Microglial and Astrocytic Responses in the Human Midcingulate Cortex in Huntington's Disease

Abstract

Huntington's disease patients can present with variable difficulties of motor functioning, mood, and cognition. Neurodegeneration occurs in the anterior cingulate cortex of some Huntington's disease patients and is linked to the presentation of mood symptomatology. Neuroinflammation, perpetrated by activated microglia and astrocytes, has been reported in Huntington's disease and may contribute to disease progression and presentation.ObjectiveThis study sought to quantify the density of mutant huntingtin protein and neuroinflammatory glial changes in the midcingulate cortex of post‐mortem Huntington's disease patients and determine if either correlates with the presentation of mood, motor, or mixed symptomatology.MethodsFree‐floating immunohistochemistry quantified 1C2 immunolabeling density as an indicative marker of mutant huntingtin protein, and protein and morphological markers of astrocyte (EAAT2, Cx43, GFAP) and microglial (Iba1, HLA‐DP/DQ/DR) activation. Relationships between the level of microglial activation, mutant huntingtin burden, and case characteristics were explored using correlative analysis.ResultsWe report alterations in activated microglia number and morphology in the midcingulate cortex of Huntington's disease cases with predominant mood symptomatology. An increased proportion of activated microglia was observed in the midcingulate of all Huntington's disease cases and positively correlated with 1C2 burden. Alterations in the astrocytic glutamate transporter EAAT2 were observed in the midcingulate cortex of patients associated with mood symptoms.InterpretationThis study presents pathological changes in microglia and astrocytes in the midcingulate cortex in Huntington's disease, which coincide with mood symptom presentation. These findings further the understanding of neuroinflammation in Huntington's disease, a necessary step for developing inflammation‐targeted therapeutics.This article is protected by copyright. All rights reserved.

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“…Additionally, thymol has been associated with reduced expression of glial fibrillary acidic protein (GFAP), an indicator of neuroinflammation. 23,71,75 The expression of GFAP could be regulated by NF-κB at the transcriptional level. 76 This further demonstrated the inhibition of NF-κB plays a central role for thymol against neuroinflammation.…”

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“…Activated glial cell counts were measured by selecting a particle size range with ImageJ Fiji 1.47 (U.S. National Institutes of Health, Bethesda, MD, USA). Cells with activated morphology tend to be larger, with a larger cell body and an increased number of primary processes [31,[68][69][70]. Particles between 1 and 699 pixels were classified as small particles, and particles between 700 and 20,000 pixels were classified as large particles and recognized as activated cells for both Iba-1 (microglia) and GFAP (astrocytes).…”

“…The role and activation of these cells are well characterized in the perpetuation of chronic inflammation but also their beneficial actions in health and disease [28,29]. Microglia and astrocyte reactivity are prevalent features of the neuroinflammatory processes that begin during the early stages of the EAE and MS and is characterized by molecular and morphological changes [26,[30][31][32][33].…”