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.