Abstract
Differentially expressed (DE) proteins in the cortical microvessels (MVs) of young, middle-aged, and old male and female mice were evaluated using discovery-based proteomics analysis (> 4,200 quantified proteins/group). Most DE proteins (> 90%) showed no significant differences between the sexes; however, some significant DE proteins showing sexual differences in MVs decreased from young (8.3%), to middle-aged (3.7%), to old (0.5%) mice. Therefore, we combined male and female data for age-dependent comparisons but noted sex differences for examination. Key proteins involved in the oxidative stress response, mRNA or protein stability, basement membrane (BM) composition, aerobic glycolysis, and mitochondrial function were significantly altered with aging. Relative abundance of superoxide dismutase-1/-2, catalase and thioredoxin were reduced with aging. Proteins participating in either mRNA degradation or pre-mRNA splicing were significantly increased in old mice MVs, whereas protein stabilizing proteins decreased. Glycolytic proteins were not affected in middle age, but the relative abundance of these proteins decreased in MVs of old mice. Although most of the 41 examined proteins composing mitochondrial complexes I–V were reduced in old mice, six of these proteins showed a significant reduction in middle-aged mice, but the relative abundance increased in fourteen proteins. Nidogen, collagen, and laminin family members as well as perlecan showed differing patterns during aging, indicating BM reorganization starting in middle age. We suggest that increased oxidative stress during aging leads to adverse protein profile changes of brain cortical MVs that affect mRNA/protein stability, BM integrity, and ATP synthesis capacity.
Highlights
Cerebral microvessels (MVs: end arterioles, capillaries, and venules) are essential for maintenance of nutrient supply for brain metabolic needs while ensuring immunological and physical sequestration of brain tissues from harmful circulating substances via the blood–brain barrier (BBB) and basement membrane (BM) [1]
While glutathione synthase (GSS) and glutathione peroxidase-1 (GPX1) levels were not significantly reduced during aging (Fig. 1E–F), the enzymes involved in the glutathione cycle were significantly differentially expressed in MVs of young, middle-aged, and old mice
We propose that reduced ROS scavenging ability coupled with subsequent increased oxidative damage and mRNA/protein stability are early, precipitating events leading to energy failure and BM disruption (Fig. 8—schematic)
Summary
Cerebral microvessels (MVs: end arterioles, capillaries, and venules) are essential for maintenance of nutrient supply for brain metabolic needs while ensuring immunological and physical sequestration of brain tissues from harmful circulating substances via the blood–brain barrier (BBB) and basement membrane (BM) [1]. MVs are the most vulnerable-tostress segments of the brain vasculature. They must maintain high ATP production rates via glycolysis and oxidative phosphorylation (OXPHOS), essential for a variety of functions: the regulation of capillary perfusion pressure, transport across the BBB, BM maintenance, and tight nutrient delivery/brain metabolism coupling. They are subject to exposure from potentially disruptive or toxic agents released from neurons or circulating blood. The role of different proteins in cortical MVs in the etiology of aging and development of neurological diseases has received little attention due to a prior focus on large arteries and because of methodological challenges in interpreting the complexity of factors involved in the synthesis and stability of proteins and protein interactions
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