Clearance of lipid droplets by chimeric autophagy-tethering compound ameliorates the age-related macular degeneration phenotype in mice lacking APOE

ABSTRACT

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly, and there is currently no clinical treatment targeting the primary impairment of AMD. The earliest clinical hallmark of AMD is drusen, which are yellowish spots mainly composed of lipid droplets (LDs) accumulated under the retinal pigment epithelium (RPE). However, the potential pathogenic role of this excessive LD accumulation in AMD is yet to be determined, partially due to a lack of chemical tools to manipulate LDs specifically. Here, we employed our recently developed Lipid Droplets·AuTophagy Tethering Compounds (LD∙ATTECs) to degrade LDs and to evaluate its consequence on the AMD-like phenotypes in apoe^−/− (apolipoprotein E; B6/JGpt-Apoe^em1Cd82/Gpt) mouse model. apoe^−/− mice fed with high-fat diet (apoe^−/−-HFD) exhibited excessive LD accumulation in the retina, particularly with AMD-like phenotypes including RPE degeneration, Bruch’s membrane (BrM) thickening, drusen-like deposits, and photoreceptor dysfunction. LD·ATTEC treatment significantly cleared LDs in RPE/choroidal tissues without perturbing lipid synthesis-related proteins and rescued RPE degeneration and photoreceptor dysfunction in apoe^−/−-HFD mice. This observation implied a causal relationship between LD accumulation and AMD-relevant phenotypes. Mechanically, the apoe^−/−-HFD mice exhibited elevated oxidative stress and inflammatory signals, both of which were mitigated by the LD·ATTEC treatment. Collectively, this study demonstrated that LD accumulation was a trigger for the process of AMD and provided entry points for the treatment of the initial insult of AMD by degrading LDs.

Abbreviations: AMD: age-related macular degeneration; APOE: apolipoprotein E; ATTECs: autophagy-tethering compounds; BODIPY: boron-dipyrromethene; BrM: Bruch’s membrane; ERG: electroretinogram; HFD: high-fat diet; LD·ATTECs: Lipid Droplets·AuTophagy Tethering Compounds; LDs: lipid droplets; OA: oleic acid; OPL: outer plexiform layer; ROS: reactive oxygen species; RPE: retinal pigment epithelium

KEYWORDS:

• age-related macular degeneration
• autophagy-tethering compounds
• B6/JGpt-Apoe^em1Cd82/Gpt
• lipid droplets
• retinal pigment epithelium

Acknowledgements

We would like to thank Dr. Yu Ding for his earlier cooperative effort in conceptualizing LD·ATTEC.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2023.2220540

Additional information

Funding

The work was supported by the National Key Research and Development Program of China [2022YFC2703900]; Science and Technology Commission of Shanghai Municipality [20JC1410900]; Innovation Program of Shanghai Municipal Education Commission [2021-01-07-00-07-E00074]; Tencent Foundation, Xplorer Prize the Open Research Funds of the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University [303060202400375]; National Natural Science Foundation of China [81925012,882050008]; the New Cornerstone Science Foundation [NCI202242]; National Natural Science Foundation of China [82020108006, 81730025, 81670864, 81525006]; Excellent Academic Leaders of Shanghai [18×D1401000]; National Key Research and Development Program of China [2022YFC2703904]