Differential regulation of brain blood vessel transcriptome and brain metabolome by Western and heart-healthy diets in Ossabaw pigs

Authors: Solano Aguilar, Gloria; MATUSZEK, GREGORY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MATTHAN, NIRUPA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LICHTENSTEIN, ALICE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WANG, XUEDI - Tufts University; Lakshman, Sukla; BARGER, KATHRYN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; BENNETT, RACHAEL - Harvard Medical School; HYMAN, BRADLEY - Harvard Medical School; LAMON-FAVA, STEFANIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/26/2023
Publication Date: 11/28/2024
Citation: Solano Aguilar, G., Matuszek, G.H., Matthan, N., Lichtenstein, A.H., Wang, X., Lakshman, S., Barger, K., Bennett, R., Hyman, B.T., Lamon-Fava, S. 2024. Differential regulation of brain blood vessel transcriptome and brain metabolome by Western and heart-healthy diets in Ossabaw pigs . Scientific Reports. https://doi.org/10.1038/s41598-024-81321-1.
DOI: https://doi.org/10.1038/s41598-024-81321-1

Interpretive Summary: Diet is a well-established and modifiable cardiovascular disease risk factor that has recently emerged as a contributor to the development and progression of cognitive impairment and Alzheimer's disease. We studied the effects of two dietary patterns, a typical Western diet (WD) and a heart-healthy diet (HHD) on the brain blood vessels of Ossabaw minipigs, an animal model of diet-induced cardiovascular disease. Thirty-two pigs were fed either the WD or the HHD for 6 months. Some of the pigs also received statin. The WD and HHD were similar in the energy, fat, carbohydrate and protein content, but the WD contained mostly saturated fat, starch and sugar, while the HHD contained mostly polyunsaturated fatty acids and whole grains. We isolated the small blood vessels of the temporal region of the brain and found that the pigs on WD had higher expression of genes related to inflammation, angiogenesis, and apoptosis, while pigs on the HHD had higher expression of genes related to cell energetics, neurotransmission, and inflammation resolution pathways. These results suggest a likely contribution of diet to brain pathologies characterized by neuroinflammation and neurodegeneration

Technical Abstract: Diet is an established and modifiable cardiovascular disease risk factor that has recently emerged as a contributor to the development and progression of neurodegenerative diseases. We studied the effects of diet on brain blood vessels in the Ossabaw minipig, an animal model of diet-induced cardiovascular disease. Thirty-two pigs (16 male and 16 females) were randomized to a Western diet (WD) or heart-healthy diet (HHD), with or without statin (S, atorvastatin) starting at the age of 4 months and for the following 6 months. The WD and HHD were isocaloric and similar in macronutrient content but differed in macronutrient quality. Neurovascular units were isolated from the brain temporal region and subjected to transcriptomic analysis. Metabolomic profiles of the temporal region were also evaluated. There were 2,172 genes differentially expressed (FDR<0.05) by diet, 796 upregulated and 1,376 downregulated in WD-fed pigs relative to HHD. Gene Set Enrichment Analysis identified 22 gene sets enriched in WD, comprising pathways related to inflammation, angiogenesis, and apoptosis, and 53 gene sets enriched in the HHD, including cell energetics, neurotransmission, and inflammation resolution pathways. An enrichment in arginine, tyrosine, and lysine was observed in WD-fed pigs and an enrichment in ergothioneine and S-adenosyl methionine in HHD-fed pigs. Our study shows a significant impact of diet on the brain vasculature, characterized by a pro-inflammatory and pro-angiogenesis phenotype and lower cellular energetics and neurotransmitter signaling in WD-fed pigs relative to HHD. These results suggest a likely contribution of diet to brain pathologies characterized by neuroinflammation and neurodegeneration.