Biology subjects

Koudelka, J.

Publications and source records attributed to Koudelka, J..

2 recordsLinked to original sources

bioRxiv2025

Prominent white matter related abnormalities associated with diverse molecular alterations in a mouse model of Col4a1 cerebral small vessel disease.

White matter abnormalities are a hallmark of cerebral small vessel disease (cSVD) and are closely linked to cognitive decline and dementia. However, despite their clinical importance, underlying mechanisms remain poorly understood. Collagen IV, encoded by genes COL4A1/COL4A2, is a major component of the basement membrane, a specialised extracellular matrix (ECM) structure. Mutations in these genes cause a genetic form of cSVD. We tested the hypothesis that ECM defects caused by a Col4a1 mutation lead to white matter pathology using an established mouse model of cSVD (Col4a1+/Svc). Behavioural testing with magnetic resonance diffusion tensor imaging, pathology and ultrastructural investigations of white matter were studied. The studies revealed that Col4a1+/Svc mice have cognitive impairments, reduced myelinating oligodendrocyte pools, axonal myelination defects, and altered white matter structural integrity. Proteomic analysis, of isolated white matter from Col4a1+/Svcmice, identified extensive changes to ECM composition and endoplasmic reticulum (ER) biology including ER stress induction. We also demonstrated that targeting protein folding to promote collagen secretion and reduce ER stress, increased myelinating oligodendrocytes and axon-glial integrity in Col4a1+/Svc mice. These data provide novel insight into the pathomolecular mechanisms of white matter abnormalities in cSVD and identify a modifiable pathway as a putative therapeutic target for cSVD.

neuroscience↗

bioRxiv2021

Pulsation changes link to impaired glymphatic function in a mouse model of vascular cognitive impairment

Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the glial-vascular unit and accumulation of amyloid-{beta} (A{beta}) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including A{beta} removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of A{beta}. Male wild- type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning and memory. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Since our findings show that BCAS may influence VCI by impaired glymphatic drainage and reduced vascular pulsation we propose that these additional targets need to be considered when treating VCI.

neuroscience↗