Estrogens and Alzheimer's disease: is cholesterol a link?

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is more prevalent in women than in men, and menopause, with its associated estrogen deficiency and altered lipid profile, is considered a significant risk factor for AD (1, 2). There is also good clinical evidence that surgical removal of the ovaries before menopause increases the risk of dementia and cognitive impairment in women (3). However, data from the Women’s Health Initiative Memory Study indicate that hormone treatment instituted years after menopause does not protect against dementia or cognitive decline in elderly women (4–6). Another major risk factor for AD is expression of the apolipoprotein E (apoE) allele apoE 4 (7), which is associated with altered circulating cholesterol levels. Experiments in animal models suggest that the welldescribed neurotrophic effects of estrogens depend on apoE, and that the apoE 4 variant is unable to support estrogendependent neurite outgrowth (8, 9). Therefore, it is reasonable to propose that the beneficial effects of estrogen treatment on cognitive function in menopausal women may be influenced by the status of the cholesterol biosynthetic and metabolic pathways as well as other aspects of lipid metabolism (see Ref. 10). The paper by Luciani et al. (11) in this issue of Endocrinology provides yet another clue to the possible interactions between cholesterol and estrogens in the etiology of AD. The ability of 17 -estradiol (E2) to attenuate -amyloidand oxidative stress-induced toxicity in human fetal neurons was abolished when small interfering RNA (siRNA) methods were used to silence the expression of seladin-1 (selective Alzheimer’s disease indicator-1) mRNA. Seladin-1 encodes the cholesterol-synthesizing enzyme 3 hydroxysterol-24-reductase (also known as DHCR24), a gene whose expression level was found to be selectively reduced in cortical regions that are particularly vulnerable to AD pathology (12, 13). E2 treatment increased cell cholesterol content, and this response was also blocked in neurons treated with seladin-1 siRNA. The authors went on to clone the human seladin-1 promoter and to identify functional, half-palindromic estrogen response elements (EREs) upstream of the transcription start site. What sets these findings apart from the dozens of other reports documenting neuroprotective effects of E2 and other estrogens in cultured cells and in vivo (see Refs. 10 and 14 for recent reviews)? First, Luciani and colleagues are one of the few investigators studying human-derived neuronal cells (perhaps more correctly termed neuroblasts). There is still considerable controversy regarding the adequacy of transgenic mouse models to mimic AD neuropathology and cognitive impairment. The long-term cell cultures used in this report (11) are derived from human fetal olfactory neuroepithelium and exhibit many properties of mature olfactory neurons, including electrical excitability, expression of neuron-specific proteins, and responsiveness to odorants (15). They also express endogenous estrogen receptor (ER) and ER , obviating the need to transfect cells and allaying concerns about interpreting the responses of cells that overexpress genes of interest. However, it is legitimate to question how readily one can extrapolate findings in long-term cultures of fetal neuroblasts to the age-related neurodegeneration associated with AD. There is already evidence that expression of seladin-1 is down-regulated when human mesenchymal stem cells are differentiated into neurons (16). Second, the functional analysis of the seladin-1 promoter in this study (11) suggests that the gene is a direct target of transcriptional activation by ER acting at half-palindromic EREs. Transient transfection assays in Chinese hamster ovary cells demonstrated that enhancement of promoter activity required both ligand and ER . The activity of ER was not evaluated, presumably because their previous studies showed that diarylpropionitrile, the ER agonist, has modest effects on seladin-1 mRNA levels in these cells (17). Moreover, two selective ER modulators used clinically for treatment of breast cancer and osteoporosis, tamoxifen and raloxifene, were also able to activate the seladin-1 promoter construct. At some concentrations, these two agents also reduced -amyloid toxicity and increased seladin-1 mRNA (17). If future studies implicate seladin-1 as an estrogenregulated cell survival factor in the aging human brain, this opens the possibility of developing targeted pharmacological therapies to slow the progression of the debilitating cognitive dysfunction and dementia of AD. Third, the use of siRNA methods in the present report (11) provides strong evidence of a causal relationship between the previously observed E2 enhancement of neuron survival in cells exposed to -amyloid or oxidative stress and the apparently ER -mediated up-regulation of seladin-1 mRNA (17). Despite intense efforts to delineate the mechanism(s) underlying E2’s neuroprotective actions in vivo and in cultured neurons, we are still in the early stages of identifying the critical molecular players that determine whether hormone-treated neurons will survive exposure to ischemia, excitotoxicity, oxidative stress, -amyloid, trauma, and other insults. Moreover, it is noteworthy in this study that treating the neuroblasts with E2 also increased cell cholesterol, an effect that was abrogated by seladin-1 siRNA. This provides a suggestive link between estrogen protection and increased cell cholesterol. However, it may seem contrary to the notion that elevated plasma cholesterol is a risk factor for AD and Abbreviations: AD, Alzheimer’s disease; apoE, apolipoprotein E; E2, 17 -estradiol; ER, estrogen receptor; ERE, estrogen response element; seladin-1, selective Alzheimer’s disease indicator-1; siRNA, small interfering RNA.