An N-terminal truncated isoform of the amyloid beta-peptide (A beta) that begins with a pyroglutamate (pE) residue at position 3 [A beta3(pE)-42] is the predominant isoform found in senile plaques. Based upon previous in vitro studies regarding A beta N-terminal truncated isoforms, it has been hypothesized that A beta3(pE)-x isoforms may aggregate more rapidly and become more toxic than corresponding Abeta1-x peptides. However, the toxicity and aggregation properties of A beta3(pE)-42 and A beta3(pE)-40 have not previously been examined. After initial solubilization and 1-week preaggregation of each peptide at 37 degrees C and pH 7.4, the toxicity of 5-50 microM A beta3(pE)-42 was similar to that of A beta1-42. Moreover, the toxicity of A beta3(pE)-40 paralleled that induced by A beta1-40 in both 1 day in vitro (DIV) cortical and 7 DIV hippocampal cells. Circular dichroism spectra did not reveal major differences in secondary structure between aged A beta1-42, A beta3(pE)-42, A beta3(pE)-40, and A beta1-40 or freshly solubilized forms of these peptides. Overall, the data indicate that the loss of the two N-terminal amino acids and the cyclization of glutamate at position 3 do not alter the extracellular toxicity of A beta.

Unveiling interactions between labeling molecules and amyloid fibrils is essential to develop new detection methods for studying amyloid structures under various conditions. This review endeavours to reflect the progress in studying interactions between molecular inhibitors and amyloid peptides using a series of experimental approaches, such as X-ray diffraction, nuclear magnetic resonance, scanning probe microscopy, and electron microscopy. The revealed binding mechanisms of anti-amyloid drugs and target proteins could benefit the rational design of drugs for prevention or treatment of amyloidal diseases.

The binding behaviour of labeling molecule copper phthalocyanine tetrasulfonate sodium (PcCu(SO(3)Na)(4)) on the assemblies of representative polyamino acids has been studied by using scanning tunneling microscopy (STM). By directly visualizing the adsorption and distribution of the labeling species on the peptide assemblies in STM images, one could obtain relative binding affinities of the labeling molecule with different amino acid residues.

Accumulation and aggregation of β-amyloid (Aβ) peptides result in neuronal death, leading to cognitive dysfunction in Alzheimer's disease. The self-assembled Aβ molecules form various intermediate aggregates including oligomers that are more toxic to neurons than the mature aggregates, including fibrils. Thus, one strategy to alleviate Aβ toxicity is to facilitate the conversion of Aβ intermediates to larger aggregates such as fibrils. In this study, we designed a peptide named A3 that significantly enhanced the formation of amorphous aggregates of Aβ by accelerating the aggregation kinetics. Thioflavin T fluorescence experiments revealed an accelerated aggregation of Aβ monomers, accompanying reduced Aβ cytotoxicity. Transgenic Caenorhabditis elegans over-expressing amyloid precursor protein exhibited paralysis due to the accumulation of Aβ oligomers, and this phenotype was attenuated by feeding the animals with A3 peptide. These findings suggest that the Aβ aggregation-promotion effect can potentially be useful for developing strategies to reduce Aβ toxicity.

The peptide assembly structures of polyglutamine (PolyQ) have been studied by using scanning tunneling microscopy (STM) with high spatial resolution in ambient conditions. 4,4'-Bipyridyl (4Bpy) was introduced into the PolyQ 7 and PolyQ 8 peptide assemblies for labeling the C-termini of the peptides. The fine structures of the 4Bpy-PolyQ 7 and 4Bpy-PolyQ 8 co-assemblies are observed, and the statistics of the apparent peptide strand length reveal different length distributions for PolyQ 7 and PolyQ 8 . One predominant apparent peptide strand length is observed for PolyQ 7 reflecting one predominant peptide conformation in assembly structures, while three major apparent strand lengths can be identified with PolyQ 8 reflecting three co-existing peptide conformations in peptide assemblies. Such drastic difference in assembling characteristics can be considered as a reflection of asymmetric adsorption effect of peptides relating to odd-even residue numbers of PolyQ 7 and PolyQ 8 .