Local amplification of glucocorticoids in the aging brain and impaired spatial memory

The hippocampus is a prime target for glucocorticoids (GCs) and a brain structure particularly vulnerable to ageing. Prolonged exposure to excess GCs compromises hippocampal electrophysiology, structure and function. Blood GC levels tend to increase with ageing and correlate with impaired spatial memory in ageing rodents and humans. The magnitude of GC action within tissues depends not only on levels of steroid hormone that enter the cells from the periphery and the density of intracellular receptors but also on the local metabolism of GCs by 11ß-hydroxysteroid dehydrogenases (11ß-HSD). The predominant isozyme in the adult brain, 11ß-HSD1, locally regenerates active GCs from inert 11-keto forms thus amplifying GC levels within specific target cells including in the hippocampus and cortex. Ageing associates with elevated hippocampal and neocortical 11ß-HSD1 and impaired spatial learning while deficiency of 11ß-HSD1 in knockout mice prevents the emergence of cognitive decline with age. Furthermore, short-term pharmacological inhibition of 11ß-HSD1 in already aged mice reverses spatial memory impairments. Here, we review research findings that support a key role for GCs with special emphasis on their intracellular regulation by 11ß-HSD1 in the emergence of spatial memory deficits with ageing, and discuss the use of 11ß-HSD1 inhibitors as a promising novel treatment in ameliorating/improving age-related memory impairments

Prenatal Stress, Glucocorticoids and the Programming of Adult Disease

Numerous clinical studies associate an adverse prenatal environment with the development of cardio-metabolic disorders and neuroendocrine dysfunction, as well as an increased risk of psychiatric diseases in later life. Experimentally, prenatal exposure to stress or excess glucocorticoids in a variety of animal models can malprogram offspring physiology, resulting in a reduction in birth weight and subsequently increasing the likelihood of disorders of cardiovascular function, glucose homeostasis, hypothalamic–pituitary–adrenal (HPA) axis activity and anxiety-related behaviours in adulthood. During fetal development, placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) provides a barrier to maternal glucocorticoids. Reduced placental 11β-HSD2 in human pregnancy correlates with lower birth weight and higher blood pressure in later life. Similarly, in animal models, inhibition or knockout of placental 11β-HSD2 lowers offspring birth weight, in part by reducing glucose delivery to the developing fetus in late gestation. Molecular mechanisms thought to underlie the programming effects of early life stress and glucocorticoids include epigenetic changes in target chromatin, notably affecting tissue-specific expression of the intracellular glucocorticoid receptor (GR). As such, excess glucocorticoids in early life can permanently alter tissue glucocorticoid signalling, effects which may have short-term adaptive benefits but increase the risk of later disease

Enhanced hippocampal long-term potentiation and spatial learning in aged 11ß-hydroxysteroid dehydrogenase type 1 knock-out mice

Glucocorticoids are pivotal in the maintenance of memory and cognitive functions as well as other essential physiological processes including energy metabolism, stress responses, and cell proliferation. Normal aging in both rodents and humans is often characterized by elevated glucocorticoid levels that correlate with hippocampus-dependent memory impairments. 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) amplifies local intracellular ("intracrine") glucocorticoid action; in the brain it is highly expressed in the hippocampus. We investigated whether the impact of 11ß-HSD1 deficiency in knock-out mice (congenic on C57BL/6J strain) on cognitive function with aging reflects direct CNS or indirect effects of altered peripheral insulin-glucose metabolism. Spatial learning and memory was enhanced in 12 month "middle-aged" and 24 month "aged" 11ß-HSD1<sup>–/–</sup> mice compared with age-matched congenic controls. These effects were not caused by alterations in other cognitive (working memory in a spontaneous alternation task) or affective domains (anxiety-related behaviors), to changes in plasma corticosterone or glucose levels, or to altered age-related pathologies in 11ß-HSD1<sup>–/–</sup> mice. Young 11ß-HSD1<sup>–/–</sup> mice showed significantly increased newborn cell proliferation in the dentate gyrus, but this was not maintained into aging. Long-term potentiation was significantly enhanced in subfield CA1 of hippocampal slices from aged 11ß-HSD1<sup>–/–</sup> mice. These data suggest that 11ß-HSD1 deficiency enhances synaptic potentiation in the aged hippocampus and this may underlie the better maintenance of learning and memory with aging, which occurs in the absence of increased neurogenesis

Exclusion of the Locus for Autosomal Recessive Pseudohypoaldosteronism Type 1 from the Mineralocorticoid Receptor Gene Region on Human Chromosome 4q by Linkage Analysis.

Pseudohypoaldosteronism type 1 (PHA1) is an uncommon inherited disorder characterized by salt-wasting in infancy arising from target organ unresponsiveness to mineralocorticoids. Clinical expression of the disease varies from severely affected infants who may die to apparently asymptomatic individuals. Inheritance is Mendelian and may be either autosomal dominant or autosomal recessive. A defect in the mineralocorticoid receptor has been implicated as a likely cause of PHA1. The gene for human mineralocorticoid receptor (MLR) has been cloned and physically mapped to human chromosome 4q31.1-31.2. The etiological role of MLR in autosomal recessive PHA1 was investigated by performing linkage analysis between PHA1 and three simple sequence length polymorphisms (D4S192, D4S1548, and D4S413) on chromosome 4q in 10 consanguineous families. Linkage analysis was carried out assuming autosomal recessive inheritance with full penetrance and zero phenocopy rate using the MLINK program for two-point analysis and the HOMOZ program for multipoint analysis. Lod scores of less than -2 were obtained over the whole region from D4S192 to D4S413 encompassing MLR. This provdes evidence against MLR as the site of mutations causing PHA1 in the majority of autosomal recessive families

Maternal obesity has little effect on the immediate offspring but impacts on the next generation

Maternal obesity during pregnancy has been linked to an increased risk of obesity and cardiometabolic disease in the offspring, a phenomenon attributed to developmental programming. Programming effects may be transmissible across generations through both maternal and paternal inheritance, although the mechanisms remain unclear. Using a mouse model, we explored the effects of moderate maternal diet-induced obesity (DIO) on weight gain and glucose-insulin homeostasis in first-generation (F1) and second-generation offspring. DIO was associated with insulin resistance, hyperglycemia and dyslipidemia before pregnancy. Birth weight was reduced in female offspring of DIO mothers (by 6%, P = .039), and DIO offspring were heavier than controls at weaning (males by 47%, females by 27%), however there were no differences in glucose tolerance, plasma lipids, or hepatic gene expression at 6 months. Despite the relative lack of effects in the F1, we found clear fetal growth restriction and persistent metabolic changes in otherwise unmanipulated second-generation offspring with effects on birth weight, insulin levels, and hepatic gene expression that were transmitted through both maternal and paternal lines. This suggests that the consequences of the current dietary obesity epidemic may also have an impact on the descendants of obese individuals, even when the phenotype of the F1 appears largely unaffected

Molecular genotyping of placental site and epithelioid trophoblastic tumours; female predominance

OBJECTIVE: To investigate a large series of placental site trophoblastic tumours (PSTT) and epithelioid trophoblastic tumours (ETT) and determine the relationship between their development and the type and sex of both the immediately antecedent and causative pregnancies. METHODS: The antecedent pregnancy was determined from patient records in 92 cases with a confirmed diagnosis of PSTT, ETT or mixed PSTT/ETT. In a subset of 57 cases, type and sex of the causative pregnancy was established by molecular genotyping of patient and tumour tissue microdissected from formalin-fixed, paraffin-embedded blocks. RESULTS: The antecedent pregnancy was a normal live birth in 59 (64%) cases, a hydatidiform mole in 19 (21%) and other pregnancy loss in 14 (15%). Where the sex was recorded, 36 (78%) of 46 antecedent normal pregnancies were female, a significantly greater proportion than expected (p<0.0001). Genotyping of 57 cases found 15 (26%) to derive from hydatidiform moles while 42 (74%) arose in non-molar pregnancies. Where the causative pregnancy was non-molar, 38 (91%) tumours arose in female conceptions, significantly greater than expected (p <0.0001). Analysis of short tandem repeats on the X chromosome in three tumours with an XY chromosomal constitution confirmed that the X chromosome was maternal in origin. CONCLUSIONS: PSTT and ETT predominantly arise in female pregnancies but can develop in male pregnancies. A male derived X chromosome is not required for the development of these tumours. While these tumours are predominantly female it is not because most originate in complete hydatidiform moles