New insights on the role of microglia in synaptic pruning in health and disease
Open accessAbstract
Recent genome-wide association studies implicate microglia in Alzheimer's disease (AD) pathogenesis; however, their biological significance remains poorly understood. Synapse loss is a significant correlate of cognitive decline that serves as a critical hallmark of AD and other neurodegenerative diseases; however, mechanisms underlying synaptic vulnerability remain elusive. Emerging research on microglia function in the healthy brain is providing new insight into fundamental roles of microglia and immune molecules in brain wiring. Among their many roles, microglia prune developing synapses and regulate synaptic plasticity and function. Here, we review and discuss how this emerging work may provide new insight into how disruptions in microglia-synapse interactions could contribute to synapse loss and dysfunction, and consequently cognitive impairment, in AD.
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Genome-wide association studies implicate microglia and complement-related pathways in Alzheimer's disease.
“Genome-wide association studies (GWAS) implicate microglia and complement-related pathways in AD (1).”
From Complement and microglia mediate early synapse loss in Alzheimer mouse models (2016) · cites this paper as [1]
Similarities between DAM and PAM support the idea that developmental gene programs are reactivated in aging and degeneration.
“The parallels between DAM and PAM support the concept that genes expressed during development are reactivated in aging and degeneration (Hong et al., 2016).”
From Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing (2019) · cites this paper as Hong et al., 2016
Synapse loss in the hippocampus and association cortices is an early hallmark of AD and strongly correlates with cognitive impairment.
“The synapse loss in the hippocampus and association cortices is an early hallmark of AD and strongly correlates with cognitive impairment (Hong et al., 2016).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Hong et al., 2016
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Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343 · see citing works
“Emerging research implicates microglia and immune-related mechanisms in brain wiring in the healthy brain (1).”
Self-citationMicroglia emerge as central players in brain disease
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Self-citationMicroglia in physiology and disease
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13 reasons why the brain is susceptible to oxidative stress
Cobley, J. N., Fiorello, M. L., & Bailey, D. M. (2018) · Redox Biology · doi:10.1016/j.redox.2018.01.008 · Cited by 1,215 · see citing works
iPSC-derived human microglia-like cells to study neurological diseases
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Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner
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Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis
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Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response
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Efficient derivation of microglia-like cells from human pluripotent stem cells
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Alzheimer’s disease hypothesis and related therapies
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Tissue macrophages: heterogeneity and functions
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The microbiome: a key regulator of stress and neuroinflammation
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Neuroprotective Effect of Antioxidants in the Brain
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Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation
Jäkel, S., & Dimou, L. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00024 · Cited by 501 · see citing works
Modeling Alzheimer’s disease with iPSC-derived brain cells
Penney, J., Ralvenius, W. T., & Tsai, L.-H. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0468-3 · Cited by 471 · see citing works
The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma.
Ramirez, A. I., de Hoz, R., Salobrar-Garcia, E., Salazar, J. J., Rojas, B., Ajoy, D., López-Cuenca, I., Rojas, P., Triviño, A., & Ramírez, J. M. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00214 · Cited by 466 · see citing works
How macrophages deal with death
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Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging
Plaza-Zabala, A., Sierra-Torre, V., & Sierra, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18030598 · Cited by 323 · see citing works
Inflammation in ALS/FTD pathogenesis
McCauley, M. E., & Baloh, R. H. (2019) · Acta Neuropathologica · doi:10.1007/s00401-018-1933-9 · Cited by 316 · see citing works
Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling
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The promises and challenges of human brain organoids as models of neuropsychiatric disease
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Super-Resolution Imaging of the Extracellular Space in Living Brain Tissue
Tønnesen, J., Inavalli, V. V. G. K., & Nägerl, U. V. (2018) · Cell · doi:10.1016/j.cell.2018.02.007 · Cited by 293 · see citing works
Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes
Dodiya, H. B., Kuntz, T., Shaik, S. M., Baufeld, C., Leibowitz, J., Zhang, X., Gottel, N., Zhang, X., Butovsky, O., Gilbert, J. A., et al. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20182386 · Cited by 288 · see citing works
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Anti-Inflammatory Effects of Resveratrol: Mechanistic Insights
Coutinho, D. D. S., Pacheco, M. T., Frozza, R. L., & Bernardi, A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19061812 · Cited by 298 · see citing works
Microglia and the brain: Complementary partners in development and disease
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Self-citationOutdoor Ambient Air Pollution and Neurodegenerative Diseases: the Neuroinflammation Hypothesis
Jayaraj, R. L., Rodriguez, E. A., Wang, Y., & Block, M. L. (2017) · Current Environmental Health Reports · doi:10.1007/s40572-017-0142-3 · Cited by 233 · see citing works
C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo
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Emerging Microglia Biology Defines Novel Therapeutic Approaches for Alzheimer’s Disease
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Prenatal infection leads to ASD-like behavior and altered synaptic pruning in the mouse offspring
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Transcriptional and epigenetic decoding of the microglial aging process
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Challenges for Alzheimer's Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects
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Identification of phagocytosis regulators using magnetic genome-wide CRISPR screens
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Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy
Zhao, X., Liao, Y., Morgan, S., Mathur, R., Feustel, P., Mazurkiewicz, J., Qian, J., Chang, J., Mathern, G. W., Adamo, M. A., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.004 · Cited by 190 · see citing works
Targeting microglia for the treatment of Alzheimer’s Disease
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Ambient air pollution and clinical dementia: systematic review and meta-analysis
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Optic Pathway Gliomas in Neurofibromatosis Type 1
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Early-life adversity and neurological disease: age-old questions and novel answers
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Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration
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Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia
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Garlic exosome-like nanoparticles reverse high-fat diet induced obesity via the gut/brain axis
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Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development
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Maternal immune activation in neurodevelopmental disorders
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Neuron–Microglia Interactions in Mental Health Disorders: “For Better, and For Worse”
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Impact of dietary fats on brain functions
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Chronic Stress Weakens Connectivity in the Prefrontal Cortex: Architectural and Molecular Changes.
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Sensory Experience Engages Microglia to Shape Neural Connectivity through a Non-Phagocytic Mechanism
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Self-citationGlia as sculptors of synaptic plasticity
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Retinal pathological features and proteome signatures of Alzheimer’s disease
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“Given the role of microglia in shaping synaptic connections (Hong et al., 2016) it has to be considered that the excessive spine numbers may in part stem from altered interaction of FoxO-deficient neurons with microglia.”
An updated assessment of microglia depletion: current concepts and future directions
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On place and time: microglia in embryonic and perinatal brain development
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Phosphatidylserine Is the Signal for TAM Receptors and Their Ligands
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The special relationship: glia–neuron interactions in the neuroendocrine hypothalamus
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Alzheimer’s Retinopathy: Seeing Disease in the Eyes
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The Gut-Microglia Connection: Implications for Central Nervous System Diseases
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A microglia-cytokine axis to modulate synaptic connectivity and function
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Microglia: Brain cells on the move
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Gut microbiota–driven brain Aβ amyloidosis in mice requires microglia
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Self-citationNew tricks for an ancient system: Physiological and pathological roles of complement in the CNS
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Self-citationOligodendrocytes and Microglia: Key Players in Myelin Development, Damage and Repair
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Microglia in the developing retina
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Microglia ablation alleviates myelin-associated catatonic signs in mice
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Microglia Are Critical in Host Defense against Prion Disease
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Microglia: Phagocytosing to Clear, Sculpt, and Eliminate
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Microglial modulation of neuronal activity in the healthy brain
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New Insights into Microglia–Neuron Interactions: A Neuron’s Perspective
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Jung, H., Lee, D., You, H., Lee, M.-H., Kim, H., Cheong, E., & Um, J. W. (2023) · Scientific Reports · doi:10.1038/s41598-023-32798-9 · Cited by 102 · see citing works
Human-specific features of spatial gene expression and regulation in eight brain regionsPreprint
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Large-Scale Transcriptomics Studies Provide Insight Into Sex Differences in Depression
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Understanding the physical basis of memory: Molecular mechanisms of the engram
Luis, C. O. S., & Ryan, T. J. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101866 · Cited by 103 · see citing works
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- Authors
- Hong, S., Dissing-Olesen, L., & Stevens, B.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- Stevens, Beth
- Venue
- Current Opinion in Neurobiology
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 36
- Pages
- 128-134
- ISSN
- 0959-4388 (ISSN-L)
- PMC
- PMC5479435
- OpenAlex
- W2225188179
- Cited by
- 557
- References
- 79
- Citations by year
- 2026: 30 · 2025: 43 · 2024: 52 · 2023: 59 · 2022: 63 · 2021: 73 · 2020: 57 · 2019: 41 · 2018: 59 · 2017: 58 · 2016: 22
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Opinion in Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Lundbeck Foundation
- Alzheimer's Research Trust
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- microglia, synaptic pruning, Alzheimer's disease, synaptic loss, synaptic plasticity, cognitive impairment, neurodegeneration, brain development, neuroinflammation
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Neuronal Plasticity, Microglia, Genome-Wide Association Study
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