Estrogen receptor a 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. Immunocytochernical staining of ER alpha, aromatase and Golgi complex (GC) was performed on paraffin embedded hippocampal tissue from women of the pre-, peri- and postmenopausal age. Canonical ER alpha mRNA amplicons, ER alpha 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 ER alpha, aromatase and the GC enhanced during aging in women indicating availability of locally synthesized estrogens that may up-regulate ER alpha by which neuronal metabolism can be augmented in the hippocampus after the menopause. In AD cases canonical and alternatively spliced ER alpha mRNA, and aromatase gene expression were down-regulated suggesting a deficit in local estrogen levels and diminished signalling through ER alpha. The major ER alpha splice variants in the hippocampus were found to be MB1 and del.4. A novel ERa 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. (c) 2006 Elsevier Inc. All rights reserved.