Kanazawa University NanoLSI Podcast:Zooming in on neurotoxic aggregates

Kanazawa University NanoLSI Podcast:Zooming in on neurotoxic aggregates

Transcript of this podcast

 Hello and welcome to the NanoLSI podcast. Thank you for joining us today. In this episode we feature the latest research led by Kenjiro Ono  at the Kanazawa University NanoLSI.

 The research described in this podcast was published in Nano Letters in May 2023

 Kanazawa University NanoLSI website

https://nanolsi.kanazawa-u.ac.jp/en/

 Zooming in on neurotoxic aggregates

Researchers at Kanazawa University report in Nano Letters how high-speed atomic force microscopy leads to insights into processes relevant to Alzheimer’s disease.  Moreover, the technique is shown to be an excellent tool for studying the effect of drugs against the disease.

According to the amyloid hypothesis, Alzheimer’s disease — the most common type of dementia — is caused by flaws in the production, accumulation, and disposal of amyloid-beta in the brain.  Amyloid-beta refers to a group of peptides (protein fragments) that over time form plaques in the brain of a person with Alzheimer’s disease.  Drugs aiming to reduce the aggregation of amyloid-beta have been developed, but recent findings show that different types of amyloid-beta aggregates have different contributions to the development of Alzheimer’s disease.  In particular, intermediate aggregates such as protofibrils are more toxic than the actual final fibrils, the main component of amyloid-beta plaques.  A precise understanding of the complex aggregation pathways is therefore necessary for the further development of efficient drugs against Alzheimer’s disease.  Kenjiro Ono from Kanazawa University and colleagues have now succeeded in visualizing the structural dynamics of protofibrils, as well as the effect of a recently developed drug based on anti-amyloiide-beta antibodies.

So how did they go about it?

The scientists looked at the formation and the structure of amyloid-beta protofibrils by means of high-speed atomic force microscopy (AFM).  The latter method has in recent years emerged as a powerful nanoimaging tool for studying biomolecules and their dynamics at high spatiotemporal resolution.  High-speed AFM observations showed that protofibrils have a nodal structure, with stable structural features — specifically, the binding angle between nodes — across several samples.  Importantly, this nodal structure is distinct from proper, mature fibrils, which have a helical structure.

Ono and colleagues then investigated the dissociation of protofibrils.  They found that the length of protofibrils depends on their concentration, suggesting that aggregates can dissociate spontaneously.

Now onto the interaction with drugs

To obtain detailed insights into the functioning of anti-amyloid-beta antibody drugs, the researchers examined the binding between amyloid-beta protofibrils and a new drug known as lecanemab.  They found that the binding ability – termed the affinity - of lecanemab for protofibrils is almost independent of the size of the protofibrils — in other words, the affinity does not substantially vary throughout the aggregation process.  High-speed AFM observations further revealed that lecanemab covers the surface of small, pre-protofibril aggregates.  In doing so, the drug inhibits the further aggregation into protofibrils, which in turn prevents the formation of proper amyloid-beta fibrils and plaques.

The results of Ono and colleagues provide direct evidence of a mechanism through which an antibody drug interferes with the amyloid-beta aggregation process.  More generally, the work confirms the versatility of high-speed-AFM as a tool for studying biochemical pathways.  

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