Affiliations: [a] Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, OR, USA
| [b] Department of Obstetrics and Gynecology, Oregon Health and Sciences University, Portland, OR, USA
| [c] Department of Internal Medicine, Texas Tech Health Science Center, Lubbock, TX, USA
| [d]
Federal University of Santa Catarina, Center of Biological Sciences, Department of Physiological Sciences, Florianópolis, SC, Brazil
Correspondence:
[*]
Correspondence to: Cynthia L. Bethea, PhD, Oregon Health and Science University, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97229, USA. Tel.: +1 503 690 5327; Fax: +1 503 690 5384; E-mail: betheac@ohsu.edu.
Note: [1] The work described in the macaque model was performed by the co-authors during their time in the senior author’s laboratory. The addresses of the co-authors are their current addresses.
Abstract: Serotonin plays a key role in mood or affect, and dysfunction of the serotonin system has been linked to depression in humans and animal models. Depression appears prior to or coincident with overt symptoms of Alzheimer’s disease (AD) in about 50% of patients, and some experts consider it a risk factor for the development of AD. In addition, AD is more prevalent in women, who also show increased incidence of depression. Indeed, it has been proposed that mechanisms underlying depression overlap the mechanisms thought to hasten AD. Women undergo ovarian failure and cessation of ovarian steroid production in middle age and the postmenopausal period correlates with an increase in the onset of depression and AD. This laboratory has examined the many actions of ovarian steroids in the serotonin system of non-human primates using a rhesus macaque model of surgical menopause with short or long-term estradiol (E) or estradiol plus progesterone (E+P) replacement therapy. In this mini-review, we present a brief synopsis of the relevant literature concerning AD, depression, and serotonin. We also present some of our data on serotonin neuron viability, the involvement of the caspase-independent pathway, and apoptosis-inducing factor in serotonin-neuron viability, as well as gene expression related to neurodegeneration and neuron viability in serotonin neurons from adult and aged surgical menopausal macaques. We show that ovarian steroids, particularly E, are crucial for serotonin neuron function and health. In the absence of E, serotonin neurons are endangered and deteriorating toward apoptosis. The possibility that this scenario may proceed or accompany AD in postmenopausal women seems likely.
