2023-05-10 17:00:12
Alzheimer’s disease, one of the most common forms of dementia, affects more than 50 million people worldwide, including 800,000 in Spain. For the moment, the possibilities of improvement are limited to mitigating the cognitive deterioration that the pathology brings with it in patients, mostly older than 65 years.
So far, Alzheimer’s research has managed to pinpoint some of the brain mechanisms underlying this complex disease, such as the buildup of a natural substance that can alter neurotransmitter activity. Indeed, it is known that formations of amyloid beta peptides (Aß, for its acronym in English) are associated with the progression of the disease.
Now, scientists led by a team from Brigham and Women’s Hospital in Boston, in the USA, have published in the journal Neuron the results of a experimental study describing the structure of a special type of Aβ plaque protein. There they review how the little ones aggregates of that protein can float through brain tissue fluid, reach many regions of the brain and alter the function of neurons.
The researchers suggest that the positive effect of the drug may be associated with its ability to adhere to those soluble Aβ aggregates that contribute to neuronal dysfunction.
In addition, the authors of the study have obtained evidence that a treatment against Alzheimer’s, recently authorized in the US, could neutralize the expansive activity of this substance, which forms small lumps that move freely.
In January, the US Food and Drug Administration (FDA) approved the lecanemaba antibody therapy to treat Alzheimer’s, developed by the pharmaceutical companies Biogen (USA) and Eisai (Japan). In a phase III trial with this clinical approach slowed cognitive decline in patients with early AD.
The researchers suggest that the positive effect of the drug may be associated with its ability to adhere to those soluble Aβ aggregates that contribute to neuronal dysfunction in oligomeric forms or as protofibrils of the protein.
In statements to SINC, Dennis Selkoefrom Brigham and Women’s Hospital and co-author of the article, points out that this treatment was able to “slow down memory loss” in patients.
In presenting his conclusions, Selkoe assures that it is a “very timely” study because, “for the first time in the history of mankind, we have a product capable of treating Alzheimer’s patients to slow down their cognitive decline” .
The researcher acknowledges that they had not been able to “say these words, until the last few months”, and confesses that he is “optimistic” with the investigations that are emerging from this work.
The accumulation of Aβ peptides and the modification of the Tau protein constitute the known brain pathological phenomena related to Alzheimer’s. However, it is also important to know that, before becoming large amyloid plaques, these small clumps can break off and disperse away from the plaques already present.
Hence the importance of “defining with structural rigor what is a protofibril or an oligomer to which lecanemab binds,” explains Andrew Stern, a neurologist at Brigham and Women’s Hospital and first author of the study.
Disease mechanisms
According to the researcher, “our work identifies this structure after isolating it from the human brain and this is important because patients and drug manufacturers will want to know what exactly lecanemab is assembled into.” Experts also wonder if this immune treatment could help discover something about the mechanisms of the disease.
The team succeeded in isolating the floating Aβ aggregates by immersing postmortem brain tissues from Alzheimer’s patients in saline solutions, which were then centrifuged at high speed.
This investigation combines “the identity of the bad guy and something that can neutralize him,” in the words of the Boston hospital investigator.
In fact, Selkoe, Stern, and their team succeeded in isolating floating Aβ aggregates by immersing brain tissues post mortem of typical AD patients in saline solutions, and these were then centrifuged at high speed.
What they have found is that tiny aggregates of Aβ protein gain access to important brain structures such as the hippocampuswhich plays a key role in memory.
In collaboration with colleagues at the Cambridge Molecular Biology Laboratory, UK, the neuroscientists determined the atomic structure of these tiny compounds, right down to the individual atom.
“If you don’t know your enemies, it’s hard to beat them,” Selkoe says. “It was a very satisfying coincidence that all this work we were doing coincided with the time that lecanemab became widely known and available,” she adds.
It should be noted that the approval of the drug lecanemab by the FDA was not without controversy, as indicated by some international scientific publications, including Natureby way of accelerated authorization, which is reserved for pathologies that have few treatments.
the next steps
Next, the team plans to observe how these small clumps of Aß disperse in the living animal brains and study how the immune system responds to these toxic substances, as confirmed by Selkoe.
Recent investigations are based on the reaction of the brain’s immune system to amyloid beta since these seem a key component of Alzheimer’s.
“If we can find out exactly how these spreading fibrils exert their toxicity, perhaps the next AD drugs may be better,” says the Brigham Hospital scientist.
Lastly, Selkoe anticipates that they will continue working on other “Aβ ‘antifibril’ antibodies that will also bind and neutralize the tiny amyloid fibrils” that they describe in this article.
Reference:
Stern, A. et al. “Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer’s disease brains”. Neuron (2023)
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