Estrogen receptor alpha and its splice variants in the hippocampus in aging and Alzheimer’s 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)alpha. We investigated whether menopause and Alzheimer’s disease (AD) cause changes in this ER subtype. Immunocytochemical staining of ERalpha, aromatase and Golgi complex (GC) was performed on paraffin embedded hippocampal tissue from women of the pre-, peri- and postmenopausal age. Canonical ERalpha mRNA amplicons, ERalpha 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 ERalpha, aromatase and the GC enhanced during aging in women indicating availability of locally synthesized estrogens that may up-regulate ERalpha by which neuronal metabolism can be augmented in the hippocampus after the menopause. In AD cases canonical and alternatively spliced ERalpha mRNA, and aromatase gene expression were down-regulated suggesting a deficit in local estrogen levels and diminished signalling through ERalpha. The major ERalpha splice variants in the hippocampus were found to be MB1 and del.4. A novel ERalpha isoform TADDI was isolated and sequenced from two female patients. It lacks 31bp at the junction between exons 3 and 4 with an insertion of 13 nucleotides from the middle of the exon 2.