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Despite their clinical significance, the pathophysiological mechanisms underlying cerebral small vessel disease remain poorly understood owing to a lack of appropriate animal models.<\/jats:p>\n                  <jats:p>We performed targeted deletion of Col4a1 in brain microvessels of adult mice using brain endothelium-specific adeno-associated virus (AAV)-BR1 vectors with clustered regularly interspaced short palindromic repeats\/CRISPR-associated protein 9 (CRISPR\/Cas9). Eight-week-old Cas9 transgenic mice received retro-orbital injections of AAV-BR1 containing single guide RNA (sgRNA) targeting Col4a1 or control Rosa26 sequences. Animals underwent longitudinal behavioural testing, including novel object recognition, Y-maze and rotarod tests, over 6 months. Brain pathology was assessed using T2*-weighted MRI, histological analysis and electron microscopy.<\/jats:p>\n                  <jats:p>For human studies, we analysed MRI and genomic data from 836 participants from the BICWALZS biobank, examining associations between genetic variants and CMB burden using linear regression and \u03c72 analyses.<\/jats:p>\n                  <jats:p>T2*-weighted MRI revealed numerous CMBs with distributions remarkably similar to human CMBs, appearing within 3 months post-injection. CMB burden increased progressively over 6 months in a dose-dependent manner. Behaviourally, mice exhibited progressive cognitive decline and motor incoordination. Histological examinations revealed haemosiderin deposits corresponding to MRI-detected CMBs, without macroscopic intracerebral haemorrhage or white matter changes. Ultrastructural analysis demonstrated significant basement membrane thinning in Col4a1-depleted microvessels. CMB accumulation was associated with widespread astrocytic reactivity extending beyond microbleed sites, whereas microglial activation remained localized.<\/jats:p>\n                  <jats:p>In human subjects, we identified significant associations between four genetic variants of TIMP2, an endogenous inhibitor of the matrix-degrading enzyme MMP2 and CMB burden, with odds ratios of 1.50\u20131.96 for increased microbleed susceptibility.<\/jats:p>\n                  <jats:p>This work provides the first animal model demonstrating that selective disruption of collagen IV in adult brain microvessels is sufficient to generate CMBs with high penetrance and dose-dependent tunability. Our findings establish that basement membrane integrity is critical for preventing microbleed formation and suggest that dysregulated collagen IV homeostasis underlies sporadic human CMB development.<\/jats:p>","DOI":"10.1093\/brain\/awag048","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T12:43:07Z","timestamp":1770208987000},"page":"3566-3581","source":"Crossref","is-referenced-by-count":0,"title":["A novel mouse model of cerebral microbleeds by targeted\n                    <i>Col4a1<\/i>\n                    editing in adult brain microvessels"],"prefix":"10.1093","volume":"149","author":[{"given":"Hyunmi","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Brain Science, Ajou University School of Medicine , Suwon 16499 ,","place":["Republic of Korea"]},{"name":"AI-Superconvergence KIURI Translational Research Center, Ajou University School of Medicine , Suwon 16499 ,","place":["Republic of 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