By analyzing human samples and multiple mouse models of Huntington’s disease, we found that complement proteins and microglia mediate early and selective loss of corticostriatal synapses. Strategies that block this process can reduce synaptic loss, increase excitatory input to the striatum and prevent the development of cognitive deficits in mice.
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References
Veldman, M. B. & Yang, X. W. Molecular insights into cortico-striatal miscommunications in Huntington’s disease. Curr. Opin. Neurobiol. 48, 79–89 (2018). This review article details HD-related pathologies in the corticostriatal pathway and speculates on how they might arise.
Crotti, A. & Glass, C. K. The choreography of neuroinflammation in Huntington’s disease. Trends Immunol. 36, 364–373 (2015). This review article is on immune system dysregulation in HD.
Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012). This paper demonstrates the role of complement and microglia in mediating synaptic elimination during visual system development.
Delva, A., Michiels, L., Koole, M., Van Laere, K. & Vandenberghe, W. Synaptic damage and its clinical correlates in people with early Huntington disease: a PET study. Neurology 98, e83–e94 (2022). This paper shows selective reduction in a presynaptic protein in the caudate and putamen of pre-symptomatic patients with HD.
Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016). This paper shows that complement and microglia contribute to synapse loss in mouse models of Alzheimer’s disease.
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This is a summary of: Wilton, D. K. et al. Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease. Nat. Med. https://doi.org/10.1038/s41591-023-02566-3 (2023).
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Innate immune mechanisms mediate loss of corticostriatal synapses in Huntington’s disease. Nat Med 29, 2718–2719 (2023). https://doi.org/10.1038/s41591-023-02616-w
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DOI: https://doi.org/10.1038/s41591-023-02616-w
