Inhibition of an Alzheimer’s disease–associated form of necroptosis rescues neuronal death in mouse models

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. 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. Necroptosis proteins in granulovacuolar degeneration (GVD) bodies were associated with neuronal loss in mouse brain regions also known to be vulnerable to GVD in the human AD brain. Necroptosis inhibitors lowered the percentage of neurons showing GVD and reduced neuronal loss, both in transgenic mice and in primary mouse neurons. This suggests that a GVD-associated form of necroptosis that we refer to as “GVD-necroptosis” may represent a delayed form of necroptosis in AD. We propose that inhibition of necroptosis could rescue this type of neuronal death in AD.