GVD-necroptosis as a driving process of neurodegeneration in Alzheimer’s disease

Accumulation of misfolded proteins and the associated neuronal dysfunction and loss are considered as most important hallmarks of neurodegenerative diseases including Alzheimer’s disease (AD). Specific for AD is the extensive deposition of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). These changes are associated with marked neuro-inflammation and cerebral atrophy. While neuronal cell death is very compelling in AD pathology, it remains unclear what factors exactly contribute to neuronal cell death and how exactly this process is executed. The paucity of suitable models that recapture AD pathology with the appearance of Aβ species and abnormal Tau conformations has impeded progress in understanding the neuronal cell death mechanisms in AD. Recently, activation of necroptosis (a controlled form of necrosis) markers such as RIPK1, RIPK3, and MLKL have been reported in multiple sclerosis (Ofengeim, D., et al., 2015), amyotrophic lateral sclerosis (Re, D.B., et al., 2014), and AD (Caccamo, A., et al., 2017). To which extent AD-related neuron loss can be attributed to necroptosis or other mechanisms of cell death, and which neurodegeneration-related proteins (APP and its cleavage products, presenilins, tau, or TDP43) are connected with the initiation of necroptosis or other cell death mechanisms in AD still needs to be understood. Likewise, upstream necroptosis inducing factors and the role of other immune cells in mediating necroptosis are not defined yet. Abnormal glial response characterized by neuroinflammatory response is a fundamental pathological feature of many chronic neurodegenerative diseases including AD. Our internal data analyzing chimeric human/mouse models of AD suggests that human neurons undergo massive neuronal cell death when exposed to amyloid plaques in the context of this model. Glia cells show a remarkable activation of necroptosis markers in glial cells in this model (Espuny-Camacho, I., et al., 2017 and unpublished data). Here we hypothesize that the aberrant neuroinflammatory response of glial cells in the proteopathic phase of the disease might induce neuronal necroptosis and that at least one of the AD-related proteins, such as APP and its cleavage products, tau, or TDP43, can be directly or indirectly involved in initiating or executing necroptosis. In this project, we seek to investigate to what extent necroptosis contributes to the neuronal cell loss in AD, . Accordingly, we will perform clinicopathological correlation studies to define whether abnormal Tau, Aβ, or TDP43 correlates with necroptosis markers in postmortem human brain samples. In addition, we want to identify upstream regulating factors of the necroptosis pathway as well as whether the neuronal cell death mechanism is a cell autonomous process or is initiated by the glial cells. Furthermore, we will evaluate to what extent necroptosis is present in different mouse and rat models available to us. Finally, we will evaluate to what extent intracerebral injection of Aβ and Tau seeds from human AD brain extracts into either mouse or rat models can induce necroptosis.