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Alzheimer disease progression: Molecular studies of Abeta amyloid peptides aggregation and trafficking in neuronal cells

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Getting down to the molecular level of Alzheimer's disease

A European project is investigating the biochemistry of Alzheimer's disease. The roles of proteins and their mutants, inflammation and damaging reactive oxygen species are coming together to complete the molecular jigsaw of this distressing condition.


A small peptide molecule, just one tiny strand of amino acids, is the main constituent of the damaging plaques found in the brains of Alzheimer's disease (AD) patients. Amyloid beta (Abeta) peptides make up the large destructive masses of amyloid deposits in the brain. Recent research has suggested it is the intermediates to these amyloids that cause the dysfunction of the nerve cells, not the large aggregates themselves. Boosting this theory, small molecules (oligomers) of Abeta have previously been found to cause degeneration of the links between nerve cells (synapses). The EU-funded Adprogres project is investigating how Abeta peptides behave biochemically to induce this neurodegenerative chaos. Interaction of Abeta molecules with the boundary membranes, plasma membranes, of nerve cells and at the synapses where the neurons connect has so far been poorly understood. The scientists also probed the action of a mutant Abeta molecule known as Ab10Para. Interestingly, this modified molecule blocked the formation of toxic oligomers and inhibited damaging reactive oxygen species (ROS) formation, thereby causing less oxygen stress. The research included an investigation of the receptor for advanced glycation end products (RAGE). Certain biochemical activity of RAGE is thought to instigate pro-inflammatory gene activation and has been implicated in other diseases like diabetes type 2 as well as AD. A protein, thioredoxin-interacting protein (TXNIP), has been found to mediate RAGE function. The project scientists found that there is a glut of TXNIP in mice with AD, implicating a role for this protein in the development of AD even further. Further research is planned before the end of this project, notably on the roles of both RAGE and TXNIP in the development of AD. AD is responsible for a huge social and financial burden. The Adprogres project is continuing to unravel the molecular cascades responsible for the disease – a huge step towards discovery of therapies to prevent the development of the disease.

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