title: Estrogen (E2) and glucocorticoid (Gc) effects on microglia and A beta clearance in vitro and in vivo.
abstract: The accumulation of fibrillar aggregates of beta Amyloid (A beta) in Alzheimer's Disease (AD) brain is associated with chronic brain inflammation. Although activated microglia (mu glia) can potentially clear toxic amyloid, chronic activation may lead to excessive production of neurotoxins. Recent epidemiological and clinical data have raised questions about the use of anti-inflammatory steroids (glucocorticoids, Gcs) and estrogens for treatment or prevention of AD. Since very little is known about steroid effects on mu glial interactions with amyloid, we investigated the effects of the synthetic Gc dexamethasone (DXM) and 17-beta estradiol (E2) in vitro in a murine mu glial-like N9 cell line on toxin production and intracellular A beta accumulation. To determine whether the steroid alterations of A beta uptake in vitro had relevance in vivo, we examined the effects of these steroids on A beta accumulation and mu glial responses to A beta infused into rat brain. Our in vitro data demonstrate for the first time that Gc dose-dependently enhanced mu glial A beta accumulation and support previous work showing that E2 enhances A beta uptake. Despite both steroids enhancing uptake, degradation was impeded, particularly with Gcs. Distinct differences between the two steroids were observed in their effect on toxin production and cell viability. Gc dose-dependently increased toxicity and potentiated A beta induction of nitric oxide, while E2 promoted cell viability and inhibited A beta induction of nitric oxide. The steroid enhancement of mu glial uptake and impedence of degradation observed in vitro were consistent with observations from in vivo studies. In the brains of A beta-infused rats, the mu glial staining in entorhinal cortex layer 3, not associated with A beta deposits was increased in response to A beta infusion and this effect was blocked by feeding rats prednisolone. In contrast, E2 enhanced mu glial staining in A beta-infused rats. A beta-immunoreactive (ir) deposits were quantitatively smaller, appeared denser, and were associated with robust mu glial responses. Despite the fact that steroid produced a smaller more focal deposit, total extracted A beta in cortical homogenate was elevated. Together, the in vivo and in vitro data support a role for steroids in plaque compaction. Our data are also consistent with the hypothesis that although E2 is less potent than Gc in impeding A beta degradation, long term exposure to both steroids could reduce A beta clearance and clinical utility. These data showing Gc potentiation of A beta-induced mu glial toxins may help explain the lack of epidemiological correlation for AD. The failure of both steroids to accelerate A beta degradation may explain their lack of efficacy for treatment of AD.
authors.affiliation: Department of Medicine, UCLA, C-128 RNRC, Los Angeles, CA 90095-1769, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Harris-White
authors.forename: T
authors.initials: T
authors.lastname: Chu
authors.forename: S A
authors.initials: SA
authors.lastname: Miller
authors.forename: M
authors.initials: M
authors.lastname: Simmons
authors.forename: B
authors.initials: B
authors.lastname: Teter
authors.forename: D
authors.initials: D
authors.lastname: Nash
authors.forename: G M
authors.initials: GM
authors.lastname: Cole
authors.forename: S A
authors.initials: SA
authors.lastname: Frautschy
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D011239:Prednisolone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014118:Toxins, Biological / Q000096:biosynthesis
chemical_list: D016229:Amyloid beta-Peptides; D005938:Glucocorticoids; D014118:Toxins, Biological; D009569:Nitric Oxide; D004958:Estradiol; D003907:Dexamethasone; D011239:Prednisolone