Lecanemab, an Alzheimer’s drug, could prevent beta amyloid from damaging the brain

2023-05-10 18:43:59

In a report published in the journal «Neuron»the scientists showed that small aggregates of the amyloid beta protein could float through brain tissue fluid, reach many regions of the brain, and alter the function of local neurons.

The research also provided evidence that a recently approved AD treatment could neutralize these small, diffusible aggregates.

AD, one of the causes of dementia, affects more than 50 million people worldwide. Previous research has found that AD patients have an abnormal buildup of a natural substance – amyloid beta protein – in the brain that can alter neurotransmission. Currently, the disease has no cure. But in recent years, scientists have developed new treatments that can reduce AD ​​symptoms, such as memory loss.

“The article is very timely because, for the first time in human history, we have an agent capable of treating Alzheimer’s patients in a way that slow down their cognitive decline», says Dennis Selkoe, author of the article in the Brigham and Women’s Hospital de Boston. “And we’ve never been able to say those words until the last few months.”

In January, the US Food and Drug Administration. approved lecanemab, an antibody therapy to treat AD. In a phase III clinical trial, lecanemab slowed cognitive decline in patients with early AD.

The scientists suspect that the drug’s positive effect may be linked to its ability to bind to and neutralize soluble amyloid beta protein aggregates, also known as protofibrils or oligomers, which are small, free-floating clumps of amyloid beta protein. These small clumps can form in the brain before further aggregating and becoming large amyloid plaques. Small aggregates can also break off and spread away from amyloid plaques that are already there.

“But no one has been able to define with structural rigor what is a ‘protofibril’ or ‘oligomer’ that lecanemab binds to,” explains Andrew Stern, a neurologist at the Brigham and Women’s Hospital and first author of the study. “Our work identifies this structure after isolating it from the human brain. This is important because patients and drug manufacturers will want to know exactly what lecanemab binds to. Could you reveal something special about how it works?

Stern, Selkoe, and their team were able to isolate the floating amyloid beta aggregates by immersing postmortem brain tissues from typical AD patients in saline solutions, which were then centrifuged at high speed. These tiny aggregations of amyloid beta protein gain access to important brain structures such as the hippocampus, which plays a key role in memory. In collaboration with colleagues from Cambridge Laboratory of Molecular Biology (UK), determined the atomic structure of these tiny aggregates, down to the individual atom.

“If you don’t know your enemies, it’s hard to beat them,” says Selkoe. “It was a very nice coincidence that all this work we were doing coincided with the time that lecanemab became widely known and available.” This investigation brings together the identity of the bad guy and something that can neutralize him.”

Next, the team plans to observe how these tiny amyloid beta aggregates travel through the brains of living animals and to study how the immune system responds to these toxic substances. Recent research has shown that the brain’s immune system’s reaction to amyloid beta is a key component of AD.

“If we can figure out exactly how these tiny diffusible fibrils exert their toxicity, perhaps the next AD drugs may be better,” says Stern.