Regional Distributions of Iron, Copper and Zinc and Their Relationships With Glia in a Normal Aging Mouse Model.

Microglia and astrocytes can quench metal toxicity to maintain tissue homeostasis, but with age, increasing glial dystrophy alongside metal dyshomeostasis may predispose the aged brain to acquire neurodegenerative diseases. The aim of the present study was to investigate age-related changes in brain metal deposition along with glial distribution in normal C57Bl/6J mice aged 2-, 6-, 19- and 27-months (n = 4/age). Using synchrotron-based X-ray fluorescence elemental mapping, we demonstrated age-related increases in iron, copper, and zinc in the basal ganglia (p < 0.05). Qualitative assessments revealed age-associated increases in iron, particularly in the basal ganglia and zinc in the white matter tracts, while copper showed overt enrichment in the choroid plexus/ventricles. Immunohistochemical staining showed augmented numbers of microglia and astrocytes, as a function of aging, in the basal ganglia (p < 0.05). Moreover, qualitative analysis of the glial immunostaining at the level of the fimbria and ventral commissure, revealed increments in the number of microglia but decrements in astroglia, in older aged mice. Upon morphological evaluation, aged microglia and astroglia displayed enlarged soma and thickened processes, reminiscent of dystrophy. Since glial cells have major roles in metal metabolism, we performed linear regression analysis and found a positive association between iron (R 2 = 0.57, p = 0.0008), copper (R 2 = 0.43, p = 0.0057), and zinc (R 2 = 0.37, p = 0.0132) with microglia in the basal ganglia. Also, higher levels of iron (R 2 = 0.49, p = 0.0025) and zinc (R 2 = 0.27, p = 0.040) were correlated to higher astroglia numbers. Aging was accompanied by a dissociation between metal and glial levels, as we found through the formulation of metal to glia ratios, with regions of basal ganglia being differentially affected. For example, iron to astroglia ratio showed age-related increases in the substantia nigra and globus pallidus, while the ratio was decreased in the striatum. Meanwhile, copper and zinc to astroglia ratios showed a similar regional decline. Our findings suggest that inflammation at the choroid plexus, part of the blood-cerebrospinal-fluid barrier, prompts accumulation of, particularly, copper and iron in the ventricles, implying a compromised barrier system. Moreover, age-related glial dystrophy/senescence appears to disrupt metal homeostasis, likely due to induced oxidative stress, and hence increase the risk of neurodegenerative diseases.

Developmental changes in the mental transformation of spatial arrays.

An experiment was conducted to investigate the spatial memory and transformation of spatial relations in a sample of 7-, 9-, and 11-year-olds and to compare their performance with that of adults. Four pictures of animals were presented at different locations on the outline of a circle. Participants were instructed to memorize the array of locations and then, in a direct retrieval task, to reconstruct it from memory on a piece of paper that included only the circle outline. Then, in the transformation task, participants were asked to randomly place one of the animals at a new position around the circle and then to place the remaining three animals so that object-to-object locations were preserved. Results from the direct retrieval task showed that 7-year-olds were less accurate than older children and adults, whereas 9- and 11-year-olds showed comparable performance to each other and to adults in reconstructing the array. Results from the transformation task revealed that adults were more accurate than children and that 11-year-olds were more accurate than 7-year-olds. There was no difference between 9- and 11-year-olds. Overall, these findings suggest that the ability to perform spatial transformations (a) develops gradually during childhood and (b) has a steeper developmental slope than the simple retrieval of memorized spatial information.

Dissociation between iron accumulation and ferritin upregulation in the aged substantia nigra: attenuation by dietary restriction.

Despite regulation, brain iron increases with aging and may enhance aging processes including neuroinflammation. Increases in magnetic resonance imaging transverse relaxation rates, R2 and R2*, in the brain have been observed during aging. We show R2 and R2* correlate well with iron content via direct correlation to semi-quantitative synchrotron-based X-ray fluorescence iron mapping, with age-associated R2 and R2* increases reflecting iron accumulation. Iron accumulation was concomitant with increased ferritin immunoreactivity in basal ganglia regions except in the substantia nigra (SN). The unexpected dissociation of iron accumulation from ferritin-upregulation in the SN suggests iron dyshomeostasis in the SN. Occurring alongside microgliosis and astrogliosis, iron dyshomeotasis may contribute to the particular vulnerability of the SN. Dietary restriction (DR) has long been touted to ameliorate brain aging and we show DR attenuated age-related in vivo R2 increases in the SN over ages 7 - 19 months, concomitant with normal iron-induction of ferritin expression and decreased microgliosis. Iron is known to induce microgliosis and conversely, microgliosis can induce iron accumulation, which of these may be the initial pathological aging event warrants further investigation. We suggest iron chelation therapies and anti-inflammatory treatments may be putative 'anti-brain aging' therapies and combining these strategies may be synergistic.

A FOXM1 Dependent Mesenchymal-Epithelial Transition in Retinal Pigment Epithelium Cells.

The integrity of the epithelium is maintained by a complex but regulated interplay of processes that allow conversion of a proliferative state into a stably differentiated state. In this study, using human embryonic stem cell (hESC) derived Retinal Pigment Epithelium (RPE) cells as a model; we have investigated the molecular mechanisms that affect attainment of the epithelial phenotype. We demonstrate that RPE undergo a Mesenchymal-Epithelial Transition in culture before acquiring an epithelial phenotype in a FOXM1 dependent manner. We show that FOXM1 directly regulates proliferation of RPE through transcriptional control of cell cycle associated genes. Additionally, FOXM1 modulates expression of the signaling ligands BMP7 and Wnt5B which act reciprocally to enable epithelialization. This data uncovers a novel effect of FOXM1 dependent activities in contributing towards epithelial fate acquisition and furthers our understanding of the molecular regulators of a cell type that is currently being evaluated as a cell therapy.

Correction of steroidopenia as a new method of hypercholesterolemia treatment.

OBJECTIVE: In 2002 we proposed a new hypothesis of the etiology and pathogenesis of hypercholesterolemia. There is paucity of information in the literature regarding the association of steroidopenia and hypercholesterolemia. Our goal is to determine if the treatment of steroidopenia with hormonorestorative therapy (HT) to youthful levels will normalize total cholesterol (TC) levels. MATERIAL AND METHODS: We retrospectively analyzed 43 hypercholesterolemic patients treated with HT. Laboratory workup included lipid profile, serum pregnenolone, dehydroepiandrosterone sulfate (DHEA-S), progesterone, total estrogen, cortisol, total testosterone, and vitamin D-3 levels at presentation with follow up ranging from 3 to 9 months. HT therapy included a combination of several agents such as pregnenolone, dehydroepiandrosterone (DHEA), triestrogen, progesterone, testosterone, hydrocortisone, and vitamin D-3. RESULTS: HT lowered mean TC from 228.8 mg/dL to 183.7 mg/dL (19.7%) (p<0.05) in all patients. In 12 men of mean age 58, HT statistically significantly lowered TC from 227.9 mg/dL to 177.1 mg/dL (22.3%) (p<0.05). Apparently it did so mostly by lowering LDL and triglycerides (TRG) while HDL did not appreciably change. In 31women, mean age 57, TC declined from 229.2 mg/dL to 186.3 mg/dL (19%) (p<0.05). HDL, LDL, and TRG are also decreased to a statistically significant degree. These results were associated with statistically significant elevations in pregnenolone, DHEA Sulfate, testosterone, progesterone but not total estrogen, cortisol or vitamin D-3 changes in both men and women. CONCLUSIONS: We conclude that correction of steroidopenia with the use of hormonorestorative therapy is an effective strategy for normalizing and maintaining cholesterol homeostasis.