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) α 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 ERα 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.