Abstract
Purpose :
Aβ42, an end product of the amyloidogenic pathway, is a component of drusen in age-related macular degeneration (AMD) and of senile plaques in Alzheimer’s disease (AD). The 5xFAD mice, transgenic model carries mutations associated with early-onset familial AD, shows a retinal degenerative pathology that is similar to our well-characterized Adiponectin receptor 1 knock-out mice (Rice et al., 2015), which have shown many deficiencies in the retinal membrane phospholipid. In this study, we used the 5xFAD to investigate the membrane lipid profile of retina and retinal pigment epithelial layer to explain the degeneration in the eyes of these animals as well as to facilitate potential treatment.
Methods :
Retinas and RPEs from 6-month-old wild type and 5xFAD mice were isolated and subjected to LC-MS analysis. The amount for each phosphatidylcholine (PC) species was calculated as the % of the total PCs in each sample. Principal Component Analysis (PCA) and Random Forest (RF) classification were used to analyze the prevalent deficient PC. For analysis of fatty acids and their derivatives, six retinas or six eye cups containing RPE were pooled and subjected to LC-MS/MS analysis.
Results :
The 5xFAD showed a significative decrease of docosahexaenoic acid (DHA), and very long-chain polyunsaturated fatty acids (VLC-PUFAs) contained PCs in which PC54:12, PC56:12, PC58:12 (contains VLC-PUFAs and DHA), PC36:8, PC38:8, and PC44:12 (contains DHA) were detected as the most deficient component after PCA and RF analyses. In contrast, the AA-contained PCs including PC36:4, PC38:4, and PC36:5 were increased in the 5xFAD mouse retina. Furthermore, our data depicted that both free 32-6 and 34-6 VLC-PUFAs, which are derived from 54-12 and 56-12 PCs, were reduced in the 5xFAD mice as well. As a consequence, the abundance of 27-mono hydroxy 32-6 and 29-mono hydroxy 34-6, the two precursors of the novel class elovanoid (ELV) mediators, was low in the 5xFAD retina.
Conclusions :
These results suggested that the balance of AA, DHA, and VLC-PUFA was altered in the retina of 5xFAD mice. In addition to the insufficient abundance of VLC-PUFAs contained PCs in the 5xFAD, the inadequate amount of free VLC-PUFA and ELV precursors indicates a possible failure to make protective mediators that might be key to protecting photoreceptor cells from degeneration.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.