Age and 17β-estradiol effects on blood–brain barrier tight junction and estrogen receptor proteins in ovariectomized rats

Age and estrogen levels alter blood–brain barrier (BBB) tight junction (TJ) regulation, impacting brain homeostasis and pathological outcomes. This examination evaluated BBB TJ and estrogen receptor (ER) protein expression changes in young (8–10 week) and middle-aged (10–12 month) ovariectomized female Fisher-344 rats with chronic 17β-estradiol or placebo treatment. Middle-aged rats showed decreased protein expression of occludin with 17β-estradiol (55 kDa band) or placebo (45, 55, 60 kDa bands) treatment compared to respective young. In young animals, 17β-estradiol treatment increased expression of the occludin 55 kDa band over placebo; however, this effect was lost in the middle-aged animals. In both young and middle-aged animals, expression of claudin-5 (23, 32 kDa bands) and ERα (66 kDa) increased with 17β-estradiol treatment, while junctional adhesion molecule-A showed no change across all groups. However, ERα expression (66 kDa) was significantly reduced in the middle-aged animals compared to young placebo treated animals. Measurement of BBB TJ permeability via in situ perfusion of 14 C-sucrose showed no change with age or treatment. Our results show that increasing age and 17β-estradiol treatment alters the expression of ERα and distinct BBB TJ protein isoforms without altering functional paracellular permeability.

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► Age directly impacts protein expression of occludin.
► 17β-Estradiol treatment differentially alters occludin isoform expression in young animals, but not in middle-aged animals.
► 17β-Estradiol treatment increases claudin-5 expression in young and middle-aged animals.
► ERα expression is reduced in the middle-aged animals compared to young.
► ERα expression increased with 17β-estradiol treatment in young and middle-aged animals.