Identification of the region of non-A beta component (NAC) of alzheimer's disease amyloid responsible for its aggregation and toxicity

The non-beta-amyloid (Aß) component of Alzheimer's disease amyloid (NAC) and its precursor a-synuclein have been linked to amyloidogenesis in several neurodegenerative diseases. NAC and a-synuclein both form ß-sheet structures upon ageing, aggregate to form fibrils, and are neurotoxic. We recently established that a peptide comprising residues 3±18 of NAC retains these properties. To pinpoint the exact region responsible we have carried out assays of toxicity and physicochemical properties on smaller fragments of NAC. Toxicity was measured by the ability of fresh and aged peptides to inhibit the reduction of the redox dye 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) by rat pheochromocytoma PC12 cells and human neuroblastoma SHSY-5Y cells. On immediate dissolution, or after ageing, the fragments NAC(8±18) and NAC(8±16) are toxic, whereas NAC(12±18), NAC(9±16) and NAC(8±15) are not. Circular dichroism indicates that none of the peptides displays ß-sheet structure; rather all remain random coil throughout 24 h. However, in acetonitrile, an organic solvent known to induce ß sheet, fragments NAC(8±18) and NAC(8±16) both form ß-sheet structure. Only NAC(8±18) aggregates, as indicated by concentration of peptide remaining in solution after 3 days, and forms fibrils, as determined by electron microscopy. These findings indicate that residues 8±16 of NAC, equivalent to residues 68±76 in a-synuclein, comprise the region crucial for toxicity.

Inhibitors of alpha-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson's disease and related disorders.

An abundance of genetic, histopathological, and biochemical evidence has implicated the neuronal protein, alpha-synuclein (alpha-syn) as a key player in the development of several neurodegenerative diseases, the so-called synucleinopathies, of which Parkinson's disease (PD) is the most prevalent. Development of disease appears to be linked to events that increase the intracellular concentration of alpha-syn or cause its chemical modification, either of which can accelerate the rate at which it forms aggregates. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or altered forms of alpha-syn, such as truncations, missense mutations, or chemical modifications by oxidative reactions. Aggregated forms of the protein, especially newly formed soluble aggregates, are toxic to cells, so that one therapeutic strategy would be to reduce the rate at which such oligomerization occurs. We have therefore designed several peptides and also identified small molecules that can inhibit alpha-syn oligomerization and toxicity in vitro. These compounds could serve as lead compounds for the design of new drugs for the treatment of PD and related disorders in the future.

Toxicity of non-abeta component of Alzheimer's disease amyloid, and N-terminal fragments thereof, correlates to formation of beta-sheet structure and fibrils.

Synucleins are small proteins that are highly expressed in brain tissue and are localised at presynaptic terminals in neurons. alpha-Synuclein has been identified as a component of intracellular fibrillar protein deposits in several neurodegenerative diseases, and two mutant forms of alpha-synuclein have been associated with autosomal-dominant Parkinson's Disease. A fragment of alpha-synuclein has also been identified as the non-Abeta component of Alzheimer's Disease amyloid. In this review we describe some structural properties of alpha-synuclein and the two mutant forms, as well as alpha-synuclein fragments, with particular emphasis on their ability to form beta-sheet on ageing and aggregate to form amyloid-like fibrils. Differences in the rates of aggregation and morphologies of the fibrils formed by alpha-synuclein and the two mutant proteins are highlighted. Interactions between alpha-synuclein and other proteins, especially those that are components of amyloid or Lewy bodies, are considered. The toxicity of alpha-synuclein and related peptides towards neurons is also discussing in relation to the aetiology of neurodegenerative diseases.

Integration of shading and texture cues: testing the linear model

One of the first attempts to develop a formal model of depth cue integration is to be found in Maloney and Landy's (1989) "human depth combination rule". They advocate that the combination of depth cues by the visual sysetem is best described by a weighted linear model. The present experiments tested whether the linear combination rule applies to the integration of texture and shading. As would be predicted by a linear combination rule, the weight assigned to the shading cue did vary as a function of its curvature value. However, the weight assigned to the texture cue varied systematically as a function of the curvature value of both cues. Here we descrive a non-linear model which provides a better fit to the data. Redescribing the stimuli in terms of depth rather than curvature reduced the goodness of fit for all models tested. These results support the hypothesis that the locus of cue integration is a curvature map, rather than a depth map. We conclude that the linear comination rule does not generalize to the integration of shading and texture, and that for these cues it is likely that integration occurs after the recovery of surface curvature.

Testing solar forcing of pervasive Holocene climate cycles

The temporal and spatial extent of Holocene climate change is an area of considerable uncertainty, with solar forcing recently proposed to be the origin of cycles identified in the North Atlantic region. To address these issues we have developed an annually resolved record of changes in Irish bog tree populations over the last 7468 years which, together with radiocarbon-dated bog and lake-edge populations, extend the dataset back to 9000 yr ago. The Irish trees underpin the internationally accepted radiocarbon calibration curve, used to derive a proxy of solar activity, and allow us to test solar forcing of Holocene climate change. Tree populations and age structures provide unambiguous evidence of major shifts in Holocene surface moisture, with a dominant cyclicity of 800 yr, similar to marine cycles in the North Atlantic, indicating significant changes in the latitude and intensity of zonal atmospheric circulation across the region. The cycles, however, are not coherent with changes in solar activity (both being on the same absolute timescale), indicating that Holocene North Atlantic climate variability at the millennial and centennial scale is not driven by a linear response to changes in solar activity.