The role of estrogen regulation in brain development and neurodegeneration

Abstract: Estrogen is a steroid hormone which regulates neuronal control of reproduction. It has other important roles in the central nervous system (CNS), including trophic effects on dendritic spine morphology that provide structural plasticity. Estrogen also modulates neurotransmission and protects the brain against neurodegeneration by enhancing cell survival. The mechanisms behind the multitude of estrogen effects in the nervous system are still not well-understood. In addition, most knowledge regarding estrogen action in the brain originates from animal studies; and the role of estrogen in the human nervous system has still not been elucidated. The overall aim of the work presented in this thesis was to explore how estrogen may influence the development of the nervous system and protect against neurodegeneration. A second aim was to investigate how cholesterol, which is gaining importance in neuronal physiology, may modulate cellsignaling pathways. The model was primary cell cultures of neuronal and glial cells of human origin. These cell cultures were derived from fetal nervous tissue obtained with the patient s permission at surgical abortions. Our gene-expression microarray analysis of human neuronal and glial cells in culture showed that the following genes are regulated by estrogen: Sox2 and Notch1, which are proposed to be involved in maintaining cells in a progenitor state during neuronal development, CDK5R1 which may be involved in neuronal migration as is TCF7L2 in pituitary development, Synaptotagmin 11, a vesicle-trafficking protein and Transgelin, of as yet unknown function in the CNS. Estrogen protects against neurodegeneration caused by Alzheimer s disease (AD), which is a form of dementia with fatal outcome. At cellular level estrogen influences processing of the amyloid precursor protein (APP), which is altered in AD and yields pathological accumulation of amyloid beta peptide. However, the mechanism behind this is unknown. We found that estrogen is able to regulate the enzymes involved in APP metabolism, i.e. gene expression of TACE (alpha-secretase) and presenilin 1 (gamma-secretase) and, most importantly, the protein expression of BACE (beta-secretase). Estrogen also has non-genomic mechanisms, which are mediated by second messengers and cellular signaling pathways. We have shown that the PI3K pathway, which is involved in both structural plasticity and cell survival, is activated in human neurons by increased Akt phosphorylation by estrogen coupled to BSA, which is believed to be membrane-impermeable. This estrogen-mediated signaling is attenuated by pharmacological cholesterol depletion of the cell membrane. These findings indicate that estrogen initiates this signaling pathway at the plasma membrane. Investigation of the effect of cholesterol depletion on cell signaling via serotonin receptors showed that 5-HT1A mediated decrease in MAPK and CREB phosphorylation was attenuated by prior cholesterol depletion. These findings increase our knowledge regarding estrogen action in human fetal brain cells. They also indicate the important function of cholesterol in cell signaling. In conclusion they support the notion that estrogen in brain regulates function, development and neuroprotection.