Mu, E. | bioRxiv Science

bioRxiv2026

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 characterized, how brain waste clearance pathways at the brain's borders change during disease progression remains poorly understood. In this study, we investigated the structural and functional adaptations of border-associated macrophages (BAMs) in the zQ175DN knock-in mouse model of HD. Immunohistochemical analysis revealed an age-dependent, selective reduction in the CD206 Lyve1 subset of leptomeningeal BAMs in 16-month-old zQ175DN mice, which tightly correlated with a profound impairment in cerebrospinal fluid (CSF) flow velocity and perivascular influx. To determine whether BAMs actively drives this CSF flow, we selectively depleted these populations of macrophages in 10-month-old zQ175DN mice via intracerebroventricular (i.c.v.) injection of clodronate liposomes (CLO). Chemical ablation of BAMs significantly exacerbated global CSF dynamic impairment, indicted by decreasing CSF fluorescent tracer distribution across perivascular parenchymal channels. Crucially, this CSF flow failure resulted in a marked accumulation of extranuclear mutant huntingtin (mHTT) aggregates in the zQ175DN HD mouse brain, while intranuclear inclusions were not significantly altered. Furthermore, BAMs depletion did not alter microglial or astrocytic gliosis in the brain, demonstrating that the exacerbation of mHTT load is a byproduct of brain waste clearance dysfunction. Together, our results indicate that BAMs are non-redundant regulators of CSF flow dynamics at the brain borders, offering a unique non-neuronal therapeutic target to combat HD.

neuroscience↗

bioRxiv2021

Red backgrounds have different effects on electrophysiological responses to fearful faces in groups with low and high autistic tendency

Visual processing differences in the magnocellular pathway have been reported across the autistic spectrum. On the basis that the firing of primate Type IV magnocellular cells is suppressed by diffuse red backgrounds, several groups have used red backgrounds as a means to investigate magnocellular contributions to visual processing in humans. Here, we measured emotional identification accuracy, and compared the P100 and N170 responses from groups with low (n=21; AQ<11) and high (n=22; AQ>22) Autism Spectrum Quotient (AQ) scores, in response to low (LSF) and high (HSF) spatially filtered fearful and neutral face stimuli presented on red and green backgrounds. For the LSF stimuli, the low AQ group correctly identified fearful expressions more often when presented on a red compared to a green background. The low AQ group also showed red backgrounds reduced the effect of LSF fearful expressions on P100 amplitudes. In contrast, the high AQ group showed that background colour did not significantly alter P100 responses to LSF stimuli. Interestingly, red background reduced the effects of HSF stimuli for the high AQ group. The effects of background color on LSF and HSF facial emotion responses were not evident for the N170 component. Our findings suggest that presenting face stimuli on a red background alters both magnocellular and parvocellular contributions to the P100 waveform, and that these effects differ for groups with low and high autistic tendencies. In addition, a theoretical model for explaining the temporal differences in facial emotion processing for low and high AQ groups is proposed.

neuroscience↗