Biology subjects

Son, S. J.

Publications and source records attributed to Son, S. J..

3 recordsLinked to original sources

bioRxiv2025

Novel mouse model of cerebral microbleeds created by Crispr/Cas9-mediated Col4a1 deletion in adult brain microvessels

Cerebral small vessel disease is a leading cause of cognitive decline and stroke in the elderly, with cerebral microbleeds (CMBs) as one of the key imaging biomarkers. Our understanding of its pathophysiology remains limited due to the lack of appropriate animal models. We report a novel mouse CMB model created by disrupting collagen IV, a core component of the vascular basement membrane (BM), specifically within brain microvessels. Targeted deletion of Col4a1 was achieved in adult mice using brain endothelial-specific AAV vectors with CRISPR/Cas9. MRI revealed numerous CMBs with distributions similar to those of human CMBs. CMB burden increased progressively over six months following Col4a1 deletion in a dose-dependent manner, accompanied by cognitive decline and motor incoordination. Histological examination revealed hemosiderin deposits corresponding to MRI-detected CMBs without evidence of macroscopic hemorrhage or white matter lesions, while ultrastructural analysis demonstrated significant BM thinning in Col4a1-depleted microvessels. Analysis of human MRI and genomic data identified significant associations between CMB susceptibility and genetic variants in TIMP2, an endogenous inhibitor of the matrix-degrading enzyme MMP2, underscoring the clinical relevance of our model. These findings establish a direct causal relationship between microvessel COL4A1 and CMB, suggesting that dysregulated collagen IV homeostasis in BM underlies CMB development.

neuroscience↗

bioRxiv2025

Periventricular Diffusivity Reflects APOE4-modulated Amyloid Accumulation and Cognitive Impairment in Alzheimers Continuum

BackgroundAltered glymphatic-related fluid dynamics are increasingly recognized as a key feature of Alzheimers disease (AD). We generalized an established diffusion imaging technique to estimate periventricular diffusivity (PVeD), hypothesizing that fast diffusion signals in the periventricular region can reflect amyloid-beta (A{beta}) deposition across the Alzheimers continuum. MethodsParticipants from two multi-site cohorts (n = 440 and 414), comprising cognitively unimpaired individuals, those with mild cognitive impairment, and patients with AD, were included. We tested and validated the association of PVeD with A{beta} burden and core AD characteristics. ResultsLower PVeD was extensively associated with greater A{beta} burden, neurodegeneration, cognitive impairment, and clinical severity. Importantly, the relationship between PVeD and A{beta} burden was significantly modulated by APOE4 status, with APOE4 carriers showing a stronger negative association. Baseline PVeD also predicted longitudinal cognitive decline. DiscussionThese findings suggest that periventricular fast diffusion signals can reflect APOE4-modulated A{beta} burden and cognitive decline in AD. Research-in-ContextO_ST_ABSSystematic reviewC_ST_ABSA comprehensive PubMed literature search indicates that fluid movement related to glymphatic activity assessed by diffusion tensor image analysis along the perivascular space (DTI-ALPS) is associated with amyloid-beta deposition in Alzheimers disease (AD). However, recent evidence underscores certain limitations of DTI-ALPS, suggesting that it may not fully capture the diffusion processes involved in amyloid clearance. Moreover, no previous studies have investigated the role of APOE4 in modulating the relationship between glymphatic-related fast diffusion signals and amyloid-beta deposition. InterpretationThe transverse diffusion process along the perivenous space in the periventricular region appears to reflect glymphatic-related dysfunction manifested by amyloid-beta deposition. Reduced periventricular diffusivity is associated with greater amyloid burden across the AD continuum. This association is notably enhanced in APOE4 carriers, who exhibit higher amyloid accumulation for a given reduction in the periventricular diffusivity. Besides, periventricular diffusivity is related to other pathological markers of AD, including clinical symptom severity and neurodegeneration, and may also predict subsequent cognitive decline. Future directionsAlthough diffusion-based neuroimaging metrics hold promise as surrogate imaging biomarkers for glymphatic-related activity, they do not comprehensively capture the complex fluid dynamics such as convective bulk flow within the glymphatic system. By leveraging multimodal neuroimaging techniques and advanced analytic approaches, future research can refine these metrics into more sensitive, non-invasive tools capable of evaluating fluid dynamics related to glymphatic dysfunction in AD.

neuroscience↗

bioRxiv2019

Sustained Ca2+ mobilizations: a quantitative approach to predict their importance in cell-cell communication and wound healing

Epithelial wound healing requires the coordination of cells to migrate as a unit over the basement membrane after injury. To understand the process of this coordinated movement, it is critical to study the dynamics of cell-cell communication. We developed a method to characterize the injury-induced sustained Ca2+ mobilizations that travel between cells for periods of time up to several hours. These events of communication are concentrated along the wound edge and are reduced in cells further away from the wound. Our goal was to delineate the role and contribution of these sustained mobilizations and using MATLAB analyses, we determined the probability of cell-cell communication events in in vitro models and ex vivo organ culture models. We demonstrated that the injury response was complex and represented the activation of a number of receptors. In addition, we found that pannexin channels mediated the cell-cell communication and motility. Furthermore, the sustained Ca2+ mobilizations are associated with changes in cell morphology and motility during wound healing. The results demonstrate that both purinoreceptors and pannexins regulate the sustained Ca2+ mobilization necessary for cell-cell communication in wound healing.

cell biology↗