Females who enter menopause prematurely via bilateral ovariectomy (surgical menopause) have a significantly increased risk for cognitive decline and dementia. To help elucidate the mechanisms underlying this phenomenon, we used an animal model of surgical menopause, long-term (10-week) bilateral ovariectomy in female rats. Herein, we demonstrate that long-term oestrogen deprivation dramatically increases sensitivity of the normally resistant hippocampal CA3 region to ischaemic stress, an effect that was gender-specific, as it was not observed in long-term orchiectomized males. Furthermore, the enhanced damage to the CA3 region correlated with a worse cognitive outcome after ischaemic stress. Long-term ovariectomized rats also displayed a robust hyperinduction of Alzheimer's disease-related proteins in the CA3 region and a switch in amyloid precursor protein processing from non-amyloidogenic to amyloidogenic following ischaemic stress CA3 hypersensitivity also extended to an Alzheimer's disease-relevant insult, as the CA3 region of long-term ovariectomized rats was profoundly hypersensitive to the neurotoxic effects of amyloid-β1-42, the most amyloidogenic form of the amyloid-β peptide. Additional studies revealed that CA3 region hypersensitivity, Alzheimer's disease-related protein induction, and amyloidogenesis are mediated by a NADPH oxidase/superoxide/c-Jun N-terminal kinase/c-Jun signalling pathway, involving both transcriptional and post-translational mechanisms. In addition, while 17β-oestradiol replacement at the end of the long-term oestrogen deprivation period could not prevent CA3 hypersensitivity and amyloidogenesis, if 17β-oestradiol was initiated at the time of ovariectomy and maintained throughout the 10-week oestrogen deprivation period, it completely prevented these events, providing support for the 'critical window' hypothesis for oestrogen replacement therapy benefit. Collectively, these findings may help explain the increased risk of cognitive decline and dementia observed in women following surgical menopause, and they provide increased support that early 17β-oestradiol replacement is critical in preventing the negative neural effects associated with bilateral ovariectomy.