Necroptosis pathway activation and its role in neuronal cell loss in Alzheimer's disease

Accumulation of misfolded, aggregated proteins and the associated neuronal cell loss are considered the most fundamental hallmarks of neurodegenerative diseases, including Alzheimer's disease (AD). Despite the prevalent neuronal cell death in AD, the modality of cell death and molecular events leading to such neuronal cell death mechanisms are seldom investigated. Lack of preclinical models that sufficiently recapitulate AD-relevant neuronal cell death has impeded progress in this area. We recently demonstrated the activation of the necroptosis pathway in post-mortem AD brains. Necroptosis markers are highly enriched inside AD lesions, correlated with TAU pathology, and inversely correlated neuronal cell density in the hippocampus & frontal cortex (Koper et al., 2019). However, the contribution of necroptosis towards neuronal cell loss and upstream activators of the pathway is unknown. Hence in the present proposal, we take full advantage of an already established iPSC-derived neuronal xenograft model, which displays classical hallmarks of AD, including TAU pathology and necroptosis activation. We will interfere with the necroptosis critical molecules of the pathway and modulate the neuroinflammation to assess the contribution of necroptosis pathway in neuronal loss. Finally, capitalizing on the cell death phenotype, we will perform in vivo full-genome CRISPR-CAS9 screen to identify the modulators of neuronal cells and validate them in clinical and preclinical models.