The Impact of High-Dose Fish Oil Supplementation on Mfsd2a, Aqp4, and Amyloid-β Expression in Retinal Blood Vessels of 5xFAD Alzheimer's Mouse Model

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Sep 14

PMID 39273347

Authors

Irena Jovanovic Macura

Desanka Milanovic

Vesna Tesic

Tamara Major

Milka Perovic

Miroslav Adzic

Sanja Ivkovic

Affiliations

Soon will be listed here.

Abstract

In patients with Alzheimer's disease (AD) and in animal models, the increased accumulation of amyloid β (Aβ) in retinal blood vessels strongly correlates with brain amyloid deposits and cognitive decline. The accumulation of Aβ in blood vessels may result from impaired transcytosis and a dysfunctional ocular glymphatic system in AD. High-dose fish oil (FO) supplementation has been shown to significantly change the expression of major facilitator superfamily domain-containing protein 2a (Mfsd2a), a key regulator of transcytosis, and Aquaporin 4 (Aqp4), an essential component of the glymphatic system in the retinas of WT mice. We examined the expression of Mfsd2a and Aqp4 in the retinas of 4-month-old 5xFAD female mice supplemented with high-dose FO for three weeks. There was a significant increase in Mfsd2a expression in 5xFAD retinas supplemented with FO compared to control 5xFAD mice. Additionally, the increase in Aqp4 expression observed in 4-month-old 5xFAD retinas, indicative of an impaired glymphatic system, was significantly decreased. Simultaneously, Aβ accumulation in 5xFAD retinal blood vessels was reduced following FO supplementation. These findings suggest that high-dose FO supplementation could serve as an adjunct in developing new treatments aimed at improving the regulation of transcytosis or the function of the glymphatic system in the AD retina.

References

Tong J, Briggs M, McIntosh T . Water permeability of aquaporin-4 channel depends on bilayer composition, thickness, and elasticity. Biophys J. 2012; 103(9):1899-908. PMC: 3491688. DOI: 10.1016/j.bpj.2012.09.025. View

van de Haar H, Jansen J, van Osch M, van Buchem M, Muller M, Wong S . Neurovascular unit impairment in early Alzheimer's disease measured with magnetic resonance imaging. Neurobiol Aging. 2016; 45:190-196. DOI: 10.1016/j.neurobiolaging.2016.06.006. View

Kalaany N, Mangelsdorf D . LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol. 2006; 68:159-91. DOI: 10.1146/annurev.physiol.68.033104.152158. View

Luo X, Feng J, Yang Z, Huang Q, Lin J, Yang B . High-dose omega-3 polyunsaturated fatty acid supplementation might be more superior than low-dose for major depressive disorder in early therapy period: a network meta-analysis. BMC Psychiatry. 2020; 20(1):248. PMC: 7238659. DOI: 10.1186/s12888-020-02656-3. View

Horton J . Sterol regulatory element-binding proteins: transcriptional activators of lipid synthesis. Biochem Soc Trans. 2002; 30(Pt 6):1091-5. DOI: 10.1042/bst0301091. View

Patch C, Hill-Yardin E, Lewis M, Ryan L, Daly E, Pearce A . The More, the Better: High-Dose Omega-3 Fatty Acids Improve Behavioural and Molecular Outcomes in Preclinical Models in Mild Brain Injury. Curr Neurol Neurosci Rep. 2021; 21(9):45. DOI: 10.1007/s11910-021-01132-z. View

Zhang C, Wang H, Li P, Hong C, Chen A, Qiu Y . Mfsd2a overexpression alleviates vascular dysfunction in diabetic retinopathy. Pharmacol Res. 2021; 171:105755. DOI: 10.1016/j.phrs.2021.105755. View

Zheng C, Zeng R, Wu G, Hu Y, Yu H . Beyond Vision: A View from Eye to Alzheimer's Disease and Dementia. J Prev Alzheimers Dis. 2024; 11(2):469-483. DOI: 10.14283/jpad.2023.118. View

Katoozi S, Rao S, Skauli N, Froehner S, Ottersen O, Adams M . Functional specialization of retinal Müller cell endfeet depends on an interplay between two syntrophin isoforms. Mol Brain. 2020; 13(1):40. PMC: 7074989. DOI: 10.1186/s13041-020-00581-w. View

10.

Brown W, Thore C . Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol. 2010; 37(1):56-74. PMC: 3020267. DOI: 10.1111/j.1365-2990.2010.01139.x. View

11.

Bell R, Zlokovic B . Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease. Acta Neuropathol. 2009; 118(1):103-13. PMC: 2853006. DOI: 10.1007/s00401-009-0522-3. View

12.

Hopperton K, Trepanier M, James N, Chouinard-Watkins R, Bazinet R . Fish oil feeding attenuates neuroinflammatory gene expression without concomitant changes in brain eicosanoids and docosanoids in a mouse model of Alzheimer's disease. Brain Behav Immun. 2017; 69:74-90. DOI: 10.1016/j.bbi.2017.11.002. View

13.

Mauch D, Nagler K, Schumacher S, Goritz C, Muller E, Otto A . CNS synaptogenesis promoted by glia-derived cholesterol. Science. 2001; 294(5545):1354-7. DOI: 10.1126/science.294.5545.1354. View

14.

Wang L, Mao X . Role of Retinal Amyloid-β in Neurodegenerative Diseases: Overlapping Mechanisms and Emerging Clinical Applications. Int J Mol Sci. 2021; 22(5). PMC: 7956232. DOI: 10.3390/ijms22052360. View

15.

Nguyen L, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X . Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature. 2014; 509(7501):503-6. DOI: 10.1038/nature13241. View

16.

Jessen N, Munk A, Lundgaard I, Nedergaard M . The Glymphatic System: A Beginner's Guide. Neurochem Res. 2015; 40(12):2583-99. PMC: 4636982. DOI: 10.1007/s11064-015-1581-6. View

17.

SanGiovanni J, Chew E . The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog Retin Eye Res. 2004; 24(1):87-138. DOI: 10.1016/j.preteyeres.2004.06.002. View

18.

Simon M, Wang M, Ismail O, Braun M, Schindler A, Reemmer J . Loss of perivascular aquaporin-4 localization impairs glymphatic exchange and promotes amyloid β plaque formation in mice. Alzheimers Res Ther. 2022; 14(1):59. PMC: 9040291. DOI: 10.1186/s13195-022-00999-5. View

19.

Liu B, Rasool S, Yang Z, Glabe C, Schreiber S, Ge J . Amyloid-peptide vaccinations reduce {beta}-amyloid plaques but exacerbate vascular deposition and inflammation in the retina of Alzheimer's transgenic mice. Am J Pathol. 2009; 175(5):2099-110. PMC: 2774073. DOI: 10.2353/ajpath.2009.090159. View

20.

Marchesi V . Alzheimer's dementia begins as a disease of small blood vessels, damaged by oxidative-induced inflammation and dysregulated amyloid metabolism: implications for early detection and therapy. FASEB J. 2011; 25(1):5-13. DOI: 10.1096/fj.11-0102ufm. View