Alzheimer’s disease is characterized by a progressive loss of nerve cells leading to a decline in memory and cognition. Now, a new study by 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 are published in Science Translational Medicine in an article titled, “Inhibition of an Alzheimer’s disease-associated form of necroptosis rescues neuronal death in a mouse model,” and led by professors Dietmar Thal, PhD, Bart De Strooper, PhD, and Sriram Balusu, PhD.
“Necroptosis is a regulated form of cell death that has been observed in Alzheimer’s disease (AD) along with the classical pathological hallmark lesions of amyloid plaques and Tau neurofibrillary tangles,” the researchers wrote. “To understand the neurodegenerative process in AD, we studied the role of necroptosis in mouse models and primary mouse neurons. Using immunohistochemistry, we demonstrated activated necroptosis-related proteins in transgenic mice developing Tau pathology and in primary neurons from amyloid precursor protein (APP)–Tau double transgenic mice treated with phosphorylated Tau seeds derived from a patient with AD but not in APP transgenic mice that only exhibited β-amyloid deposits.”
“Nerve cells die in the context of Alzheimer’s disease as a consequence of a well-defined sequence of biochemical reactions, called ‘necroptosis’,” explained Balusu, a postdoctoral researcher in the lab of De Strooper at the VIB-KU Leuven Center for Brain & Disease Research.
Last year, Balusu and his colleagues 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 explored the role of necroptosis in different mouse models for Alzheimer’s in the current study. They discovered 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,” explained Thal, professor of 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.
De Strooper added, “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.”
The findings open up new research avenues in the search for therapies that could halt or prevent the accumulation of brain damage occurring in AD.
