Abstract
Purpose :
Apolipoprotein E (ApoE) is a protein that regulates lipid homeostasis. In the central nervous system, astrocytes express the most ApoE, followed by microglia. This study investigated the role of ApoE in the pathogeneses of age-related macular degeneration (AMD) and Alzheimer’s disease (AD). Both are age-related neurodegenerative diseases of the eye and brain and share commonalities.
Methods :
Apoe-knockout (Apoe-ko) mice (B6.129P2-Apoetm1Unc/J) and C57BL/6J wildtype controls (n=16, 4 per group, females) at two different ages (3-4 and 9-10 months) were used. Expression levels of 8 selected microRNAs (miRNAs) were determined in 4 different brain regions (for the AD), eye tissues and tears (for the AMD). Next, expression level of 20 target messenger RNAs (mRNAs) and 4 protein markers associated with Aβ accumulation (6E10) and neuroinflammation (glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (IBA1), and triggering receptor expressed myeloid cells 2 (TREM2)) were studied in the neocortex-hippocampus and eye tissues by immunofluorescence (IF). Additionally, eye tissues and tears of Apoe-ko mice raised with high-fat and regular diets (n=5 per group, females) were screened for miRNAs and mRNAs at 9-10 months old.
Results :
With ageing, the expression levels of miRNAs were generally high and mRNAs were generally low in both brain and eye tissues of Apoe-ko mice. Similar to eye tissues, the expression levels of miRNAs were high in the tears of older Apoe-ko mice. The retina of older Apoe-ko mice showed a significant (or a trend towards) increase for IF for glia proteins GFAP, IBA1 and TREM2 along with 6E10. Similarly, in the neocortex-hippocampus of older Apoe-ko mice, GFAP, IBA1 and TREM2 proteins showed increased IF, but no Aβ accumulations.
Conclusions :
Overall, the expression levels of miRNAs and mRNAs showed an opposite relationship in both brain and eye tissues, as expected. Circulating tear miRNAs reflected the changes in miRNAs’ levels in the eye tissues. With ageing, glia proteins showed a significant (or a trend towards) increase in both retina and neocortex-hippocampus of Apoe-ko mice, suggesting impaired glia homeostasis due to impaired lipid metabolism in both eye and brain. In addition to inflammation, Aβ accumulations within the inner retina may contribute to AMD pathogenesis in this mouse model.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.