C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection

Recent work suggests that timing of 17 beta-estradiol (E2) therapy may be critical for observing a beneficial neural effect. Along these lines, E2 neuroprotection, but not its uterotropic effect, was shown to be lost following long-term E2 deprivation (LTED), and this effect was associated with a significant decrease of estrogen receptor-alpha (ER alpha) in the hippocampus but not the uterus. The purpose of the current study was to determine the mechanism underlying the ER alpha decrease and to determine whether aging leads to a similar loss of hippocampal ER alpha and E2 sensitivity. The results of the study show that ER alpha in the rat hippocampal CA1 region but not the uterus undergoes enhanced interaction with the E3 ubiquitin ligase C terminus of heat shock cognate protein 70 (Hsc70)-interacting protein (CHIP) that leads to its ubiquitination/proteasomal degradation following LTED (10-wk ovariectomy). E2 treatment initiated before but not after LTED prevented the enhanced ER alpha-CHIP interaction and ER alpha ubiquitination/degradation and was fully neuroprotective against global cerebral ischemia. Administration of a proteasomal inhibitor or CHIP antisense oligonucleotides to knock down CHIP reversed the LTED-induced down-regulation of ER alpha. Further work showed that these observations extended to natural aging, because aged rats showed enhanced CHIP interaction; ubiquitination and degradation of both hippocampal ER alpha and ER beta; and, importantly, a correlated loss of E2 neuroprotection against global cerebral ischemia. In contrast, E2 administration to middle-aged rats was still capable of exerting neuroprotection. As a whole, the study provides support for a critical period for E2 neuroprotection of the hippocampus and provides important insight into the mechanism underlying the critical period.