Endothelial ether lipids link the vasculature to blood pressure, behavior, and neurodegeneration

Spears LD, Adak S, Dong G, Wei X, Spyropoulos G, Zhang Q, Yin L, Feng C, Hu D, Lodhi IJ, Hsu F, Rajagopal R, Noguchi KK, Halabi CM, Brier L, Bice AR, Lananna BV, Musiek ES, Avraham O, Cavalli V, Holth JK, Holtzman DM, Wozniak DF, Culver JP, and Semenkovich CF. (2021) Endothelial ether lipids link the vasculature to blood pressure, behavior, and neurodegeneration. Journal of Lipid Research

Vascular disease can be caused by hypertension, diabetes, or hyperlipidemia and is a risk factor for neurodegenerative disorders. Especially when combined with other risk factors including the APOE ε4 allele or tau and amyloid accumulation, cardiovascular dysfunction encourages dementia. Vascular dysfunction causes changes in blood pressure and although unclear, blood pressure abnormalities are thought to increase the risk of dementia in old age. Plasmalogens could be the link between vascular dysfunction and neurodegeneration. Plasmalogens are a class of lipids that contain a vinyl ether bond at sn-1 and make up ~20% of all phospholipids in the human body. There are also many associations between plasmalogens and neurodegeneration: plasmalogens decrease in serum and brain with age, and a complete loss of plasmalogens results in an ultra-rare disease called rhizomelic chondrodysplasia punctata (RCDP) that is characterized by severe cognitive deficits. Mouse models of plasmalogens deficiency show neurodegeneration, and plasmalogens are decreased in patients with Alzheimer’s disease (AD). Spears et al wanted to investigate the role of vascular plasmalogens in neurodegeneration by developing a conditional plasmalogen knock-out mouse model.

There are many different mouse models of plasmalogen deficiency, but they more closely resemble disorders caused by a complete plasmalogen deficiency such as RCDP. In neurodegenerative disorders related to aging, such as AD, the hypothesis is that plasmalogen levels are normal throughout development and early life, but progressively decline with age resulting in cognitive impairment. To model this AD progression, researchers targeted the PexRAP gene, a peroxisomal enzyme in the plasmalogen biosynthesis pathway. They developed an inducible model in which tamoxifen administration caused the loss of PexRAP function in endothelial cells (PEKO). Although only the endothelial cells were targeted in PEKO animals, plasmalogen analyses showed decreased plasmalogen levels in the plasma. This was an unexpected finding, as it was hypothesized that only the endothelial cells lining of vascular tissue would be affected.

The endothelial tissue targeted in the PEKO mice was the vasculature lining, therefore blood pressure was determined using a tail cuff to detect if a plasmalogen reduction would have any effect on the vascular function. Systolic, diastolic, and mean blood pressure were all found to be decreased in the PEKO mice compared to the control mice, while heart rate was unaffected. To ensure this effect was caused by tamoxifen-induced loss of PexRAP and not just this alteration in the genome, mice without Cre and PexRAP mice with Cre were treated with the vehicle and did not show any difference in blood pressure.

To investigate if the loss of PexRAP function in endothelial cells promoted neurodegeneration, histology was used to analyze the blood brain barrier and behavior tests were performed to detect any cognitive or memory deficits. Although silver staining did not demonstrate any differences, tyrosine hydroxylase-positive neuron area was decreased in PEKO locus coerleus compared to control mice. As well, gliosis was increased in the hippocampus of PEKO mice compared to control mice. There was no difference in ambulation and rearing present between the PEKO and control mice, however the novel object recognition test showed that PEKO mice spent less time with the novel object. This finding indicates a limited awareness of objects and changes to the environment, suggesting potential memory impairment.

Spears et al determined the role of vascular plasmalogens on dementia and neurodegeneration using a conditional model for plasmalogen deficiency in endothelium cells, which make up the blood brain barrier. Spears et al found that even though the PEKO gene was only knocked out in endothelium cells, the plasmalogen reduction could also be seen in the plasma. As vasculature lining is composed of endothelial cells, systolic, diastolic, and mean blood pressure were analyzed to detect whether any changes would be present and all were found to decrease in the PEKO animals. They also demonstrated that there was increased gliosis in the hippocampus of PEKO mice and that these animals had possible memory defects. This work provides support for there being a relationship between plasmalogen level in endothelium of vascular and the neural environment. Further work looking into the relationship between plasmalogen level and other vascular risk factors may provide more information on the link between vascular disease and neurodegeneration.