Abstract
Purpose :
R-carvedilol suppresses neuronal hyperactivity early in the progression of experimental Alzheimer’s disease (AD), modifying cognitive trajectory but not β-amyloid plaque load in the brain. It is unclear if R-carvedilol can correct prodromal visual performance declines and rod photoreceptor hyperactivity in a preclinical AD model, the hypothesis tested herein.
Methods :
Light-adapted wildtype (WT) and 5xFAD C57BL/6J (B6J) mice were treated with either R-carvedilol or vehicle (0.01% DMSO) added to the drinking water between 3 and 4 mo of age. Visual performance indices were assessed by optokinetic tracking (OKT). We further measured i) the thickness of the external limiting membrane - retinal pigment epithelium (ELM-RPE) as a proxy for energy-dependent pH-triggered water removal, and ii) an index of mitochondrial configuration within photoreceptors measured from the profile shape aspect ratio (MCP/AR) of the hyperreflective band posterior to the ELM. Retinal laminar thicknesses were also evaluated.
Results :
Untreated 5xFAD mice showed lower-than-normal contrast sensitivity, intact acuity, contracted ELM-RPE thickness on the superior side but not inferior side, and greater-than-normal MCP/AR on both sides. R-carvedilol and DMSO each corrected visual performance and ELM-RPE thickness abnormalities, while supernormal MCP/AR was unresponsive to either drug. Modest thinning of the outer nuclear and inner nuclear layers in the 5xFAD mice were not corrected by either R-carvedilol or DMSO.
Conclusions :
Notably, R-carvedilol and DMSO vehicle were similarly beneficial. These results raise the possibility that very low doses of DMSO per se are therapeutic during prodromal Alzheimer’s disease.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.