Pyroptotic and necroptotic cell death in Alzheimer's disease: pathological relevance and potential as therapeutic targets

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder, resulting in memory loss and cognitive dysfunction. The major neuropathological hallmarks of AD are accumulations of amyloid β (Aβ) and hyperphosphorylated Tau protein (pTau), accompanied by neuron loss and neuroinflammation. The mechanisms leading to neuronal death in AD and the contribution of glial cells in these processes are still not sufficiently understood. Moreover, drugs to modify the disease progression of AD provide limited clinical efficacy. Accordingly, the question arises whether interference with AD-associated cell death mechanisms could modify the course of the disease. Pyroptosis and necroptosis are inflammation-related forms of regulated cell death. Although canonical inflammasome activation has been reported in AD, the downstream activation of pyroptotic cell death has not been investigated. On the other hand, necroptosis has been shown to correlate with neuronal loss in AD. For my project, I will identify the impact of pyroptosis activation on micro- and astroglial cell dysfunction and degeneration, as well as on neuronal death in AD. Additionally, I will explore the therapeutic potential of inhibiting necroptosis to prevent neuron loss in mouse models for AD pathology. Preliminary findings already indicate expression of the pyroptotic effector gasdermin-D in glial cells and neurons in AD, and upregulation of necroptosis activation in a mouse model with both pTau and Aβ pathology. I will further investigate whether pyroptosis plays a role in AD and if so, whether it is associated with Aβ or pTau pathology, and whether inhibition of necroptosis prevents neuron loss in the mouse model of AD pathology. To realize these goals, I will use postmortem brain tissue from AD patients and transgenic mice to study the presence of pyroptosis- and necroptosis-related proteins. In the end, I aim to identify novel therapeutic targets for the treatment of AD.