Breakthrough research illustrates how neurons initiate a programmed form of cell death – and how neuron death can be prevented.
A research team has finally discovered how neurons die in Alzheimer’s disease – a subject that has been the subject of much scientific discussion over the last few decades.
Now a significant research paper published in Science details how neurons initiate a programmed form of cell death – known as necroptosis – when they are exposed to amyloid plaques and tau tangles, the hallmark misfolded proteins implicated in Alzheimer’s. Excitingly, the research team was able to prevent the death of neurons, rescuing them in the process – a discovery that opens new pathways for potential future treatments [1].
Longevity.Technology: Alzheimer’s disease (AD) is one of the most common forms of dementia, accounting for 60 to 70% of dementia diagnoses. Each year, between six and seven million patients are diagnosed with AD, and as a debilitating disease that often comes with a major emotional and psychological burden for both patients and their families, it represents a growing societal challenge and has been classified as public health priority by the World Health Organisation. Even though the past few years have seen some developments in treatments that slow down disease progression, there currently is no cure for Alzheimer’s, as the underlying cause of the disease is still not fully understood.
The new research, coordinated by a research team led by Professor Bart De Strooper (VIB-KU Leuven and the UK Dementia Research Institute) and Dr Sriram Balusu (VIB-KU Leuven), lifts part of the veil over the biological mechanisms underpinning this debilitating disease.
Professor Bart De Strooper, who is Group Leader at the VIB-KU Leuven Center for Brain and Disease Research and the UK Dementia Research Institute at University College London, said: “Our study sheds light on the previously murky waters of Alzheimer’s disease, revealing a potential key player in neuronal loss – an RNA gene called MEG3, and the process of necroptosis. These findings are an important step forward in furthering our understanding of the basic mechanisms underlying this complex and often misunderstood disease [2].”
A new way to crack the Alzheimer’s enigma
One of the key challenges in understanding Alzheimer’s has been connecting its defining hallmarks – amyloid plaques, tau tangles and neuron death – to each other. Most mouse models used in research were not able to naturally replicate these features, leaving scientists with unanswered questions about how they relate to disease progression.
In order to bridge the gap, the research team created a new model, as Balusu, who is a postdoctoral researcher at the De Strooper lab and first author of the paper, explains.
“We implanted both healthy human and mouse neurons into the brains of AD mouse models,” he said. “The human cells degenerated much like their counterparts in the human brain, allowing us to study them during brain aging and shine a new light on the processes underlying AD [2].”
Notably, only the human neurons, and not their rodent counterparts, displayed Alzheimer’s features seen in the brains of patients, including tau tangles and significant neuronal cell loss. This suggests that there may be human-specific factors at play in AD that standard mouse models can’t replicate. Understanding why mouse neurons are more resilient to amyloid pathology will not only help model the disease better, but might also stimulate research into pathways that protect against neurodegeneration.
Identifying the culprit
Using their new model, the research team looked deeper, seeking answers on just how neurons die in Alzheimer’s. The study revealed a critical breakthrough: a pathway known as necroptosis, a form of programmed cell death, was activated in the model, leading to the death of neurons.
In addition, the researchers discovered that levels of a molecule known as MEG3 were strongly increased in human neurons, as seen in Alzheimer’s patients. Strikingly, just the presence of MEG3 alone was enough to trigger the pathway of necroptosis in human neurons in a lab setting. The study also found that by reducing MEG3 and preventing necroptosis, researchers could, in turn, prevent the death of cells. While more research is needed to understand exactly how MEG3 triggers necroptosis, the discovery represents a crucial advancement in understanding how Alzheimer’s leads to the loss of neurons in the brain.
“Necroptosis is already an active area of drug development in cancer and ALS,” says De Strooper, who has been studying Alzheimer’s at the VIB-KU Leuven Center for Brain & Disease research for over 30 years. “While there’s much more to explore, our findings open up promising avenues for potential therapies targeting AD, alongside traditional approaches aimed at amyloid and tau [2].”
[1] https://www.science.org/doi/10.1126/science.abp9556
[2] https://tinyurl.com/m9tp6pja
