The Abeta (amyloid-beta peptide) has long been associated with Alzheimer's disease, originally in the form of extracellular plaques. However, in the present paper we review the growing evidence for the role of soluble intracellular Abeta in the disease progression, with particular reference to Abeta found within the mitochondria. Once inside the cell, Abeta is able to interact with a number of targets, including the mitochondrial proteins ABAD (amyloid-binding alcohol dehydrogenase) and CypD (cyclophilin D), which is a component of the mitochondrial permeability transition pore. Interference with the normal functions of these proteins results in disruption of cell homoeostasis and ultimately cell death. The present review explores the possible mechanisms by which cell death occurs, considering the evidence presented on a molecular, cellular and in vivo level.

It is well established that the intracellular accumulation of Aβ (amyloid β-peptide) is associated with AD (Alzheimer's disease) and that this accumulation is toxic to neurons. The precise mechanism by which this toxicity occurs is not well understood; however, identifying the causes of this toxicity is an essential step towards developing treatments for AD. One intracellular location where the accumulation of Aβ can have a major effect is within mitochondria, where mitochondrial proteins have been identified that act as binding sites for Aβ, and when binding occurs, a toxic response results. At one of these identified sites, an enzyme known as ABAD (amyloid-binding alcohol dehydrogenase), we have identified changes in gene expression in the brain cortex, following Aβ accumulation within mitochondria. Specifically, we have identified two proteins that are up-regulated not only in the brains of transgenic animal models of AD but also in those of human sufferers. The increased expression of these proteins demonstrates the complex and counteracting pathways that are activated in AD. Previous studies have identified approximate contact sites between ABAD and Aβ; on basis of these observations, we have shown that by using a modified peptide approach it is possible to reverse the expression of these two proteins in living transgenic animals and also to recover mitochondrial and behavioural deficits. This indicates that the ABAD-Aβ interaction is potentially an interesting target for therapeutic intervention. To explore this further we used a fluorescing substrate mimic to measure the activity of ABAD within living cells, and in addition we have identified chemical fragments that bind to ABAD, using a thermal shift assay.

The association of 17β-hydroxysteroid dehydrogenase 10 (HSD10) with β-amyloid in the brain is known to contribute to the progression of Alzheimer's disease. Further, it has been shown that the interaction between the purified HSD10 and β-amyloid inhibits its enzymatic activity. However, to date no system has been developed to enable the study of HSD10 activity in intact living cells. To address this significant shortcoming, we have developed a novel fluorogenic probe, (-)-cyclohexenyl amino naphthalene alcohol [(-)-CHANA], to observe and measure the activity of HSD10 in living cells. The oxidation of (-)-CHANA by HSD10 results in the production and accumulation of a fluorescent product, which can be measured using real-time fluorescence microscopy. This compound permits the measurement of mitochondrial HSD10 activity and its inhibition by both a small molecule HSD10 inhibitor and by β-amyloid, in living cells. Herein, we define the parameters under which this probe can be used. This compound is likely to prove useful in future investigations aimed at developing therapeutic compounds targeting the HSD10-β-amyloid association.

Guanidine‐ and arginine‐containing proteins are commonly used in the manufacture of formaldehyde‐based thermosetting resins; however, the polymer structures of these resins were not known. 13C‐NMR spectroscopy has now been applied to demonstrate that guanidine does react and form crosslinks in formaldehyde reactions. Ethylguanidine was used to model arginine in soy proteins, and the NMR analysis indicates that guanidine side chains in proteins also react and form crosslinks in biobased adhesives. Furthermore, these reaction products change with pH demonstrating that the formation of desired polymer species can be controlled and optimized. Finally, the products of the two most widely manufactured amino resins, melamine–formaldehyde and urea–formaldehyde, were then compared with those of guanidine–formaldehyde and ethylguanidine–formaldehyde. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012

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