A research team from VIB-KU Leuven and the UK Dementia Research Institute has discovered how neurons die in Alzheimer’s disease, opening new pathways for potential future treatments.
A new research paper published in Science illustrates how neurons initiate a programmed form of cell death, known as necroptosis, when they are exposed to amyloid plaques and tau tangles.
The research team was also able to prevent the death of neurons, rescuing them in the process.
Alzheimer’s disease (AD) has been classified as public health priority by the World Health Organisation (WHO). There currently is no cure as the underlying cause of the disease is still not fully understood.
The research team was led by Professor Bart De Strooper, Group Leader at the VIB-KU Leuven Center for Brain and Disease Research and the UK Dementia Research Institute at University College London, and Dr Sriram Balusu, postdoctoral researcher at the De Strooper lab, VIB-KU Leuven.
Professor De Strooper said: “Our study sheds light on the previously murky waters of AD, 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.”
A new AD mouse model
One of the key challenges in understanding AD has been connecting its defining hallmarks – amyloid plaques, tau tangles, and death of neurons – to each other, as most mouse models can’t naturally replicate these features.
“To bridge this gap, we created a new model,” said Balusu. “We implanted both healthy human and mouse neurons into the brains of AD mouse models. The human cells degenerated much like their counterparts in the human brain, allowing us to study them during brain ageing and shine a new light on the processes underlying AD.”
Only the human neurons, and not their rodent counterparts, displayed AD 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.
Preventing the death of cells
The study revealed that a pathway known as necroptosis, a form of programmed cell death, was activated in the model, leading to death of neurons.
The researchers saw that levels of a molecule known as MEG3 were strongly increased in human neurons, as seen in AD patients. Just the presence of MEG3 alone was enough to trigger the pathway of necroptosis in human neurons in a lab setting. They found that by reducing MEG3 and preventing necroptosis, researchers could in turn prevent the death of cells.
“Necroptosis is already an active area of drug development in cancer and ALS,” added Professor De Strooper. “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.”