The effects of estrogens on cognition and Alzheimer's dementia

Abstract

Several lines of evidence suggest that mood and behavior effects of estrogen reflect the direct action of this hormone on neurons and other components of the central nervous system (CNS). Elements within the CNS that are responsive to estrogens encompass structural neuronal systems, blood flow, energy delivery and utilization, dendrite activity, neurotransmitters, and neuromodulators as well as intraneuronal and other processes. Estrogens readily cross the blood-brain barrier where they interact with nuclear estrogen receptors present in neuronal populations from different brain regions and with membrane-bound receptors (Sherwin 1997; Kawata 1995). Estrogen modulates growth proteins specifically associated with axonal elongation (Shugrue and Dorsa 1993), enhances the outgrowth or nerve processes in cultured neurons (Toran- Allerand 1984), and promotes the formation of dendrite spines and synapses (Chung et al. 1988). The viability of in vitro cultures of differentiated amygdala (Arimatsu and Hatamaka 1986) or hypothalamic (Faivre-Bauman et al. 1981) neurons is prolonged by the addition of estrogen. Neurite outgrowth in the developing brain is stimulated by estrogens (Toran-Allerand 1993). Dendritic growth is stimulated by estrogen and is responsive to the hormonal fluctuations along the estrous cycle (McEwen et al. 1997). The physiological relevance of some of these estrogen effects is suggested by enhanced long-term potentiation (Warren et al. 1995), in parallel with increased synapse formation in the CA1 region of the hippocampus (Woolley and McEwen 1993) during the proestrus (high-estrogen) phase of the rat estrus cycle. Estrogen influences several neurotransmitter systems, including those using acetylcholine (Singh et al. 1994), norepinephrine (Sar and Stumpf 1981), serotonin (Kendall et al. 1981), dopamine (Toran-Allerand 1984), and other neurotransmitters. Cholinergic and noradrenergic neurons from the basal forebrain, noradrenergic neurons from the brain stem locus caeruleus, and serotonergic neurons from the midbrain regions are all substantially affected by estrogens (Coyle et al. 1983). Estrogen's interactions with the cholinergic systems are especially noteworthy in the context of this chapter. Cholinergic mechanisms are critically involved in attentional processes, learning, and memory: cognitive functions that are critically affected by Alzheimer's disease (AD) (Bartus et al. 1981). Basal forebrain cholinergic neurons possess nuclear receptors for estrogen and low-affinity receptors for nerve growth factor (Torran-Allerand et al. 1992). Nerve growth factor prevents atrophy of cholinergic neurons after experimental injury (Hefti et al. 1993), and estrogens may regulate or modulate neurotrophins (Sorabji et al. 1994). Even though the hippocampus contains few estrogen and progestin receptors, this structure displays a robust response to exposure to exogenous estrogen and progestin treatment and to endogenous ovarian steroids during the natural estrous cycle (Toran-Allerand 1984). This first became apparent with the finding of cyclic variations in the threshold of the dorsal hippocampus to elicitation of seizures, with the greatest sensitivity occurring during proestrus (Terasawa and Timiras 1968). Morphologic studies indicate that estrogen induces dendritic spines and new synapses in the venteromedial hypothalamus of the female rat but also increases density of dendritic spines on pyramidal neurons in the hippocampus (McEwen and Woolley 1994). Spine density also changes cyclically during the estrus cycle of the female rat. These findings indicate that synapses are formed and broken down rapidly during the natural reproductive cycle. It is of significance that several gender differences in brain development are regulated by estrogen. In the CAl region of males, estrogen treatment fails to induce as great a number of spine synapses as in females, but blockade at birth of the aromatization of testosterone to estradiol in male neonates increases the number of spine synapses induced by estrogen treatment in adulthood (Wong and Moss 1992). This suggests that the responsiveness of the hippocampus to estrogenic regulation of synapse formation is defeminized in males by the neonatal actions of testosterone. Ovarian steroids regulate the midbrain serotonergic system by mechanisms as yet undefined. Estrogen increases serotonergic post synaptic responsivity (Rosencrans 1970) and increases both the number of serotonergic receptors and neurotransmitter uptake (Rosencrans 1970). Estrogen also increases 5-hydroxytryptamine (5-HT) synthesis and 5-HTlA levels; it upregulates 5-HT1 receptors and downregulates 5-HT2 receptors. It decreases monoamine oxidase activity (Chakravorthy and Halbreich 1997) and increases the responsitivity of postsynaptic receptors to stimulation with the serotonergic agonist mCPP (Halbreich et al. 1995. The cumulative effect of estrogen on serotonergic function is as a 5-HT agonist (Kahn and Halbreich 1999). © 2005 Springer-Verlag/Wien.