Elovl2 and Elovl4 reduction in Adipor1-/- and Mfrprd6 Leads to Neuroinflammation and Neurodegeneration

Abstract

The omega-3 fatty acid docosahexaenoic acid (DHA) is enriched in the central nervous system, including the retina, where it preserves vision by maintaining photoreceptor disc integrity. DHA plays a central role in neural cell homeostasis, having antioxidative, anti- inflammatory, and antiapoptotic properties through derived lipid mediators. We have discovered that mutant Adipor1 and Mfrp mice have a selective reduction of DHA and very long- chain polyunsaturated fatty acids (VLC-PUFAs; >28 carbons) formed notably by elongases ELOVL2 and 4 (ELOngation of Very Long chain fatty acids). These mice have impaired retinal function and progressive loss of photoreceptor cells. We have now determined the underlying mechanism leading to inflammaging in these models for retinal degeneration. We harvested retinas and RPE-eyecups from Adipor1-/-, Mfrprd6 and C57BL/6J (wild- type; WT) male and female mice and performed capillary Jess (Protein Simple) Western blot for Elovl2 and Elovl4. FAM-FLICA Caspase-1 Assay was performed on eye sections to determine caspase-1 activation. Immunohistochemistry was performed with Iba-1 antibody to determine microglia invasion in mutant mice. Protein expressions of Elovl2 and 4 were reduced in the mutants. FAM-FLICA showed Adipor1-/- and Mfrprd6 had a 47% and 189% increase in caspase 1 activity. Immunostaining demonstrated greater Iba-1 positive cells in both mutant retinas. Adipor1-/- and Mfrprd6 are susceptible to uncontrolled neuroinflammation, leading to microglia invasion and caspase 1-dependent retina damage, suggesting pyroptotic immune response and targeting of the inflammasome pathway.