Copper May Promote Formation of Toxic Species in Alzheimer’s Disease

Alzheimer’s disease affects more than 26 million people worldwide, and shall rise to greater prevalence in coming years as factors that increase susceptibility are increasing, including diabetes and life expectancy. Modest delays in onset and disease progression would be capable of saving many from suffering this debilitating disease; in fact, it has been estimated that reducing both progression and onset by a single year would be sufficient for there to be 9.2 million fewer cases by 2050, a year which is otherwise projected to have 115.4 million sufferers. Unfortunately, no treatments are currently forthcoming, largely as there is still a lot we do not understand in Alzheimer’s pathology.

In recent years, a large part of the scientific community have come to view a small protein fragment, amyloid-beta, as central to Alzheimer’s disease. In a healthy brain amyloid-beta exists as a single molecule; however, in the brains of those with Alzheimer’s disease, amyloid-beta self-associates to form a variety of aggregates. Some of these assemblies can kill brain cells, whereas others are relatively benign. What triggers the formation of toxic groupings of amyloid-beta is one of the key questions in Alzheimer’s disease research, as well as how these toxic groupings kill neurons, with suggestions including oxidative stress and the puncturing of cell membranes. Additionally, it’s been shown that an amyloid-beta fragment of a particular size, 42 amino acids long, conveys greater neurotoxicity than the most commonly sized fragment, that of 40 amino acids long. Why this should be the case is not yet clear.

An accidental contamination in the drinking water of high-cholesterol rabbits found that copper gave the rabbits Alzheimer’s like symptoms. This discovery, together with the knowledge that patients with Alzheimer’s disease have elevated levels of copper, prompted my own research group, headed by Dr. Viles, to investigate whether copper has any impact on how amyloid-beta comes together.

Artificial cell membranes disrupted by the 42 amino acid fragment of amyloid beta. The images in red show disruption without copper present, where the amyloid beta forms many long, straight fibres. Those in blue show disruption when copper is also present, and the amyloid beta is stabilised as small, flexible protofibrils. Unlike the fibres, these protofibrils readily form complete breaks in the membrane.

We found that whereas low levels of copper promotes assembly of the 40 amino acid fragment into long fibres, under the same conditions the 42 amino acid peptide formed small flexible protofibrils. These protofibrils were able to disrupt artificial cell membranes much more readily than the larger, straighter fibres. This study suggests that copper and cell membrane disruption could have a crucial role in the development of Alzheimer’s disease, and also that copper may exacerbate differences in the neurotoxicity of these two peptide fragments.  Consequently copper dysregulation could be a valuable future therapeutic target.

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A final year PhD student, studying the role of metal ions in Alzheimer's disease at Queen Mary University, London. If you enjoy my articles, you can follow me on twitter to stay updated (twitter.com/Chris_Matheou).

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