Abstract
Purpose :
Non-human primates (NHP) are superb animal models of age-related macular degeneration (AMD) because they possess a macula and spontaneously develop sub-retinal pigment epithelial (sub-RPE) lipid deposits resembling drusen in AMD. The purpose of this study is to characterize the plasma lipidomic profile of rhesus macaques with drusen to determine if they share similar metabolite associations with human AMD.
Methods :
We collected fasting plasma samples from 122 aged rhesus macaques (age 19.1± 2.83 years) which were phenotypically characterized by clinical ophthalmic examination, color fundus photographs, and spectra-domain optical coherence tomography (OCT) imaging. Animals were classified based on the presence of soft drusen (small, medium, large), drusenoid punctate lesions, or normal controls. 8 drusen primates underwent 6 month of high fat diet. Untargeted lipidomics analysis was performed using ultra-high performance liquid chromatography (LC) coupled to high-resolution mass spectrometry (MS).
Results :
We identified 25 of 122 (20%) macaques with soft drusen (mild 13, moderate 12, severe 1), and 22 of 122 (18%) with punctate lesions. Soft drusen were found to consist of sub-RPE lipid deposits, while punctate lesions were lipid-laden RPE cells with intracellular lipid accumulations. A total of 314 lipids were annotated with high confidence by matching their precursor mass-to-charge ratio, isotope distribution, and tandem mass spectra against database. To achieve a comprehensive profiling, we annotated 3 classes of lipids including Phosphatidylcholine (PC), Glycerophosphoethanolamines (PE), Glycerophosphocolines (LPC) that belong to the glycerophospholipid pathway. Lipid metabolites with significant changes in PC 34:2 |PC 16:0_18:2 (2.4 fold increase, p=0.018) and PE 38:5| PEO18:1_20:4 (3 fold decrease, p=0.018) in soft drusen versus control; and in LPC 16:1/0:0 (2.6 fold increased, p=0.034), PC 34:2 |PC 16:0_18:2 (1.8 fold increase, p=0.0090), and PC 36:2 |PC 18:0_18:2 (1.9 fold increase, p=0.0387) in moderate-severe drusen versus control. Drusenoid punctate lesions and high fat diet in drusen had no significant metabolites alterations.
Conclusions :
The glycerophospholipid pathway is associated with age-related drusen in NHPs and with patients with AMD, suggesting similar pathogenic mechanisms between NHP drusen and human AMD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.