Estrogen reduces neuronal generation of Alzheimer β-amyloid peptides

Xu, Huaxi; Gouras, Gunnar K.; Greenfield, Jeffrey P.; Vincent, Bruno; Näslund, Jan; Mazzarelli, Louis; Fried, Gabriel; Jovanovic, Jasmina N.; Seeger, Mary; Relkin, Norman; Liao, Francesca‐Fang; Checler, Frédéric; Buxbaum, Joseph D.; Chait, Brian T.; Wang, Shuai; Sisodia, Sangram S.; Wang, Rong; Greengard, Paul; Gandy, Sam

doi:10.1038/nm0498-447

Cited by 515 publications

(311 citation statements)

References 32 publications

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“…Estradiol increases APP expression in neuronal cells ( [35,109,256]) and reduces Ab peptide production while enhancing its clearance ( [36,137,256]). A modification of Ab levels was induced by estradiol treatment in the Tg2576 AD model [267].…”

Section: Estrogens and Alzheimer's Diseasementioning

confidence: 99%

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Vegeto

Benedusi

Maggi

2008

Frontiers in Neuroendocrinology

271

206

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a b s t r a c tRecent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia.

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Section: Estrogens and Alzheimer's Diseasementioning

confidence: 99%

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Vegeto

Benedusi

Maggi

2008

Frontiers in Neuroendocrinology

271

206

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“…For example, 17␤-estradiol and testosterone have been shown to alter neuronal A␤PP processing toward the non-amyloidogenic pathway both in vitro and in vivo. 17␤-estradiol at concentrations between 2 and 2000 nM increases ␣-A␤PPs production and reduces the generation of A␤ in both mouse and human cell lines and primary cultures of rat, mouse, and human embryonic cerebrocortical neurons (52)(53)(54)(55). Likewise, testosterone treatment (200 -2000 nM) of mouse neuroblastoma cells and rat primary cerebrocortical neurons increases secretion of ␣-A␤PPs and decreases the secretion of A␤ (56).…”

Section: Contribution Of Sex Steroids and Gonadotropins To Amyloidosis-mentioning

confidence: 99%

Luteinizing Hormone, a Reproductive Regulator That Modulates the Processing of Amyloid-β Precursor Protein and Amyloid-β Deposition

Bowen

Verdile

Liu

et al. 2004

Journal of Biological Chemistry

165

132

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Hormonal changes associated with the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis following menopause/andropause have been implicated in the pathogenesis of Alzheimer's disease (AD). Experimental support for this has come from studies demonstrating an increase in amyloid-␤ (A␤) deposition following ovariectomy/castration. Because sex steroids and gonadotropins are both part of the HPG feedback loop, any loss in sex steroids results in a proportionate increase in gonadotropins. To assess whether A␤ generation was due to the loss of serum 17␤-estradiol or to the up-regulation of serum gonadotropins, we treated C57Bl/6J mice with the anti-gonadotropin leuprolide acetate, which suppresses both sex steroids and gonadotropins. Leuprolide acetate treatment resulted in a 3.5-fold (p < 0.0001) and a 1.5-fold (p < 0.024) reduction in total brain A␤1-42 and A␤1-40 concentrations, respectively, after 8 weeks of treatment. To further explore the role of gonadotropins in promoting amyloidogenesis, M17 neuroblastoma cells were treated with the gonadotropin luteinizing hormone (LH) at concentrations equivalent to early adulthood (10 mIU/ml) or post-menopause/andropause (30 mIU/ml). LH did not alter amyloid-␤ precursor protein (A␤PP) expression but did alter A␤PP processing toward the amyloidogenic pathway as evidenced by increased secretion and insolubility of A␤, decreased ␣A␤PP secretion, and increased A␤PP-C99 levels. These results suggest the marked increases in serum LH following menopause/andropause as a physiologically relevant signal that could promote A␤ secretion and deposition in the aging brain. Suppression of the age-related increase in serum gonadotropins using anti-gonadotropin agents may represent a novel therapeutic strategy for AD.Alzheimer's disease (AD) 1 is a neurodegenerative disorder of the elderly that leads to progressive memory loss, impairments in behavior, language, visuo-spatial skills, and ultimately death. The one or more underlying biochemical mechanisms leading to AD are unknown. Genetic studies have shown that mutations in A␤PP and the presenilin genes lead to early onset (Յ65 years) AD, which accounts for ϳ5% of all AD cases. The vast majority of these mutations promote the overproduction and deposition of amyloid-␤ (A␤) (1-7), the major component of the extracellular amyloid plaques, in the hippocampus and frontal cortex (8,9). Amyloid deposition also is a hallmark of the late-onset or "sporadic" form of AD, which accounts for ϳ95% of AD cases. The primary factors responsible for A␤ deposition and disease progression in late onset AD remain to be elucidated.Aging, the strongest risk factor for late-onset AD, is associated with major changes in serum concentrations of all hormones that comprise the hypothalamic-pituitary-gonadal (HPG) axis, including declines in the serum concentrations of the sex steroids, 17␤-estradiol and testosterone. Such changes have been correlated with the prevalence of the disease (e.g. Refs. 10 -14), and it has been shown that there is a decreased i...

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“…It is likely that these protective actions involve a number of other actions of estrogens besides inducing synapses. These include suppression of the production of the toxic form of ␤-amyloid protein (59,153) and inhibition of free radical-induced toxicity (10,48). It should also be noted that estrogens affect many regions of the brain, including the basal forebrain cholinergic systems, the serotonergic system, the dopaminergic system, and the noradrenergic system [for review, see (93,94)], so that the hippocampus is not the only target that may be involved in these cognitive changes.…”

Section: Importance Of Sex Differences and Sex Hormonesmentioning

confidence: 99%

Stress and the Aging Hippocampus

McEwen

1999

Frontiers in Neuroendocrinology

205

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The ''glucocorticoid cascade hypothesis'' of hippocampal aging has stimulated a great deal of research into the neuroendocrine aspects of aging and the role of glucocorticoids, in particular. Besides strengthening the methods for investigating the aging brain, this research has revealed that the interactions between glucocorticoids and hippocampal neurons are far more complicated than originally envisioned and involve the participation of neurotransmitter systems, particularly the excitatory amino acids, as well as calcium ions and neurotrophins. New information has provided insights into the role of early experience in determining individual differences in brain and body aging by setting the reactivity of the hypothalamopituitary-adrenal axis and the autonomic nervous system. As a result of this research and advances in neuroscience and the study of aging, we now have a far more sophisticated view of the interactions among genes, early development, and environmental influences, as well as a greater appreciation of events at the cellular and molecular levels which protect neurons, and a greater appreciation of pathways of neuronal damage and destruction. While documenting the ultimate vulnerability of the brain to stressful challenges and to the aging process, the net result of this research has highlighted the resilience of the brain and offered new hope for treatment strategies for promoting the health of the aging brain. KEY WORDS: stress; hippocampal aging; glucocorticoid cascade hypothesis. 1999 Academic Press INTRODUCTIONThe hippocampus is a particularly vulnerable and sensitive region of the brain that is also very important for declarative and spatial learning and memory (36). Hippocampal neurons are vulnerable to seizures, strokes, and head trauma, as well as responding to stressful experiences (27,92,130). At the same time they show remarkable plasticity, involving long-term synaptic potentiation and depression, dendritic remodeling, synaptic turnover, and neurogenesis in the case of the dentate gyrus (Fig 1) (17,27,92).The work of aus der Muhlen and Ockenfels (3) first drew attention to potentially toxic actions of adrenal steroids. The reported darkly stained neurons in the hippocampus of guinea pigs exposed to high levels of glucocorticoids, an observation that has been confirmed and extended to repeated stress in subsequent studies (41,100), although there are still some doubts as to whether ''dark neurons'' may be artifacts of tissue trauma (18). In 1968, we discovered receptors for adrenal steroids in hippocampus (95), and it is now known that two types of adrenal steroid receptors exist in the hippocampus and other brain regions and mediate a variety of adrenal steroid effects on excitability, neurochemistry, and structure (27). Landfield (68) and then Sapolsky (127,128) provided evidence for a role of adrenal steroids in neuronal aging in the hippocampus, leading to the formulation of the ''glucocorticoid cascade hypothesis '' (130). This hypothesis states that glucocorticoids participate in a ...

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Estrogen reduces neuronal generation of Alzheimer β-amyloid peptides

Cited by 515 publications

References 32 publications

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Luteinizing Hormone, a Reproductive Regulator That Modulates the Processing of Amyloid-β Precursor Protein and Amyloid-β Deposition

Stress and the Aging Hippocampus

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