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The 3D structure of Aβ protein assemblies reveals a new mechanism of toxicity

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The brains of millions of people with Alzheimer’s disease (AD) are slowly and inevitably depleted of neurons, which leads to the characteristic loss of memory and cognitive function associated with this condition.

However, the cause of neuronal death is still unknown. The treatments available are aimed at slowing the development of dementia and only contribute to improving the quality of life for short periods. Therefore, treatments to actually cure AD are an unmet medical need.

Researchers led by Natalia Carulla, IRB Barcelona Alumni, former group leader at the European Institute of Chemistry and Biology (IECB) in Bordeaux, and currently project manager at Grup CIEF, revealed for the first time the atomic structure of l amyloid beta (Aβ) protein assemblies.

Knowledge of this structure reveals a new mechanism of toxicity for these assemblies, with the ability to disturb the neuronal membrane, allowing water and ions to cross it and causing the death of these cells.

Several studies have proposed that the interaction of the Aβ protein with the neuronal membrane is responsible for the neuronal death observed in AD.

However, the Aβ protein is a difficult therapeutic target because it is “sticky” and self-assembles, adopting distinct shapes and sizes.

Knowing the characteristics that characterize these protein assemblies, such as the number of molecules that make them and the form that they adopt, is crucial to design effective therapeutic strategies that target the forms of the Aβ assemblies responsible for neurotoxicity in AD. “

Natalia Carulla, IRB Barcelona Alumni, Former Group Leader, European Institute of Chemistry and Biology (IECB)

An in vitro approach to guarantee the stability of Aβ shapes

To combat the instability of the different conformations, the team first studied the Aβ protein in vitro– in simplified model systems which imitate the neuronal membrane – to develop conditions making it possible to prepare stable Aβ forms of uniform composition and shape.

Once the different compositions were identified, they studied their structure and their mode of neurotoxicity, establishing a 3D arrangement of all the atoms making up the Aβ set.

“Our study suggests that certain Aβ associations can perforate the membrane of neurons, alter their osmotic balance, and consequently trigger their death,” explain Sonia Ciudad and Eduard Puig, first authors of the article.

Ciudad is a former student of the IRB in Barcelona, ​​currently an R&D scientist at Biokit, a company in Werfen; while Puig is now a postdoctoral fellow in the research unit on asymmetric synthesis at the IRB in Barcelona.

Target the pores of the membranes to avoid neurotoxicity

This study highlighted two sets of Aβ proteins, one formed by four Aβ proteins and the other by eight, whose arrangement has the capacity to disturb the cell membrane, by proposing them as candidates to cause neurodegeneration in AD.

Future work should focus on approaches to prevent the formation of this set, thereby preventing rupture of the membrane.

Currently, the drug discovery pipeline in this area does not include any drugs targeting membrane-associated Aβ assemblies, so this discovery could make a significant breakthrough in the treatment of AD.

Source:

Journal reference:

City, S., et al. (2020) Aβ tetramer and octamer structures (1-42) reveal edge conductivity pores as a mechanism of membrane damage. Nature Communications. doi.org/10.1038/s41467-020-16566-1.

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