Human chorionic gonadotropin (a luteinizing hormone homologue) decreases spatial memory and increases brain amyloid-β levels in female rats

Abstract

Numerous studies have suggested that estradiol (E) improves spatial memory as female rats with E perform better than those without E. However there is an inverse relationship between E and luteinizing hormone (LH) levels and LH could play a role. We examined whether treatment with the LH homologue human chorionic gonadotropin (hCG), would impair spatial memory of adult Etreated female rats. In the Object Location Memory Task, ovariectomized (ovxed) rats treated with E and either a single high dose (400IU/kg) or a lower repeated dose of hCG (75 IU/kg hourly for 8 hours) showed spatial memory disruption compared to ovxed rats treated with estradiol alone. Impairment was attributed to memory disruption as performance improved with shortened delay between task exposure and testing. Tests on another spatial memory task, the Barnes maze, confirmed that hCG (400IU/kg) can impair memory: although E + veh treated animals made significantly fewer hole errors across time, E + hCG treated did not. In humans, high LH levels have been correlated with Alzheimer's Disease (AD). Because brain amyloid-beta (Aβ) species have been implicated as a toxic factor thought to cause memory loss in AD, we analyzed whether hCG-treated animals had increased Aβ levels. Levels of Aβ from whole brains or hippocampi were assessed by Western Blot. hCG treatment to E-implanted females significantly increased soluble Aβ40 and Aβ42 levels. These results indicate that high levels of LH/hCG can impair spatial memory, and an increase in brain Aβ species may account for the memory impairment in hCG-treated rats.

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…For examples, total brain levels of A␤, a traditional histological marker for AD, are increased by high LH levels [such as after ovariectomy (Frye et al, 2007)], and decreased by the gonadotropin superagonist leuprolide acetate Casadesus et al, 2006;Berry et al, 2008). Cogni-1 Abbreviations: A␤, amyloid ␤; A␤PP, amyloid ␤ precursor protein; ACT, ␣1-antichymotrypsin; AD, Alzheimer's disease; Akt, protein kinase B; apoE, apolipoprotein E; BBB, blood-brain barrier; CD14, cluster determinant 14; CNS, central nervous system; CRP, C-reactive protein; CSF, cerebrospinal fluid; DPP-4, dipeptidyl peptidase-4; EPO, erythropoietin; FSH, follicle-stimulating hormone; GLP-1, glucagon-like peptide-1; GSK, glycogen synthase kinase; IFN, interferon; IL, interleukin; LH, luteinizing hormone; NP12, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; SB216763, 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione; SZT, streptozotocin; T2DM, type 2 diabetes; TBI, traumatic brain injury; TNF, tumor necrosis factor.…”

Direct Exposure of Guinea Pig CNS to Human Luteinizing Hormone Increases Cerebrospinal Fluid and Cerebral Beta Amyloid Levels

“…More recently, a small percentage (<1%) of radio-labelled human chorionic gonadotropin (hCG) injected into rats was shown to cross the blood-brain barrier (BBB) into the CSF and was also detected in the hippocampus [10]. In addition, peripheral administration of the LH analogue, hCG, to rodents has been shown to impair hippocampal-associated behaviours [10,11,12]. Together, these studies provide evidence that systemic gonadotropins can enter the CNS and can impact on memory and learning.…”

“…We have previously shown that exposure of neuronal cells in culture to LH results in an accumulation of Aβ. Further, our group and others have shown that peripheral administration of hCG to rodents increases cerebral Aβ [11,12]. However, whether LH directly alters Aβ metabolism in the CNS in vivoremains to be determined.…”

Sex difference and menstrual cycle effects on semantic priming and remembering<p>Anlamsal hazırlama ve hatırlamada cinsiyet farkı ve menstural dönem etkileri

“…Casadesus et al, 2006) support the relationship between LH levels and Alzheimer's diesease. They show that high LH levels diminish the memory performance (Berry, Tomidokoro, Ghiso, & Thornton, 2008). Thus, in our study we speculate that the poorer memory performance of women in ovulation phase might be correlated with the LH levels that was assumed to be highest in ovulatory phase of the menstrual cycle.…”