Estrogen receptor α and its splice variants in the hippocampus in aging and Alzheimerʹs disease

Clinical and experimental studies show that estrogens can have beneficial effects on hippocampus-dependent cognitive functions that may be mediated by estrogen receptor (ER)α. We investigated whether menopause and Alzheimerʹs disease (AD) cause changes in this ER subtype. Immunocytochemical staining of ERα, aromatase and Golgi complex (GC) was performed on paraffin embedded hippocampal tissue from women of the pre-, peri- and postmenopausal age. Canonical ERα mRNA amplicons, ERα splice variants (del.2, del.4, del.7, MB1) and aromatase transcripts were measured by Q-PCR in frozen hippocampal samples of AD and matched control cases. Nuclear ERα, aromatase and the GC enhanced during aging in women indicating availability of locally synthesized estrogens that may up-regulate ERα by which neuronal metabolism can be augmented in the hippocampus after the menopause. In AD cases canonical and alternatively spliced ERα mRNA, and aromatase gene expression were down-regulated suggesting a deficit in local estrogen levels and diminished signalling through ERα. The major ERα splice variants in the hippocampus were found to be MB1 and del.4. A novel ERα isoform TADDI was isolated and sequenced from two female patients. It lacks 31 bp at the junction between exons 3 and 4 with an insertion of 13 nucleotides from the middle of the exon 2.