Alzheimer’s disease is characterized by a progressive loss of nerve cells, leading to a decline in memory and cognition. A team of researchers from KU Leuven and VIB investigated the molecular sequence of events in this cellular demise and identified specific inhibitors that could prevent nerve cell loss in different mouse models of the disease. The findings open new research opportunities in the search for therapies that can halt or prevent the accumulation of brain damage in Alzheimer’s disease.
Alzheimer’s disease, the leading cause of dementia, affects more than 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 known.
Despite extensive research, for decades the only available treatments for Alzheimer’s disease provided temporary symptom control at best. Recently, however, the first drugs designed to target amyloid plaques have received (controversial) approval. Although these new treatments successfully remove amyloid plaques, their clinical benefit in terms of improving cognition and memory has yet to be convincingly demonstrated. A riddle that once again underlines the need to prevent the death of nerve cells to stop the cognitive disorders that affect Alzheimer’s patients.
From a new study published in Scientific translational medicinea team of researchers led by Prof. Dietmar Thal, Prof. Bart De Strooper and Dr. Sriram Balusu demonstrate that they can indeed prevent nerve cell loss in a mouse model of Alzheimer’s disease using specific inhibitors.
Necroptosis
“Nerve cells die in the context of Alzheimer’s disease due to a well-defined series of biochemical reactions, called ‘necroptosis’“, explains Balusu, postdoctoral researcher in De Strooper’s laboratory at the VIB-KU Leuven Center for Brain and Disease Research. Last year, Balusu and his colleagues announced that they had identified triggers for such necroptosis in human nerve cells that had been transplanted into people with Alzheimer’s disease. brains of mice.
To better understand the neurodegenerative process, and how it can be stopped, the team has now further investigated the role of necroptosis in several mouse models of Alzheimer’s disease. They found that necroptosis was activated in mouse models with tau tangles, but not in models with tau tangles only exhibit amyloid plaques. “Our results suggest that there is a disease-related, delayed form of necroptosis, which is activated by a specific form of tau.“, explains Thal, professor of Neuropathology at KU Leuven. Importantly, specific inhibitors that intercept the activation of necroptosis not only prevent nerve cell loss but also improve the mice’s social recognition memory.
Our findings indicate that inhibition of necroptosis should be further explored as a potential therapeutic strategy that could complement current amyloid- and tau-targeted therapies for the treatment of Alzheimer’s disease.”
De Strooper VIB, KU Leuven, VK DRI
This research was supported by the Scientific Research Fund (FWO), ERC, KU Leuven and the Alzheimer Research Foundation.
Source:
Magazine reference:
Copper, MJ, et al. (2024). Inhibition of an Alzheimer’s disease-associated form of necroptosis rescues neuronal death in mouse models. Scientific translational medicine. doi.org/10.1126/scitranslmed.adf5128.