Decreased alternative splicing of estrogen receptor-α mRNA in the Alzheimer's disease brain

In this study we identified 62 estrogen receptor alpha (ERα) mRNA splice variants in different human brain areas of Alzheimer's disease (AD) and control cases and classified them into 12 groups. Forty-eight of these splice forms were identified for the first time. The distribution of alternatively spliced ERα mRNAs was brain area- and case-specific. The dominant negative deletion (del.) 7 isoform appeared to be the major splice variant. The average number of ERα splice forms per brain area was lower in AD cases compared with controls, although the incidence of large deletions with alternative usage of 5' and 3' splice sites inside exons was more frequent in AD female cases. Relative transcription levels of del. 7 and del. 2 (missing exon 2) variants were decreased in the temporal cortex of AD patients, whereas the expression of the wild type ERα mRNA did not change. Our data show that alternative splicing of ERα mRNA is diminished in the AD brain and more prominently in AD female case

Changes in metabolic activity and estrogen receptors in the human medial mamillary nucleus: relation to sex, aging and Alzheimer's disease

The medial mamillary nucleus (MMN) is situated caudally in the human hypothalamus and is involved in memory processes. In search for putative sites of action in estrogen replacement therapy on memory both in aging and Alzheimer's disease (AD), we aimed at determining whether changes would occur in estrogen receptors (ER) or metabolic activity in the MMN neurons under these conditions in a sex-dependent way. The Golgi apparatus (GA) and cell size, that were previously shown to be good measures of changes in neuronal metabolic activity. were measured in the MMN of 10 young (20-50 years old), 11 elderly (56-76 years old) control men and women and 11 AD patients (54-78 years old). In addition, we investigated whether estrogen receptor alpha or beta (ERalpha or ERbeta) immunoreactivity was altered in the MMN in aging or AD. There were no sex- or AD-related differences in the GA or cell size in the MMN. Both the GA and cell size of the MMN neurons were found to be increased in postmenopausal compared to young control women accompanied by a decrease in the amount of nuclear ERbeta. The percentage of nuclear ERalpha-positive MMN neurons was markedly enhanced in AD patients compared to controls and most prominently in AD men. In AD patients the proportion of nuclear ERalpha-positive neurons was positively correlated to the Braak stages that indicate the progression of the disease. No differences in the proportion of ERbeta-positive neurons were observed between AD and control patients. We propose that estrogens play an inhibitory role with respect to the metabolic activity of human MMN, which is mediated via ERbeta. This inhibitory effect is diminished in postmenopausal women. The role of the enhanced nuclear ERalpha staining in AD. that was also found in other brain areas, remains to be elucidated. (C) 2003 Elsevier Science Inc. All rights reserve

Estrogen receptors and metabolic activity in the human tuberomamillary nucleus: changes in relation to sex, aging and Alzheimer's disease

The human tuberomamillary nucleus (TMN), that is the sole Source of histamine in the brain, is involved in arousal, learning and memory and is impaired in Alzheimer's disease (AD) as shown by the presence of cytoskeletal alterations, a reduction in the number of large neurons, a diminished neuronal metabolic activity and decreased histamine levels in the hypothalamus and cortex. Experimental data and the presence of sex hormone receptors Suggest an important role of sex steroids in the regulation of the function of TMN neurons. Therefore, we investigated sex-, age- and Alzheimer-related changes in estrogen receptor alpha and beta (ERalpha and ERbeta) in the TMN. In addition, metabolic activity changes of TMN neurons were determined by measuring Golgi apparatus (GA) and cell size. In the present study, ERalpha immunocytochemical expression in AD patients did not differ from that ill elderly controls. However, a larger amount of cytoplasmic ERbeta was found in the TMN cells of AD patients. Earlier studies, using the GA size as a parameter, have shown a clearly decreased metabolic activity in the TMN neurons in AD. In the present study, the size of the GA did not change during aging, indicating the absence of strong metabolic changes. Cell size of the TMN neurons appeared to increase during normal aging in men but not ill women. Concluding, the enhanced cytoplasmic expression of ERbeta in the TMN may be involved in the diminished neuronal metabolism of these neurons in AD patients. (C) 2003 Elsevier B.V. All rights reserve

Diminished aromatase immunoreactivity in the hypothalamus, but not in the basal forebrain nuclei in Alzheimer's disease

In previous studies we have shown in Alzheimer's disease (AD) an enhanced nuclear estrogen receptor (ER) alpha expression in the cholinergic basal forebrain nuclei, i.e. the vertical limb of the diagonal band of Broca (VDB) and the nucleus basalis of Meynert (NBM), and in a number of hypothalamic nuclei, i.e. the supraoptic nucleus (SON), the infundibular nucleus (INF), the medial mamillary nucleus (MMN). We aimed at determining whether the increase in nuclear ERalpha seen in AD patients was related to a rise in local production of estrogens by aromatase (P-450arom), which is a key enzyme that catalyzes the biosynthesis of estrogens from precursor aromatizable androgens. We confirmed for the first time the presence of aromatase mRNA in neurons and glial cells in the human NBM and the tuberomamillary nucleus by RT-QPCR using laser microdissection. Enhanced aromatase immunoreactivity (ir) was indeed observed in the NBM in AD. However, in contrast a decreased aromatase-ir was found in the SON, INF and MMN of AD patients. In addition, P-450arom-ir was clearly diminished in ependymal and choroid plexus cells in AD. While an increase in aromatase-ir was found in the NBM and SON during normal aging, a decrease in staining was observed in the MMN. No sex differences in young control, elderly control or AD patients were present in any of the nuclei studied. In conclusion, brain P-450arom-ir and the relationship of its regulation with plasma sex steroid levels, estrogen and androgen receptors in the human hypothalamus and basal forebrain are region-specific. (C) 2004 Elsevier Inc. All rights reserve