Mitochondrial β-amyloid in Alzheimer's disease

Abstract

It is well established that the intracellular accumulation of beta-amyloid is associated with 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 in developing treatments for Alzheimer’s disease. One intracellular location where the accumulation of beta-amyloid can have a major effect is within mitochondria has identified mitochondrial proteins that act as binding sites for beta-amyloid and when binding occurs a toxic response results. For one of these identified sites, an enzyme known as ‘ABAD’, we have identified the changes in gene expression in the brain cortex following beta-amyloid accumulation within mitochondria. Specifically, we have identified two proteins that are upregulated in the brains of transgenic animal models for Alzheimer’s disease but also human sufferers. The increased expression of these proteins demonstrates the complex and counter-acting pathways that are activated in Alzheimer’s disease. Previous studies have identified the approximate contact sites between ABAD and beta-amyloid, and based on these observations we have shown that using a modified peptide approach, it is possible to reverse the expression of these two proteins in living transgenic animals and also recover both mitochondrial and behavioural deficits. This indicates that the ABAD-beta-amyloid 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, by using a thermal shift assay.