Targeting necroptosis could halt nerve cell loss in Alzheimer's

Alzheimer's disease is characterized by a progressive loss of nerve cells leading to a decline in memory and cognition. A team of researchers at KU Leuven and VIB explored the molecular sequence of events in this cellular demise and identified specific inhibitors that could prevent the loss of nerve cells in different mouse models of the disease. The findings open up new research avenues in the search for therapies that could halt or prevent the accumulation of brain damage occurring in Alzheimer's.

Alzheimer's disease, the leading cause of dementia, affects over 55 million people worldwide. The disease is characterized by the buildup of amyloid-beta plaques and tau protein tangles in the brain, which disrupt cell communication and lead to the widespread death of nerve cells. The consequences of this massive cell loss are the heartbreaking cognitive decline and memory loss for which the condition is well known.

Despite extensive research, for decades the only treatments available for Alzheimer's offered temporary symptom management at best. Recently, however, the first drugs designed to target amyloid plaques have received (controversial) approval. While these new treatments successfully remove amyloid plaques, their clinical benefit in terms of improving cognition and memory has yet to be convincingly demonstrated. A conundrum underscoring once more the need to prevent nerve cell death to stop the cognitive impairment that affects Alzheimer's patients.

In a new study published in Science Translational Medicine, a team of researchers led by Prof. Dietmar Thal, Prof. Bart De Strooper, and Dr. Sriram Balusu demonstrates they can indeed prevent loss of nerve cells in a mouse model of Alzheimer's using specific inhibitors.

Necroptosis

"Nerve cells die in the context of Alzheimer's disease as a consequence of a well-defined sequence of biochemical reactions, called 'necroptosis'," explains Balusu, postdoctoral researcher in the lab of De Strooper at the VIB-KU Leuven Center for Brain & Disease Research. Last year, Balusu and his colleagues already announced they had mapped triggers for such necroptosis in human nerve cells transplanted into Alzheimer's affected mouse brains.

To better understand the neurodegenerative process, and how it could be halted, the team now further explored the role of necroptosis in different mouse models for Alzheimer's. They found that necroptosis was activated in mouse models with tau tangles but not in those that only exhibit amyloid plaques. "Our results suggest that there exists a disease-related, delayed form of necroptosis, that is activated by a specific form of tau," explains Thal, professor Neuropathology at KU Leuven. Importantly, specific inhibitors intercepting activation of necroptosis not only prevent nerve cell loss, but also improve the social recognition memory of the mice.

Our findings indicate that necroptosis inhibition should be investigated further as a potential therapeutic strategy that could complement current amyloid and tau-directed therapies for treating Alzheimer's disease."

De Strooper VIB, KU Leuven, UK DRI

This research was supported by Research Foundation Flanders (FWO), ERC, KU Leuven, and Stichting Alzheimer Onderzoek.