Biology subjects

Corson, T.

Publications and source records attributed to Corson, T..

2 recordsLinked to original sources

bioRxiv2025

M&uumlller glial Kir4.1 channel Dysfunction in APOE4-KI model of Alzheimer's disease

Alzheimers disease (AD), particularly late-onset AD (LOAD), affects millions worldwide, with the apolipoprotein {varepsilon}4 (APOE4) allele being a significant genetic risk factor. Retinal abnormalities are a hallmark of LOAD, and our recent study demonstrated significant age-related retinal impairments in APOE4-knock-in (KI) mice, highlighting that retinal impairments occur before the onset of cognitive decline in these mice. Muller cells (MCs), key retinal glia, are vital for retinal health, and their dysfunction may contribute to retinal impairments seen in AD. MCs maintain potassium balance via specialized inwardly rectifying K+ channels 4.1 (Kir4.1). This study posits that Kir4.1 channels will be impaired in APOE4-KI, resulting in MC dysfunction. Additionally, we demonstrate that MC dysfunction in APOE4-KI stems from alterations in mitochondrial dynamics and oxidative stress. Kir4.1 expression and function were studied using immunofluorescence and through the whole-cell voltage clamp, respectively. In parallel, rat Muller cells (rMC-1) were used to create an in vitro model for further mechanistic studies. Mitoquinol (MitoQ) was used to evaluate its potential to mitigate APOE4-induced deficits. APOE4 retinas and APOE4-transfected rMC-1 significantly reduced Kir4.1 expression, K+ buffering capacity, and increased mitochondrial damage. APOE4-transfected rMC-1 showed reduced mitochondrial membrane potential ({Delta}{Psi}m) and increased mitochondrial reactive oxygen species (ROS). MitoQ treatment significantly reduced mitochondrial ROS and restored Kir4.1 expression in APOE4-expressing cells. Our results demonstrate that APOE4 causes mitochondrial dysfunction and MC impairment, which may contribute to retinal pathology in AD. MitoQ restored mitochondrial health and Kir4.1 expression in APOE4-expressing rMC-1, suggesting targeting mitochondria may offer a promising therapeutic strategy for AD. Main PointsO_LIAPOE4 impairs Muller cell health by reducing Kir4.1 expression and buffering. C_LIO_LIAPOE4 causes mitochondrial dysfunction with decreased {Delta}{Psi}m and increased ROS. C_LIO_LIMitoQ restores Kir4.1 expression and reduces ROS in APOE4-transfected cells. C_LI

neuroscience↗

bioRxiv2019

Calcitriol and Non-Calcemic Vitamin D Analogue, 22 Oxacalcitriol, Attenuate Developmental and Pathological Ocular Angiogenesis Ex Vivo and In Vivo

Aberrant ocular blood vessel growth can underpin vision loss in leading causes of blindness, including neovascular age-related macular degeneration, retinopathy of prematurity and proliferative diabetic retinopathy. Current pharmacological interventions require repeated invasive administrations, lack efficacy in some patients and are associated with poor patient compliance and tachyphylaxis. Small molecule vitamin D has de novo pro-differentiative, anti-proliferative, immunomodulatory, pro-apoptotic and anti-angiogenic properties. Here, our aim was to validate the anti-angiogenic activity of the biologically active form of vitamin D, calcitriol, and a selected vitamin D analogue, 22-oxacalcitriol, across a range of ocular angiogenesis models.\n\nFirst, we validated the anti-angiogenic activity of calcitriol, showing calcitriol to significantly inhibit choroidal sprouting in an ex vivo mouse choroidal fragment sprouting assay. Viability studies in human RPE cell line, ARPE-19, suggested non-calcemic vitamin D analogues have the least off-target anti-proliferative activity compared to calcitriol and additional analogues. Thereafter, the ocular anti-angiogenic activity of non-calcemic vitamin D analogue, 22-oxacalcitriol, was demonstrated in the ex vivo mouse choroidal fragment sprouting assay. In zebrafish larvae, 22-oxacalcitriol was anti-angiogenic, inducing a dose-dependent reduction in choriocapillary angiogenesis. Inhibition of mouse retinal vasculature development was not induced by systemically delivered calcitriol. However, both calcitriol and 22-oxacalcitriol administered intraperitoneally significantly attenuate choroidal neovascularisation lesion volume in the laser-induced CNV mouse model. 22-oxacalcitriol presented with a more favourable safety profile than calcitriol.\n\nIn summary, calcitriol and 22-oxacalcitriol attenuate ex vivo and in vivo choroidal vasculature angiogenesis. Vitamin D has potential as a preventative or interventional treatment for ophthalmic neovascular indications.

pharmacology and toxicology↗