A new mechanism of toxicity in Alzheimer’s disease revealed by the three-dimensional structure of the protein

The brains of people with Alzheimer’s disease (AD) are slowly and inevitably being depleted of neurons, leading to the characteristic loss of memory and cognitive function associated with this condition. However, the cause of neuronal death is still unknown. Available treatments aim to delay the development of dementia and only help improve quality of life for short periods. Therefore, treatments to cure AD are an unmet medical need.

Researchers led by Natalia Carulla, IRB Barcelona Alumni, former group leader at the Institut Européen de Chimie et Biologie (IECB) in Bordeaux, and currently project manager at Grup CIEF have revealed for the first time the atomic structure of amyloid-beta (Aβ ) Protein assemblies. Knowledge of this structure reveals a new toxicity mechanism for these assemblies, with the ability to alter the neuronal membrane, allowing water and ions to pass through it and cause 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, taking on different shapes and sizes.

“Knowing the characteristics that characterize these sets of proteins, such as the number of molecules that form them and the shape they adopt, is crucial to design effective therapeutic strategies that target the forms of Aβ sets responsible for neurotoxicity in AD” , explains Carulla.

An in vitro approach to ensure stable forms of Aβ

To address the instability of conformations, the team first studied the Aβ protein in vitro, in simplified model systems that mimic the neuronal membrane, to develop conditions for preparing stable Aβ forms of uniform composition and shape. Once the compositions were identified, they studied their structure and mode of neurotoxicity, establishing a three-dimensional arrangement of all the atoms that make up the Aβ set.

“Our study suggests that some Aβ associations can pierce the neurons’ membrane, alter their osmotic balance and, consequently, cause their death,” say Sonia Ciudad and Eduard Puig, first authors of the article. Ciudad is a former student at IRB Barcelona, ​​currently an R&D scientist at Biokit, a Werfen company; Puig is now a postdoctoral fellow in the Asymmetric Synthesis Research Unit at IRB Barcelona.

Targeting the pores of the membrane to avoid neurotoxicity.

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

Further work should focus on approaches to prevent the formation of this set, thus avoiding membrane disruption. Currently, the line of drug discovery in this field does not include any set of membrane-associated Aβ drugs, so this finding could be a significant advance in the treatment of AD.