Mechanisms for neuroprotective effects of estrogens: the role of cholesterol

There is experimental and clinical evidence that estrogens have neuroprotective effects. Nevertheless, the role of this class of hormones in the prevention or treatment of neurodegenerative diseases, and among these Alzheimer’s disease (AD), remains a controversial issue. At the beginning of the new millennium, a new gene, named seladin-1 (for Selective Alzheimer’s Disease indicator-1), was identified and found to be down regulated in vulnerable brain regions in AD. Seladin-1 was found to have neuroprotective properties, because of its anti-apoptotic activity. It was demonstrated that seladin-1 has also enzymatic activity [3-β-hydroxysterol delta-24-reductase, (DHCR24)]. DHCR24 is the enzyme that converts desmosterol into cholesterol. There is evidence that an optimal amount of membrane cholesterol is required to protect neuronal cells against toxic insults and to inhibit the production of beta-amyloid, the hallmark of AD. Our recent research activity was focused on the possible relationship between estrogens, membrane cholesterol and neuroprotection. We first demonstrated that estrogens increase the expression of seladin-1 and the amount of cell cholesterol in human neuronal precursors. Functionally, active half-palindromic estrogen responsive elements were identified upstream the coding region of the seladin-1 gene. Estrogens treatment effectively protected these cells against beta-amyloid toxicity and oxidative stress. Then, we found that, upon seladin-1 silencing, the protective effects of estrogens were abolished, thus indicating that this protein can be regarded as a fundamental mediator of the neuroprotective effects of these hormones. Overall, our results indicate that seladin-1 may be considered a multi-faceted protein, which appears to play an important role in brain homeostasis as a link between estrogens and cholesterol.