Locally Synthetized 17--Estradiol Reverses Amyloid--42-Induced Hippocampal Long-Term Potentiation Deficits

Amyloid beta 1-42 (A beta 42) aggregates acutely impair hippocampal long-term potentiation (LTP) of synaptic transmission, and 17 beta-estradiol is crucial for hippocampal LTP. We tested whether boosting the synthesis of neural-derived 17 beta-estradiol (nE2) saves hippocampal LTP by the neurotoxic action of A beta 42. Electrophysiological recordings were performed to measure dentate gyrus (DG) LTP in rat hippocampal slices. Using a pharmacological approach, we tested the ability of nE2 to counteract the LTP impairment caused by acute exposure to soluble A beta 42 aggregates. nE2 was found to be required for LTP in DG under physiological conditions. Blockade of steroid 5 alpha-reductase with finasteride, by increasing nE2 synthesis from testosterone (T), completely recovered LTP in slices treated with soluble A beta 42 aggregates. Modulation of the glutamate N-methyl-D aspartate receptor (NMDAR) by memantine effectively rescued the LTP deficit observed in slices exposed to A beta 42, and memantine prevented LTP reduction observed under the blocking of nE2 synthesis. nE2 is able to counteract A beta 42-induced synaptic dysfunction. This effect depends on a rapid, non-genomic mechanism of action of nE2, which may share a common pathway with glutamate NMDAR signaling.