Non-invasive optical imaging of retinal Aβ plaques using curcumin loaded polymeric micelles in APPswe/PS1ΔE9 transgenic mice for the diagnosis of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease clinically characterized by impaired memory and progressive cognitive decline. Despite the advances in AD research, an effective method to timely diagnose AD has remained elusive, and until now, most AD patients receive the available symptomatic treatments late. Although the pathological hallmarks of AD have been traditionally described in the brain, recent studies have shown similar pathological changes in the retina which is developmentally an extension of the forebrain. Interestingly, retinal beta-amyloid (Aβ) accumulation preceded that of the brain in a transgenic mouse model of AD. In the quest of finding an early reliable biomarker for AD, researchers have targeted the optical imaging of retinal Aβ plaques as a method of diagnosing AD. One promising polyphenol compound that has found application in this area is curcumin due to its natural binding affinity to Aβ fibrils and oligomers while giving out a strong fluorescence signal. However, the clinical applications of curcumin have been difficult due to problems related to its bioavailability and retention in the body since it is a hydrophobic molecule. To address these limitations, we herein report the development of anionic and water-soluble DSPE-PEG₂₀₀₀ curcumin polymeric micelles (also referred to as curcumin micelles) that can label both brain and retinal Aβ plaques ex vivo. Following their intravitreal injection in the APP_swe/PS1_ΔE9 transgenic mouse model of AD, green-labeled retinal deposits were optically imaged live using a rodent retinal microscope. Furthermore, these micelles had excellent intraocular biocompatibility, low hemolytic ratio, and were safe for use in two key retinal cell lines (ARPE-19 and 661W cells). Taken together, these findings provide an alternative insight into the optical imaging of Aβ plaques for the diagnosis of AD using the eyes. More importantly, this study can be translated to humans in the future to improve on early diagnosis and timely management of the disease.