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Changes in Estrogen Receptor- and -ß in the Infundibular Nucleus of the Human Hypothalamus Are Related to the Occurrence of Alzheimer’s Disease Neuropathology

Netherlands Institute for Brain Research (A.H., D.F.S.), Amsterdam 1105 AZ, The Netherlands; and Department of Obstetrics and Gynecology (A.H.), Faculty of Medicine, University of Indonesia, Jakarta 10430, Indonesia

Address all correspondence and requests for reprints to: Dick F. Swaab, M.D., Ph.D., Professor of Neurobiology, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands. E-mail: d.swaab{at}nih.knaw.nl.

The expression of estrogen receptor (ER) and -ß in the infundibular nucleus of the hypothalamus was studied immunocytochemically in 28 control subjects and 14 patients with Alzheimer’s disease (AD). A shift was found from more nuclear staining of ER in young female controls to more cytoplasmic staining in elderly female controls, whereas no such change was observed in elderly male controls. The shift of ER from nucleus to cytoplasm in elderly female controls was accompanied by a relative absence of AD neuropathology, i.e. hyperphosphorylated tau stained by hyperphosphorylated tau protein (AT8). In contrast, male and female AD patients showed more nuclear ER and a much stronger AD neuropathology. It is proposed that the shift of ER from nucleus to the cytoplasm may reflect activation of neurons and that hyperactivity decreases the risk that neurons in the course of aging develop AD neuropathology. In contrast, the presence of nuclear ER seems to predispose to reduced activity and increases the risk of some neurons to develop AD neuropathology. ERß in basket-like terminals was preferentially observed in elderly male controls and AD patients, a novel phenomenon. This suggests that the presence of basket-like ERß may reflect reduced activity, which is-associated with an increase in hyperphosphorylated tau staining. However, the neurons inside the basket-like ERß showed signs of hyperactivity and did not stain for AT8. All AT8-positive neurons in the infundibular nucleus contained MSH as a marker for proopiomelanocortin neurons. These neurons produce ß-endorphin that inhibits GnRH release. Because they diminish in activity in postmenopausal women, this may contribute to the hyperactivity of GnRH neurons. The regulation of the gonadal axis may thus be affected by AD neuropathology independent of AD neuropathology in cognition-related brain structures.

This work was supported by the Hersenstichting Nederland, Internationale Stichting Alzheimer Onderzoek, Nederlandse Alzheimer Stichting, Research Institute for Diseases in the Elderly, Ministry of Education and Science, and Ministry of Health, Welfare, and Sports through The Netherlands Organization for Scientific Research.

Abbreviations: AD, Alzheimer’s disease; ApoE, apolipoprotein E; AT8, hyperphosphorylated tau protein; ER, estrogen receptor; ER-IR, ER immunoreactivity; ERß-IR, ERß-immunoreactivity; GABA, -amino butyric acid; GAL, galanin; NBM, nucleus basalis of Meynert; NFT, neurofibrillary tangle; NKB, neurokinin B; NPT, neuropil thread; NPY, neuropeptide Y; POMC, proopiomelanocortin; SP, substance P; SS, somatostatin.

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