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Updated: Jun 2, 2026
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Published on: March 11, 2020
Activated microglia proliferate at neurites of mutant huntingtin-expressing neurons
Andrew D Kraft1, Linda S Kaltenbach, Donald C Lo
1Neurotoxicology Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Abstract:
In Huntington's disease (HD), mutated huntingtin (mhtt) causes striatal neurodegeneration which is paralleled by elevated microglia cell numbers. In vitro corticostriatal slice and primary neuronal culture models, in which neuronal expression of mhtt fragments drives HD-like neurotoxicity, were employed to examine wild type microglia during both the initiation and progression of neuronal pathology. As neuronal pathology progressed, microglia initially localized in the vicinity of neurons expressing mhtt fragments increased in number, demonstrated morphological evidence of activation, and expressed the proliferation marker, Ki67. These microglia were positioned along irregular neurites, but did not localize with mhtt inclusions nor exacerbate mhtt fragment-induced neurotoxicity. Prior to neuronal pathology, microglia upregulated ionized calcium binding adaptor molecule 1 (Iba1), signaling a functional shift. With neurodegeneration, interleukin-6 and complement component 1q were increased. The results suggest a stimulatory, proliferative signal for microglia present at the onset of mhtt fragment-induced neurodegeneration. Thus, microglia effect a localized inflammatory response to neuronal mhtt expression that may serve to direct microglial removal of dysfunctional neurites or aberrant synapses, as is required for reparative actions in vivo.
Insights
Microglia proliferate and activate early in Huntington's disease (HD) models, responding to mutated huntingtin (mhtt) expression before significant neurodegeneration. This suggests microglia initiate a localized inflammatory response to clear damaged neuronal components.
Area of Science:
- Neuroscience
- Cell Biology
- Neuroinflammation
Background:
- Huntington's disease (HD) is characterized by striatal neurodegeneration.
- Mutated huntingtin (mhtt) expression drives this neurotoxicity.
- Microglia numbers are elevated in HD, but their role during early pathology is unclear.
Purpose of the Study:
- To investigate the behavior and activation state of microglia during the initiation and progression of neurodegeneration in in vitro HD models.
- To understand the early microglial response to neuronal mhtt expression.
Main Methods:
- Utilized in vitro corticostriatal slice and primary neuronal culture models expressing mhtt fragments.
- Examined microglia localization, morphology, proliferation (Ki67), and expression of inflammatory markers (Iba1, IL-6, C1q).
Main Results:
- Microglia increased in number, activated morphologically, and proliferated (Ki67+) near neurons with mhtt fragments as pathology progressed.
- Activated microglia localized along irregular neurites but not mhtt inclusions.
- Upregulation of Iba1 preceded neurodegeneration, indicating an early functional shift.
- Interleukin-6 and complement component 1q increased with neurodegeneration.
Conclusions:
- A stimulatory and proliferative signal for microglia is present at the onset of mhtt-induced neurodegeneration.
- Microglia mount a localized inflammatory response to neuronal mhtt expression.
- This response may facilitate the clearance of dysfunctional neurites or synapses, aiding in vivo repair.
