Soluble Neuregulin-1 from Microglia Enhances Amyloid Beta-induced Neuronal Death

Abstract

Neuregulin-1 (NRG-1) is a ligand of the epidermal growth factor receptor (erbB), and its interaction involves activation of the glutamatergic N-methyl-D-aspartate receptor, which increases the expression of the beta 2 subunit of the gamma-aminobutyric acid receptor and subunits of the nicotinic acetylcholine receptor. In the dentate gyrus of 14-month-old Tg2576 mice, NRG-1 was strongly expressed compared with age-matched controls. The supernatant of oligomeric amyloid beta peptide (A beta(42))-treated glial cells enhanced the A beta(42)-induced cytotoxic effects, but the expression of Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand in microglial cells was not changed upon cytotoxic treatment. This suggests that the oligomeric form of A beta(42) toxicity is not related to apoptosis, which is mediated by cell-to-cell interaction. During the 24-h incubation, the secretion of the soluble form of NRG-1 was increased, but interleukin 6 secretion was not changed. Further, soluble NRG-1 increased A beta(42)-induced toxicity. In conclusion, soluble NRG-1 significantly enhanced oligomeric A beta(42)-induced toxicity through the activation of endoplasmic reticulum stress by the increase of a phospho-translation initiation factor 2 alpha (p-eIF2 alpha).