Prolonged Hypoestrogenicity Leads to Enhanced Alzheimer's Disease-Related Protein Induction and Ischemic Stress Damage in the Hippocampus.

Abstract

Surgical menopause is associated with an increased risk of Alzheimer's disease (AD), although the mechanisms are poorly understood. The current study addressed whether long term ovariectomy might alter the sensitivity of the hippocampus to E2 neuroprotection, ischemic damage and AD-related protein induction. To address the question, adult rats were subjected to global cerebral ischemia one week (short term E2 deprived) or ten weeks (long term E2 deprived) (LTED) after ovariectomy. Western blot and immunohistochemistry were conducted at various times after ischemia for measurement of AD proteins and neuronal cell death. The results revealed that E2 neuroprotection in the hippocampal CA1 region was lost in long-term E2 deprived rats. Furthermore, estrogen receptor-alpha levels were shown to be significantly attenuated in the hippocampal CA1 region of LTED animals, which may explain the loss of E2 neuroprotection. Interestingly, the CA3 region became hypersensitive to ischemic damage in long-term E2 deprived animals, and there was a marked elevation of ischemia-induced beta-amyloid, amyloid precursor protein, and beta-secretase 1 proteins. There was also an elevation of the free radical inducing enzyme, NADPH (NOX2) oxidase in the CA3 of long-term E2 deprived rats. The study suggests that E2 has a critical protective and AD protein regulatory role in the hippocampal CA3 which is revealed upon prolonged loss of estrogen. The studies may have relevance to the increased risk of AD reported after surgical menopause in women. (platform)