Depletion of border-associated macrophages impairs CSF flow and exacerbates extranuclear mutant Huntingtin aggregation in the zQ175DN mouse model of Huntington disease
Huntington disease (HD) is a fatal, neurodegenerative disorder driven by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, resulting in neuronal toxicity and brain atrophy, initially in the most vulnerable brain region striatum and expanding to the cortex and other brain regions along disease progression. While cell-autonomous mechanisms within neurons have been extensively…
Huntington's disease (HD) is a progressive neurodegenerative condition caused by a mutation in the huntingtin (HTT) gene, leading to neuronal loss and brain atrophy, particularly in the striatum and later spreading to other brain regions. While the role of cellular mechanisms within neurons has been thoroughly researched, the impact of brain waste clearance pathways at the borders of the brain during disease progression has remained unclear.
In this study, researchers examined the structural and functional changes in border-associated macrophages (BAMs) within the zQ175DN mouse model of HD. Immunohistochemical examination showed a progressive decrease in the CD206 Lyve1 subset of leptomeningeal BAMs in 16-month-old zQ175DN mice, which was closely associated with a significant decline in cerebrospinal fluid (CSF) flow velocity and perivascular influx.
To investigate the potential role of BAMs in CSF flow regulation, researchers selectively depleted these macrophages in 10-month-old zQ175DN mice using intracerebroventricular (i.c.v.) injection of clodronate liposomes (CLO). The depletion of BAMs resulted in a substantial worsening of overall CSF dynamic impairment, indicated by reduced CSF fluorescent tracer distribution across perivascular parenchymal channels.
Importantly, this failure in CSF flow led to a marked accumulation of extranuclear mutant huntingtin (mHTT) aggregates in the brains of the zQ175DN HD mice, while intranuclear inclusions remained relatively unchanged. Notably, the depletion of BAMs did not affect microglial or astrocytic gliosis in the brain, indicating that the exacerbated accumulation of mHTT aggregates was a consequence of impaired brain waste clearance.
The findings of this research suggest that BAMs play a critical, non-redundant role in regulating CSF flow dynamics at the borders of the brain, offering a novel and unique target for therapeutic intervention in the management of HD.
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