17?-Estradiol attenuates oxidative impairment of synaptic Na+/K+-ATPase activity, glucose transport, and glutamate transport induced by amyloid ?-peptide and iron

Abstract

Synapse loss, deposits of amyloid beta-peptide (Abeta), impaired energy metabolism, and cognitive deficits are defining features of Alzheimer's disease (AD). Estrogen replacement therapy reduces the risk of developing AD in postmenopausal women. Because synapses are likely sites for initiation of neurodegenerative cascades in AD, we tested the hypothesis that estrogens act directly on synapses to suppress oxidative impairment of membrane transport systems. Exposure of rat cortical synaptosomes to Abeta25-35 (Abeta) and FeSO4 induced membrane lipid peroxidation and impaired the function of the plasma membrane Na+/K+-ATPase, glutamate transporter, and glucose transporter. Pretreatment of synaptosomes with 17beta-estradiol or estriol largely prevented impairment of Na+/K+-ATPase activity, glutamate transport, and glucose transport; other steroids were relatively ineffective. 17Beta-estradiol suppressed membrane lipid peroxidation induced by Abeta and FeSO4, but did not prevent impairment of membrane transport systems by 4-hydroxynonenal (a toxic lipid peroxidation product), suggesting that an antioxidant property of 17beta-estradiol was responsible for its protective effects. By suppressing membrane lipid peroxidation in synaptic membranes, estrogens may prevent impairment of transport systems that maintain ion homeostasis and energy metabolism, and thereby forestall excitotoxic synaptic degeneration and neuronal loss in disorders such as AD and ischemic stroke.

Mechanistic investigations on the antioxidant action of a neuroprotective estrogen derivative

“…Several compounds, including estrogens, have been shown to reduce oxidative stress on neurons [5,6,13,15,17]. In addition to binding to ERs in the cellular membrane, cytoplasm and nucleus [48], estrogens may also interact with lipid-transport proteins [49].…”

“…Various in vitro and in vivo models show that estrogens are capable to protect neurons in a concentration range of 0.1 nM to 50 µM suggesting the involvement of different modes of action [11][12][13][14][15]. The complex events by which estrogens orchestrate neuronal survival have not been clearly understood [16].…”

Estrogen suppresses brain mitochondrial oxidative stress in female and male rats

“…B. Wang, D. N. Krause, S. P. Duckles, and V. Procaccio, unpublished observations). These findings are consistent with receptor-activation by physiological estrogen concentrations, but are in contrast to direct antioxidant actions of the 17β-estradiol molecule that have been reported with high concentrations of this steroid (Behl et al, 1997;Keller et al, 1997;Prokai et al, 2003).…”

Neuroprotective Effects of 17β-Estradiol and Nonfeminizing Estrogens against H2O2Toxicity in Human Neuroblastoma SK-N-SH Cells

“…E 2 stabilizes mitochondrial function against actions of mutant presenilin-1 and inhibits mitochondrial F0F1-ATP synthase/ATPase by binding to one of its subunits (Zheng and Ramirez, 1999). Estrogen can attenuate oxidative impairment of synaptic Na ϩ /K ϩ -ATPase activity, glucose transport, and glutamate transport induced by amyloid ␤-peptide and iron (Keller et al, 1997). In cerebral blood vessels, E 2 enhanced expression of mitochondrial specific proteins such as cytochrome c and subunit IV of complex IV (Stirone et al, 2005).…”