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Recycling within amyloid-beta fibrils might be a clue to the cause of Alzheimer’s disease

Date:
April 13, 2011
Source:
Institute for Research in Biomedicine-IRB
Summary:
New research demonstrates that the aggregation of amyloid-beta (A) proteins into amyloid fibrils characteristic of Alzheimer's disease (AD) is not irreversible, as previously thought. The A protein molecules that comprise the fibrils are continuously detaching from and re-attaching to the fibrils, resulting in molecular recycling. These findings suggest that recycling could be a source of small non-fibrillar A aggregates, which are believed to be responsible for the neurodegeneration observed in AD.

Initial A40 molecules dissociate and reassociate through both ends of the fibrils faster than the A42 molecules (Initial molecules: grey circles; recycled molecules: orange circles).
Credit: Image courtesy of IRB

A research study, published recently in the Journal of the American Chemical Society (JACS), demonstrates that the aggregation of amyloid-beta (Aβ) proteins into amyloid fibrils characteristic of Alzheimer's disease (AD) is not irreversible, as previously thought. The Aβ protein molecules that comprise the fibrils are continuously detaching from and re-attaching to the fibrils, resulting in molecular recycling. These findings suggest that recycling could be a source of small non-fibrillar Aβ aggregates, which are believed to be responsible for the neurodegeneration observed in AD. The authors of this study, experts in protein structure and aggregation at IRB Barcelona and other research centers, led by the ICREA researcher Ntalia Carulla, believe that modulation of fibril recycling may lead to the development of new therapeutic approaches to treat this disease.

New insights into the dynamics of amyloid fibrils

AD is a progressive neurodegenerative disease characterized by the presence of amyloid plaques in the brain. Previous analysis of these plaques revealed that their main constituents are fibrillar aggregates of the Aβ protein known as amyloid fibrils. This is the reason why initial studies proposed that Aβ fibrils caused the disease. Later, it was observed that there were only weak correlations between levels of amyloid fibrils in the brain and the severity of dementia. This finding led to the formulation of new hypotheses in which small Aβ protein aggregates formed before the development of fibrils are thought to be responsible for neurodegeneration. Recent data have shown that fibrillar plaques are a potential reservoir of small toxic Aβ protein aggregates. In this scenario, "understanding the molecular basis of the disease requires knowledge about the interconversion between the different species present during Aβ protein aggregation," says Carulla.

The team of researchers at IRB Barcelona has now characterized molecular recycling of two Aβ proteins, Aβ40 and Aβ42, the latter being the most associated with AD. After monitoring recycling during 40 days using hydrogen/deuterium exchange experiments, they found that Aβ40 and Aβ42 molecules recycle within the fibril population, although to different extents: after 40 days, 80 % of the molecules making up Aβ40 fibrils underwent recycling while only 30 % did so in Aβ42 fibrils. These observations imply that Aβ42 recycles more slowly.

"In the context of AD, demonstrating that recycling occurs in the fibrils is a step forward but it is also crucial to identify the recycling species involved; whether they are individual Aβ units or small aggregates made of several units," explains Carulla. "It will be important to address if differences in the recycling species within Aβ40 and Aβ42 fibrils are relevant in the development of Alzheimer's disease. We are now working towards this aim," emphasized Carulla. "Once we have this information, we will be in a position to devise new therapeutic strategies that can modulate recycling."


Story Source:

The above story is based on materials provided by Institute for Research in Biomedicine-IRB. Note: Materials may be edited for content and length.


Journal Reference:

  1. Laia Sánchez, Sergio Madurga, Tara Pukala, Marta Vilaseca, Carmen López-Iglesias, Carol V. Robinson, Ernest Giralt, Natàlia Carulla. Aβ40 and Aβ42 Amyloid Fibrils Exhibit Distinct Molecular Recycling Properties. Journal of the American Chemical Society, 2011; 110412105212003 DOI: 10.1021/ja1117123

Cite This Page:

Institute for Research in Biomedicine-IRB. "Recycling within amyloid-beta fibrils might be a clue to the cause of Alzheimer’s disease." ScienceDaily. ScienceDaily, 13 April 2011. <www.sciencedaily.com/releases/2011/04/110413090019.htm>.
Institute for Research in Biomedicine-IRB. (2011, April 13). Recycling within amyloid-beta fibrils might be a clue to the cause of Alzheimer’s disease. ScienceDaily. Retrieved October 1, 2014 from www.sciencedaily.com/releases/2011/04/110413090019.htm
Institute for Research in Biomedicine-IRB. "Recycling within amyloid-beta fibrils might be a clue to the cause of Alzheimer’s disease." ScienceDaily. www.sciencedaily.com/releases/2011/04/110413090019.htm (accessed October 1, 2014).

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