Effects of Estrogen on Beta-Amyloid-Induced Cholinergic Cell Death in the Nucleus Basalis Magnocellularis

Alzheimer disease is characterized by accumulation of P-amyloid (A beta) and cognitive dysfunctions linked to early loss of cholinergic neurons. As estrogen-based hormone replacement therapy has beneficial effects on cognition of demented patients, and it may prevent memory impairments, we investigated the effect of estrogen-pretreatment on A beta-induced cholinergic neurodegeneration in the nucleus basalis magnocellularis (NBM). We tested which A beta species induces the more pronounced cholinotoxic effect in vivo. We injected different A beta assemblies in the NBM of mice, and measured cholinergic cell and cortical fiber loss. Spherical A beta oligomers had the most toxic effect. Pretreatment of ovariectomized mice with estrogen before A beta injection decreased cholinergic neuron loss and partly prevented fiber degeneration. By using proteomics, we searched for proteins involved in estrogen-mediated protection and in A beta toxicity 24 h following injection. The change in expression of, e.g., DJ-1, NADH ubiquinone oxidoreductase, ATP synthase, phosphatidylethanolamine-binding protein 1, protein phosphatase 2A and dimethylarginine dimethylaminohydrolase 1 support our hypothesis that A beta induces mitochondrial dysfunction, decreases MAPK signaling, and increases NOS activation in NBM. On the other hand, altered expression of, e.g., MAP kinase kinase 1 and 2, protein phosphatase 1 and 2A by A beta might increase MAPK suppression and NOS signaling in the cortical target area. Estrogen pretreatment reversed most of the changes in the proteome in both areas. Our experiments suggest that regulation of the MAPK pathway, mitochondrial pH and NO production may all contribute to A beta toxicity, and their regulation can be prevented partly by estrogen pretreatment. Copyright (C) 2010 S. Karger AG, Basel