Amyloid precursor protein 17-mer peptide (APP 17-mer peptide) is an active fragment of amyloid precursor protein (APP) in the nervous system that mediates various neuronal activities and functions. Estrogen deprivation during menopause disproportionately increases the risk of many neurodegenerative diseases, including Alzheimer's disease (AD). Currently, therapeutic approaches to treat Alzheimer's disease are less than effective. We have previously shown that APP 17-mer peptide participates in neuronal function in aged-hippocampal neurons. In this study, we investigate the effects of estrogen and APP 17-mer peptide on hippocampal neurodegeneration in ovariectomized rats. The results showed that decreases in learning and memory function in ovariectomized rats were associated with degenerative changes in hippocampal neurons. Estrogen deprivation also enhances apoptotic cell death and decreases expression of the anti-apoptotic protein Bcl-2. Administration of APP 17-mer peptide ameliorates changes associated with estrogen deprivation without affecting estrogen levels. These results indicate that APP 17-mer peptide may prevent neurodegeneration caused by estrogen deficiency. Our findings also suggest that estrogen deficiency-induced neurodegeneration is regulated by activation of an intracellular "cross talk" signaling pathway, connecting neurotrophins with APP 17-mer peptide. (C) 2009 Published by Elsevier Ireland Ltd.