{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T14:35:19Z","timestamp":1793025319896,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,30]]},"group-title":"Neuroscience","reference-count":25,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["NS127344"],"award-info":[{"award-number":["NS127344"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NS124084"],"award-info":[{"award-number":["NS124084"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Huntington\u2019s disease (HD) is a neurodegenerative disorder driven by a CAG trinucleotide repeat expansion in the\n                  <jats:italic>huntingtin<\/jats:italic>\n                  (\n                  <jats:italic>HTT<\/jats:italic>\n                  ) gene, resulting in neuronal degeneration. While cell-autonomous mechanisms within neurons have been extensively characterized, how brain waste clearance pathways at the brain\u2019s 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\u207a Lyve1\u207a 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 drive 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, Acute BAMs depletion had no impact on microglial or astrocytic activation in the brain, demonstrating that the exacerbation of mHTT load is a byproduct of brain waste clearance dysfunction rather than gliosis. Together, our results indicate that BAMs are non-redundant regulators of CSF flow dynamics at the brain borders, offering a unique non-neuronal mechanism to mHTT accumulation and potential a therapeutic target to combat HD.\n                <\/jats:p>","DOI":"10.64898\/2026.09.24.754172","type":"posted-content","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:00:11Z","timestamp":1790805611000},"source":"Crossref","is-referenced-by-count":0,"title":["Depletion of border-associated macrophages impairs CSF flow and exacerbates extranuclear mutant Huntingtin aggregation in the zQ175DN mouse model of Huntington\u2019s disease"],"prefix":"10.64898","author":[{"given":"Yanli","family":"Jiang","sequence":"first","affiliation":[{"name":"Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul","family":"Sondawle","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Moniz","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Mu","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhen","family":"Duan","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, Maryland, USA"},{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"name":"Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026102607003886000_2026.09.24.754172v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90585-E"},{"issue":"1","key":"2026102607003886000_2026.09.24.754172v2.2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S1474-4422(10)70245-3","article-title":"Huntington\u2019s disease: from molecular pathogenesis to clinical treatment","volume":"10","year":"2011","journal-title":"The Lancet Neurology"},{"key":"2026102607003886000_2026.09.24.754172v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(22)00120-X"},{"key":"2026102607003886000_2026.09.24.754172v2.4","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003748&lt;\/otherinfo&gt;"},{"issue":"9","key":"2026102607003886000_2026.09.24.754172v2.5","doi-asserted-by":"crossref","first-page":"104987","DOI":"10.1016\/j.isci.2022.104987","article-title":"The glymphatic system: Current understanding and modeling","volume":"25","year":"2022","journal-title":"iScience"},{"issue":"1","key":"2026102607003886000_2026.09.24.754172v2.6","doi-asserted-by":"crossref","first-page":"4878","DOI":"10.1038\/s41467-018-07318-3","article-title":"Flow of cerebrospinal fluid is driven by arterial pulsations through perivascular channels","volume":"9","year":"2018","journal-title":"Nature Communications"},{"issue":"8","key":"2026102607003886000_2026.09.24.754172v2.7","first-page":"457","article-title":"Clearance of Alzheimer\u2019s amyloid-\u03b2; from basic science to clinical application","volume":"11","year":"2015","journal-title":"Nature Reviews Neurology"},{"key":"2026102607003886000_2026.09.24.754172v2.8","doi-asserted-by":"crossref","first-page":"102647","DOI":"10.1016\/j.coph.2026.102647","article-title":"Glymphatic dysfunction in neurodegeneration: From impaired clearance to mechanism-driven therapeutic innovation","volume":"89","year":"2026","journal-title":"Curr Opin Pharmacol"},{"issue":"7","key":"2026102607003886000_2026.09.24.754172v2.9","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1002\/acn3.70328","article-title":"Functional and Structural Evidence of Neurofluid Circuit Aberrations in Huntington Disease","volume":"13","year":"2026","journal-title":"Ann Clin Transl Neurol"},{"key":"2026102607003886000_2026.09.24.754172v2.10","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26749"},{"key":"2026102607003886000_2026.09.24.754172v2.11","doi-asserted-by":"crossref","unstructured":"Solomon, A. , et al., Multimodal Characterization of Glymphatic-Related Magnetic Resonance Imaging Markers in Huntington\u2019s Disease: A Multi-Cohort Retrospective Study. 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