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

Abstract

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