protein coupled receptors that allows for the study of receptors without knowing the immediate ligand, and demonstrate its use for the β2-adrenergic receptor in microglia.
- Rouven Schulz
- , Medina Korkut-Demirbaş
- & Sandra Siegert
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Article
| Open AccessMicroglia coordinate cellular interactions during spinal cord repair in mice
Here the authors show, using microglia-specific depletion techniques and single cell transcriptomics, that optimal repair after murine spinal cord injury (SCI) requires microglia.
- Faith H. Brennan
- , Yang Li
- & Phillip G. Popovich
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Matters Arising
| Open AccessMotor deficits seen in microglial ablation mice could be due to non-specific damage from high dose diphtheria toxin treatment
- Jiyun Peng
- , Qian Zou
- & Bao-Ming Li
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Article
| Open AccessEndothelial cell heterogeneity and microglia regulons revealed by a pig cell landscape at single-cell level
Pigs are important large animal models for biomedical research. Here, the authors construct a single-cell landscape of pig tissues, unravelling the phenotypic heterogeneity of blood endothelial cells in adipose tissues and the evolutionally conserved regulons of microglia in brains.
- Fei Wang
- , Peiwen Ding
- & Yonglun Luo
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Article
| Open AccessSingle-cell RNA sequencing reveals time- and sex-specific responses of mouse spinal cord microglia to peripheral nerve injury and links ApoE to chronic pain
Microglia subpopulations may differentially contribute to pain. Here, the authors show that peripheral nerve injury induces time- and sex-specific transcriptional changes in mouse spinal cord microglia subpopulations and that ApoE is linked to neuropathic pain hypersensitivity in mice and humans.
- Shannon Tansley
- , Sonali Uttam
- & Arkady Khoutorsky
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Article
| Open AccessMicroglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
Whether microglial activation constitutes a primary pathological event in synucleinopathies is not known. Here, the authors generated a mouse model over-expressing α-synuclein in microglial cells and found these mice developed progressive dopaminergic neuron degeneration and microglia developed a reactive, pro-inflammatory state with phagocytic exhaustion.
- Simone Bido
- , Sharon Muggeo
- & Vania Broccoli
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Article
| Open AccessIn situ and transcriptomic identification of microglia in synapse-rich regions of the developing zebrafish brain
Microglia remodel synapses and engulf apoptotic cells. The molecular program underlying these distinct functions are unclear. Here, the authors identify distinct microglial subsets associated with synaptic vs. neurogenic regions of the developing zebrafish brain.
- Nicholas J. Silva
- , Leah C. Dorman
- & Anna V. Molofsky
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Article
| Open AccessSelective targeting of the TLR2/MyD88/NF-κB pathway reduces α-synuclein spreading in vitro and in vivo
The mechanisms underlying the spreading of α-synuclein in various α-synucleinopathies are unclear. Here, the authors show that targeting the TLR2/MyD88/NF-κB pathway can reduce α-synuclein spreading, reduce neuroinflammation, and protect dopaminergic neurons in vitro and in mouse models
- Debashis Dutta
- , Malabendu Jana
- & Kalipada Pahan
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Comment
| Open AccessMicroglia have a grip on brain microvasculature
Microglia are brain resident immune cells with multiple functions. However, little is known about microglia-vascular interactions. In a recent paper published in Nature Communications, Bisht et al. identify a signalling mechanism that attracts and maintains microglia at the capillary wall. Moreover, they show that microglia regulate capillary vascular tone, playing a more significant role in blood flow regulation than previously thought.
- Kassandra Kisler
- , Angeliki Maria Nikolakopoulou
- & Berislav V. Zlokovic
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Article
| Open AccessCapillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice
Microglia are involved in debris clearance and synaptic pruning, among other processes. However, their direct interaction with the brain vasculature is less clear. Here, the authors show that capillary-associated microglia (CAMs) regulate vascular tone via PANX1-P2RY12 signalling.
- Kanchan Bisht
- , Kenneth A. Okojie
- & Ukpong B. Eyo
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Article
| Open AccessMicroglia modulate stable wakefulness via the thalamic reticular nucleus in mice
Here, the authors show that microglia depletion results in unstable wakefulness and altered levels of ceramide, influencing microglia in the mouse thalamic reticular nucleus (TRN). Stable wakefulness can be restored by activation of the TRN or inhibition of ceramide production in the mouse brain.
- Hanxiao Liu
- , Xinxing Wang
- & Qiaojie Xiong
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Article
| Open AccessPhospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease
Microglia can clear amyloid plaques in Alzheimer’s disease. Here, the authors show that specific isoforms of the phospholipid forming APOE lipoproteins activate microglia in pre-clinical mouse models of Alzheimer’s disease.
- Nicholas F. Fitz
- , Kyong Nyon Nam
- & Radosveta Koldamova
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Article
| Open AccessTranscriptional signature in microglia associated with Aβ plaque phagocytosis
Microglia associated with Aβ plaques may have a distinct transcriptional signature compared to those in plaque-free areas of the brain in Alzheimer’s disease (AD) models. Here the authors show that amyloid plaque phagocytosis is associated with a specific microglia transcriptional signature in a mouse model of AD.
- Alexandra Grubman
- , Xin Yi Choo
- & Jose M. Polo
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Article
| Open AccessLoss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration
Microglial SIRPα regulates synaptic pruning during development. Its role in neurodegeneration is unclear. Here, the authors show microglial SIRPα declines in the model of Alzheimer’s disease, leading to excessive microglia mediated synapse elimination as well as impaired cognitive function.
- Xin Ding
- , Jin Wang
- & Liang Li
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Article
| Open AccessSingle cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease
Imbalance of microglial phenotypes in the aging brain might underlie their involvement in late onset neurodegenerative diseases. Here we report the population structure of microglia in the aged human brain and the reduction of a particular microglia subset in individuals with Alzheimer’s disease .
- Marta Olah
- , Vilas Menon
- & Philip L. De Jager
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Article
| Open AccessGene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease
Mutations in TREM2 alter risk for Alzheimer’s disease, though the mechanisms underlying risk in human cells are unclear. Here, the authors use iPS-microglia and chimeric mice to highlight altered survival, phagocytosis, migration, and transcriptional programs in microglia lacking TREM2.
- Amanda McQuade
- , You Jung Kang
- & Mathew Blurton-Jones
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Article
| Open AccessSynucleinopathy alters nanoscale organization and diffusion in the brain extracellular space through hyaluronan remodeling
The nanoscale organisation of the brain extracellular space can be studied in vivo. Here, the authors investigate how it changes in response to α-synuclein pathology, and identify interactions between microglia and the extracellular matrix.
- Federico N. Soria
- , Chiara Paviolo
- & Erwan Bezard
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Article
| Open AccessThe TSPO-NOX1 axis controls phagocyte-triggered pathological angiogenesis in the eye
Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Here, the authors show that microglia-specific deletion of TSPO and chemical inhibition of TSPO prevent neuroinflammation and vascular damage in a mouse model of AMD.
- Anne Wolf
- , Marc Herb
- & Thomas Langmann
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Article
| Open AccessPTSD is associated with neuroimmune suppression: evidence from PET imaging and postmortem transcriptomic studies
Neuroinflammation has been proposed to accompany the peripheral inflammation observed in PTSD. Here, authors find lower in vivo and postmortem levels of neuroimmune marker TSPO (translocator protein) in PTSD, in association with greater PTSD severity and higher plasma CRP.
- Shivani Bhatt
- , Ansel T. Hillmer
- & Kelly P. Cosgrove
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Article
| Open AccessTransient microglial absence assists postmigratory cortical neurons in proper differentiation
Microglia temporarily disappear from the cortical plate in the midembryonic stage. This study demonstrated that microglial transient absence from the cortical plate is required for postmigratory neurons to appropriately fine-tune the expression of molecules needed for their proper differentiation.
- Yuki Hattori
- , Yu Naito
- & Takaki Miyata
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Article
| Open AccessHuman iPSC-derived mature microglia retain their identity and functionally integrate in the chimeric mouse brain
Human microglia present unique features; therefore, chimeric mouse models can enhance modelling of human microglia response in health and disease. Here, the authors show that hiPSC-derived mature microglia developed in the mouse brain, retain their identity and respond to demyelination.
- Ranjie Xu
- , Xiaoxi Li
- & Peng Jiang
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Article
| Open AccessMicroglial metabolic flexibility supports immune surveillance of the brain parenchyma
Glucose is the main source of fuel in the brain. Here, the authors show that in the absence of glucose, glutamine is required for microglia to maintain their immune surveillance function.
- Louis-Philippe Bernier
- , Elisa M. York
- & Brian A. MacVicar
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Article
| Open AccessMicroglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration
Microglia perform important supporting roles for neurons in the brain. Here, the authors show that microglia clear neuron-derived α-synuclein through selective autophagy (synucleinphagy) to prevent accumulation of misfolded α-synuclein and subsequent neurodegeneration in a mouse model of disease.
- Insup Choi
- , Yuanxi Zhang
- & Zhenyu Yue
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Article
| Open AccessDual microglia effects on blood brain barrier permeability induced by systemic inflammation
Although it is known that microglia respond to injury and systemic disease in the brain, it is unclear if they modulate blood–brain barrier (BBB) integrity, which is critical for regulating neuroinflammatory responses. Here authors demonstrate that microglia respond to inflammation by migrating towards and accumulating around cerebral vessels, where they initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 before switching, during sustained inflammation, to phagocytically remove astrocytic end-feet resulting in impaired BBB function
- Koichiro Haruwaka
- , Ako Ikegami
- & Hiroaki Wake
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Article
| Open AccessSustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model
Genetics implicate microglia in Alzheimer’s disease pathogenesis, but their roles remain unclear. Here, the authors find that microglial depletion in a mouse model of Alzheimer’s disease impairs plaque formation and that Aβ-induced changes in neuronal gene expression are microglia-mediated.
- Elizabeth Spangenberg
- , Paul L. Severson
- & Kim N. Green
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Article
| Open AccessGalectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’s disease
The authors show that Galectin-3 is up–regulated in brain tissues from patients and a mouse model of Huntington’s disease (HD) and correlates with disease severity. Galectin-3 accumulates at damaged lysosomes in HD microglia, prevents the clearance of damaged lysosomes, and promotes inflammation.
- Jian Jing Siew
- , Hui-Mei Chen
- & Yijuang Chern