Scientists find elusive cause of cell death in Alzheimer's

Researchers think they have worked out how neurons die off in Alzheimer's disease, a question that has gone unanswered for decades, opening new avenues for research and a potential new drug target called MEG3.

The scientists, from the UK Dementia Research Institute and VIB-KU Leuven in Belgium, believe that neurons are triggered into a form of programmed cell death called necroptosis after exposure to amyloid plaques and tau tangles.

The role of amyloid and tau is well-established and has been a major driver of drug development in Alzheimer's disease. What is new in the research – published in the journal Science – is the mechanism behind amyloid and tau and neuronal death.

Put in simple terms, their hypothesis is that amyloid and tau build-up causes inflammation in the brain, leading to changes in their internal chemistry that include a marked increase in levels of a molecule called MEG3.

The presence of MEG3 on its own was enough to trigger necroptosis in human neurons in lab studies, and further testing showed that degeneration of the cells could be prevented by reducing its levels.

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, said: "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."

The discovery is welcome news for companies developing amyloid and tau drugs, providing further scientific rationale for the therapies, but also the intriguing possibility of blocking the death of neurons directly and more effectively.

The first amyloid-targeted drugs, led by Eisai and Biogen's Leqembi (lecanemab), have shown modest effects on stopping the loss of memory and cognition in Alzheimer's, leading to hopes that combination with tau therapies may offer an improvement.

The MEG3 pathway has the potential to drive the development of other therapies, but it could be years before they reach the clinical testing stage, let alone be ready to treat patients.

The finding was facilitated through the creation of a new model of Alzheimer's disease based on the implantation of healthy human and mouse neurons into the brains of AD mouse models, according to Dr Sriram Balusu, postdoctoral researcher at the De Strooper lab and first author of the paper.

"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," he added.

Only the implanted human cells, and not the mouse counterparts, showed the features of Alzheimer's degeneration - such as amyloid plaques, tau tangles, and cell death - suggesting that comparisons between humans and mice could unlock further elements of the necroptosis pathway.

Photo by Robina Weermeijer on Unsplash.