Estrogen receptor-alpha in the Alzheimer's disease brain

Abstract

The decline in estrogen levels around the menopause was suggested to be an important factor in the pathogenesis of Alzheimer's disease (AD). Therefore, we investigated whether estrogen receptors (ER) may change in the brain of AD patients. ER alpha and its splice variants were studied at the mRNA level using polymerase chain reaction and DNA sequencing in the frozen human brain samples and at the protein level in the paraffin embedded sections using immunocytochemistry. Nuclear ER alpha expression was increased in the cholinergic basal forebrain (the nucleus basalis of Meynert (NBM) and the vertical limb of the diagonal band of Broca (VDB)) and in the hypothalamic nuclei but was diminished in the hippocampus of AD cases. These alterations in nuclear ER alpha staining could not be related to the occurrence of neurofibrillary tangles or to the changes in the local estrogen biosynthesis. We further identified 62 ER alpha mRNA splice variants in the brain of AD patients andelderly control donors and classified them according to the type of deletion and the presence ofinserts. Forty-eight of these ER alpha splice forms were found for the first time. The average number of the ER alpha mRNA splice variants per brain area was significantly lower in the AD cases compared with control donors. The incidence of large deletions with alternative usage of 5' and 3' splice sites inside exons was more prevalent in AD female cases. Immunoreactivity of the hippocampal ER alpha splice variant TADDI was decreased in the hippocampus, the NBM and the tuberomamillary nucleus of the hypothalamus of AD women. Our data show that alternative splicing of the ER alpha mRNA is reduced in the AD brain and more significantly in AD female cases. High incidence of the dominant negative del.7 isoform in the brain of the elderly suggests diminished estrogen signaling through both canonical ER alpha and beta. It is plausible that the brain area-specific alterations in nuclear ER alpha may be related to the differential degree of the tau pathology in the hypothalamus, basal forebrain and hippocampus that may affect the intracellular trafficking of the receptor.