Douglas B. Gould

The first Vascular Contributions to Cognitive Impairment and Dementia (VCID) Workshop, held on May12-16, 2025 at The Jackson Laboratory, provided scientific content and career development training in the latest developments in VCID and Alzheimer’s Disease (AD) and related dementia (ADRD). The Workshop aimed to foster interdisciplinary collaborations and empower the next generation of diverse scientists to advance ADRD research from mechanism to intervention. The meeting placed a strong emphasis on neurovascular pathology, its central role in ADRD pathogenesis, its modulation by both central and peripheral factors, and the critical need to dissect the mechanistic basis of VCID through experimental models. The workshop included talks from both faculty and trainees and was bookended by two keynote addresses by Drs. Donna Wilcock and Costantino Iadecola, leaders and pioneers in the VCID field. The second VCID workshop is planned for April 28-May 1, 2026, to be held at Washington University in St. Louis.

Introduction: Cerebral small vessel disease (cSVD) is a leading cause of stroke and vascular contributions to cognitive impairment and dementia (VCID). Studying monogenic forms of cSVD can elucidate molecular pathways that are dysfunctional in the common sporadic forms and may serve as potential therapeutic targets. Mutations in COL4A1 and COL4A2 cause highly penetrant cSVD as part of the multisystem disorder known as Gould syndrome, which includes cerebrovascular manifestations such as porencephaly, early-onset stroke, leukoencephalopathy, and intracerebral hemorrhage (ICH). Methods: To investigate how allelic heterogeneity influences cerebrovascular phenotypes, we examined five Col4a1 mutant mouse strains that collectively model the clinical spectrum of Gould syndrome. Each strain underwent multimodal magnetic resonance imaging (MRI) at 14.1 Tesla to assess radiological features characteristic of cSVD. Results: Multimodal MRI successfully identified typical cSVD-associated lesions across all Col4a1 mutant strains. The imaging revealed heterogeneous expressivity among the allelic variants in terms of lesion prevalence, size, and number. Furthermore, analysis across strains identified brain regions that were consistently more vulnerable to cSVD-related lesions. Discussion: These findings demonstrate that high-field multimodal MRI can sensitively detect and differentiate cerebrovascular abnormalities among Col4a1 mutant mouse models of Gould syndrome. The approach provides a powerful, noninvasive platform for assessing genotype–phenotype relationships and for identifying brain regions at heightened risk in cSVD, supporting its potential use in early diagnosis and mechanistic studies of vascular pathology.

Collagen IV is a basement membrane component that is encoded by six genes in mammals (COL4Α1–COL4A6). The α-chains encoded by these genes assemble into three known heterotrimers — collagen α1α1α2(IV), α3α4α5(IV) and α5α5α6(IV) — that provide structure and act as multifunctional signalling platforms. The ancestral collagen superfamily members collagen alpha-1(IV) chain (COL4Α1) and collagen alpha-2(IV) chain (COL4Α2) are present throughout the animal kingdom and in all developing and most mature mammalian tissues. Consistent with this broad distribution, variants in COL4A1 and COL4A2 cause a congenital multisystem disorder called Gould syndrome (GS), which is characterized by cerebral, ocular, muscular and kidney defects. The main clinical consequences involve the cerebral vasculature (porencephaly, small-vessel disease, leukoencephalopathy and intracerebral haemorrhage). However, the full clinical spectrum, including the organs affected and acquired phenotypes such as vascular dementia, is still being defined. By contrast, variants in COL4A3, COL4A4 or COL4A5 cause Alport syndrome (AS), a disorder of variable severity that affects the kidney, ear and eye. AS nephropathies often progress from haematuria to proteinuria, renal impairment and kidney failure. The auditory features include sensorineural hearing loss, whereas the ocular features comprise corneal dystrophy, lenticonus, dot-and-fleck retinopathy and maculopathy. Although GS and AS have little clinical resemblance, the high conservation of the genes and proteins suggests common elements of underlying pathophysiology. Conventional therapies that modify haemodynamics have lengthened the time to kidney failure for patients living with AS. However, no curative or mechanism-based interventions exist for GS. Gene-editing approaches hold promise for both disorders.

Background: The COL4A1 and COL4A2 genes encode the alpha-1 and alpha-2 chains of type IV collagen, which are fundamental components of the basement membrane, playing key roles in both structural support and cellular regulation

Gould syndrome is caused by mutations in the genes encoding collagen IV alpha 1 (COL4A1) and 2 (COL4A2)—fundamental basement membrane components that form collagen α1α1α2(IV) heterotrimers

Basement membranes (BMs) are specialized extracellular matrix (ECM) structures essential for organ morphogenesis, architecture, and function. BM composition and properties vary between tissues, developmental stages, and disease states, and there is only a rudimentary understanding of BM dynamics. Here, we introduce a versatile mouse model carrying a multifunctional dual-color fluorescence tagged allele with knockout potential for the fundamental BM component type IV collagen alpha 1 (COL4A1). This allele enables the characterization of cell type- and time-specific contributions to BMs and the generation of a conditional Col4a1 null allele. We demonstrate the utility of this unique genetic resource in providing clinically relevant insights for individuals with Gould syndrome – a multisystem disorder caused by COL4A1 and COL4A2 mutations. We show active COL4A1 turnover in postnatal cerebrovascular BMs, identifying a potential interventional window for cerebrovascular manifestations associated with Gould syndrome. We also demonstrate that heterozygous Col4a1 deletion is significantly less pathogenic than dominant Col4a1 missense mutations, which has important implications for gene therapy.

Purpose: Mutations in the genes encoding type IV collagen alpha 1 (COL4A1) and alpha 2 (COL4A2) cause a multisystem disorder that includes ocular anterior segment dysgenesis (ASD) and glaucoma. We previously showed that transforming growth factor beta (TGFβ) signaling was elevated in developing anterior segments from Col4a1 mutant mice and that reducing TGFβ signaling ameliorated ASD, supporting a role for the TGFβ pathway in disease pathogenesis. Here, we tested whether altered TGFβ signaling also contributes to glaucoma-related phenotypes in Col4a1 mutant mice. Methods: To test the role of TGFβ signaling in glaucoma-relevant phenotypes, we genetically reduced TGFβ signaling using mice with mutated Tgfbr2, which encodes the common receptor for all TGFβ ligands in Col4a1^+/G1344D mice. We performed slit-lamp biomicroscopy and optical coherence tomography for qualitative and quantitative analyses of anterior and posterior ocular segments, histological analyses of ocular tissues and optic nerves, and intraocular pressure assessments using rebound tonometry. Results: Col4a1^+/G1344D mice showed defects of the ocular drainage structures, including iridocorneal adhesions, and phenotypes consistent with glaucomatous neurodegeneration, including thinning of the nerve fiber layer, retinal ganglion cell loss, optic nerve head excavation, and optic nerve degeneration. We found that reducing TGFβ receptor 2 (TGFBR2) was protective for ASD, ameliorated ocular drainage structure defects, and protected against glaucomatous neurodegeneration in Col4a1^+/G1344D mice. Conclusions: Our results suggest that elevated TGFβ signaling contributes to glaucomatous neurodegeneration in Col4a1 mutant mice.