Improvement of retinal function in Alzheimer disease-associated retinopathy by dietary lysophosphatidylcholine-EPA/DHA

Abstract

Alzheimer disease (AD) is the most prevalent cause of dementia in the elderly. Although impaired cognition and memory are the most prominent features of AD, abnormalities in visual functions often precede them, and are increasingly being used as diagnostic and prognostic markers for the disease. Retina contains the highest concentration of the essential fatty acid docosahexaenoic acid (DHA) in the body, and its deficiency is associated with several retinal diseases including diabetic retinopathy and age related macular degeneration. In this study, we tested the hypothesis that enriching retinal DHA through a novel dietary approach could ameliorate symptoms of retinopathy in 5XFAD mice, a widely employed model of AD. The results show that 5XFAD mice have significantly lower retinal DHA compared to their wild type littermates, and feeding the lysophosphatidylcholine (LPC) form of DHA and eicosapentaenoic acid (EPA) rapidly normalizes the DHA levels, and increases retinal EPA by several-fold. On the other hand, feeding similar amounts of DHA and EPA in the form of triacylglycerol had only modest effects on retinal DHA and EPA. Electroretinography measurements after 2 months of feeding the experimental diets showed a significant improvement in a-wave and b-wave functions by the LPC-diet, whereas the TAG-diet had only a modest benefit. Retinal amyloid β levels were decreased by about 50% by the LPC-DHA/EPA diet, and by about 17% with the TAG-DHA/EPA diet. These results show that enriching retinal DHA and EPA through dietary LPC could potentially improve visual abnormalities associated with AD.

The Expression of Major Facilitator Superfamily Domain-Containing Protein2a (Mfsd2a) and Aquaporin 4 Is Altered in the Retinas of a 5xFAD Mouse Model of Alzheimer’s Disease

“…Recent research confirmed that storax attenuated BBB disruption by upregulating Mfsd2a and inhibiting Cav-1 in the endothelial cells in order to arrest the progression of cerebral ischemia [ 67 ]. Similarly, treatment with LPC-DHA, transported through Mfsd2a, strongly improved retinal function in 5xFAD mice [ 68 ], and treatment with fish oil significantly increased Mfsd2a expression and blood vessel coverage in the retinas of wild-type mice [ 69 ]. Finally, the overexpression of Mfsd2a in the eye was reported to decrease retinal neovascularization and vascular leakage in mouse models of retinopathy and, importantly, co-treatment with DHA had a synergistic positive effect [ 26 ].…”

Exploring Zika Virus Impact on Endothelial Permeability: Insights into Transcytosis Mechanisms and Vascular Leakage

“…This integral membrane transporter plays a central role in facilitating Na+-dependent uptake of omega-3 polyunsaturated fatty acid (ω−3 fatty acids). It prevents the formation of caveolae vesicles, which are essential for the maintenance of membrane lipid composition in CNS endothelial cells, particularly docosahexaenoic acid (DHA), in the form of zwitterionic lysolipids such as lysophosphatidylcholine (LPC-DHA) [ 111 ]. DHA is not only the predominant ω−3 fatty acid in brain tissue, which protects the integrity of the BBB, but is also an essential component of cell membranes, structurally and functionally interacting with cholesterol and integral membrane proteins that are critical for brain growth, learning, and vision [ 112 , 113 ].…”

Biomarker evidence of early vision and rod energy-linked pathophysiology benefits from very low dose DMSO in 5xFAD mice

“…Intriguingly, the retina, which is embryologically derived from brain tissue, shows characteristic AD pathology (i.e., soluble amyloid β-peptide oligomers and plaque, phosphorylated tau and neurofibrillary tangles) well before the appearance of AD pathology in the brain [16-21, 26, 27]. In addition, there is evidence for retinal oxidative stress in a common experimental model of AD, 5xFAD mice, as early as 1 month of age [28][29][30]. For example, preventative treatment with an anti-oxidant, methylene blue, can mitigate cognitive declines in experimental AD [29,30].…”