ArticleNature medicine2023
Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington's disease.
Article in Nature medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 102 papers.
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Who cites it
102 citing papers in PubMed, 142 citations in OpenAlex.
- Article
- C3 and CD47 mediate sensory-motor circuit refinement during spinal cord development.The Journal of experimental medicine · 2026Article
- Huntingtin Aggregate-Responsive Autophagy Gene Circuit Mitigates Disease Pathology in R6/2 Mice.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Chemically modified CRISPR enzymes for multi-organ genome editingbioRxiv : the preprint server for biology · 2026Article
- Neuroimmune interactions: from molecular mechanisms to therapeutic targets.Molecular biomedicine · 2026Review
- Microglia and neuroinflammation: An in-depth analysis from functional diversity to disease mechanisms.Clinical and translational medicine · 2026Review
- BDKRB2 upregulation by dystrophic microglia drives pain hypersensitivity in aged mice.Acta pharmacologica Sinica · 2026Article
- Complement contributes to hyperactive behavior in the 16p11.2 hemideletion mouse model.Brain, behavior, and immunity · 2026Article
- Unraveling Neurodegeneration: Common Molecular Mechanisms and Novel Therapeutic Concepts in Major Neurodegenerative Disorders.Brain and behavior · 2026Review
- Oligodendroglial Mutant Huntingtin Contributes to Neuroinflammation in Huntington's Disease Mice.Neuroscience bulletin · 2026Article
- scVIP: personalized modeling of single-cell transcriptomes for developmental and disease phenotypes.bioRxiv : the preprint server for biology · 2026Article
- Csf1r-mediated depletion of myeloid cells prevents dopaminergic neuron loss during chronic colitis.Journal of neuroinflammation · 2026Article
- Exploration of the genetic neuroinflammatory environment in the human midcingulate cortex in Huntington's disease.Communications medicine · 2026Article
- An Open-Label Phase 1b Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of ANX005 in Patients with Huntington's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Shifting From Systemic to Precision-Targeted Complement Therapies: Opportunities and Hurdles.European journal of immunology · 2026Review
- Single-cell transcriptomics and mouse model phenotyping for biomarker screen of peripheral blood in Huntington's disease.Scientific reports · 2026Article
- Cannabidiol and other non-psychotropic cannabinoids from Cannabis sativa as therapeutics for microglial-mediated neuroinflammation and neurodegeneration.Journal of cannabis research · 2026Review
- Three cryo-EM structures of complement C3d-bound αScience advances · 2026Article
- Microglial Plasticity in Vascular Dementia: Mechanisms and Therapeutic Reprogramming.International journal of molecular sciences · 2026Review
- TREM2-mediated microglial phagocytosis of inhibitory synapses contributes to prolonged FS-induced epileptogenesis.Cell death discovery · 2026Article
42 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
15 authors at 6 institutions in 2 countries.
Funding
Abstract
Huntington's disease (HD) is a devastating monogenic neurodegenerative disease characterized by early, selective pathology in the basal ganglia despite the ubiquitous expression of mutant huntingtin. The molecular mechanisms underlying this region-specific neuronal degeneration and how these relate to the development of early cognitive phenotypes are poorly understood. Here we show that there is selective loss of synaptic connections between the cortex and striatum in postmortem tissue from patients with HD that is associated with the increased activation and localization of complement proteins, innate immune molecules, to these synaptic elements. We also found that levels of these secreted innate immune molecules are elevated in the cerebrospinal fluid of premanifest HD patients and correlate with established measures of disease burden.In preclinical genetic models of HD, we show that complement proteins mediate the selective elimination of corticostriatal synapses at an early stage in disease pathogenesis, marking them for removal by microglia, the brain's resident macrophage population. This process requires mutant huntingtin to be expressed in both cortical and striatal neurons. Inhibition of this complement-dependent elimination mechanism through administration of a therapeutically relevant C1q function-blocking antibody or genetic ablation of a complement receptor on microglia prevented synapse loss, increased excitatory input to the striatum and rescued the early development of visual discrimination learning and cognitive flexibility deficits in these models. Together, our findings implicate microglia and the complement cascade in the selective, early degeneration of corticostriatal synapses and the development of cognitive deficits in presymptomatic HD; they also provide new preclinical data to support complement as a therapeutic target for early intervention.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.