X-ray fluorescence microscopic measurement of elemental distribution in the mouse retina with age.

The biologically important metals such as zinc, copper and iron play key roles in retinal function, yet no study has mapped the spatio-temporal distribution of retinal biometals in healthy or diseased retina. We investigated a natural mouse model of retinal degeneration, the Cln6nclf mouse. As dysfunctional metabolism of biometals is observed in the brains of these animals and deregulated metal homeostasis has been linked to retinal degeneration, we focused on mapping the elemental distribution in the healthy and Cln6nclf mouse retina with age. Retinal and RPE elemental homeostasis was mapped in Cln6nclf and C57BL6/J mice from 1 to 8 months of age using X-ray Fluorescence Microscopy at the Australian Synchrotron. In the healthy retina, we detected a progressive loss of phosphorus in the outer nuclear layer and significant reduction in iron in the inner segments of the photoreceptors. Further investigation revealed a unique elemental signature for each retinal layer, with high areal concentrations of iron and sulfur in the photoreceptor segments and calcium, phosphorus, zinc and potassium enrichment predominantly in the nuclear layers. The analysis of retinae from Cln6nclf mice did not show significant temporal changes in elemental distributions compared to age matched controls, despite significant photoreceptor cell loss. Our data therefore demonstrates that retinal layers have unique elemental composition. Elemental distribution is, with few exceptions, stably maintained over time in healthy and Cln6nclf mouse retina, suggesting conservation of elemental distribution is critical for basic retinal function with age and is not modulated by processes underlying retinal degeneration.

Quantitative determination of metal and metalloid spatial distribution in hydrated and fresh roots of cowpea using synchrotron-based X-ray fluorescence microscopy.

Many metals and metalloids, jointly termed metal(loid)s, are toxic to plants even at low levels. This has limited the study of their uptake, distribution, and modes of action in plant roots grown at physiologically relevant concentrations. Synchrotron-based X-ray fluorescence microscopy was used to examine metal(loid)s in hydrated cowpea (Vigna unguiculata L.) roots exposed to Zn(II), Ni(II), Mn(II), Cu(II), Hg(II), Se(IV), Se(VI), As(III), or As(V). Development of a mathematical model enabled in situ quantitative determination of their distribution in root tissues. The binding strength of metals influenced the extent of their movement through the root cylinder, which influenced the toxic effects exerted-metals (e.g. Cu, Hg) that bind more strongly to hard ligands had high concentrations in the rhizodermis and caused this tissue to rupture, while other metals (e.g. Ni, Zn) moved further into the root cylinder and did not cause ruptures. When longitudinal distributions were examined, the highest Se concentration in roots exposed to Se(VI) was in the more proximal root tissues, suggesting that Se(VI) is readily loaded into the stele. This contrasted with other metal(loid)s (e.g. Mn, As), which accumulated in the apex. These differences in metal(loid) spatial distribution provide valuable quantitative data on metal(loid) physiology, including uptake, transport, and toxicity in plant roots.

beta-Amyloid as a molecular therapeutic target in Alzheimer's disease.

Alzheimer's disease is the most common form of dementia, primarily affecting individuals during or after their sixth decade of life. Despite decades of research, there are still no effective disease-modifying drugs available to treat this neurodegenerative disorder. Current FDA-approved medications primarily offer symptomatic relief and are based upon known neurotransmitter deficits. There are, however, many drugs in preclinical and clinical development which target other aspects of AD pathogenesis. Principal among these are drugs which modulate beta-amyloid, a protein that is believed to be central to the cascade which leads to the development of Alzheimer's disease. This article will outline the metabolism of beta-amyloid and review a number of different strategies, including pitfalls and future directions of such methods that are directed towards the modulation of this protein. It will become clear that beta-amyloid represents a potent molecular target for pharmacological manipulation to perhaps prevent the onset and progression of Alzheimer's disease.