Alzheimer’s disease (AD) is marked by the buildup of abnormal tau protein inside brain cells and the gradual loss of neurons that are essential for memory and thinking. Although tau accumulation closely tracks disease progression, it does not fully explain why certain groups of neurons are especially vulnerable. Increasing evidence suggests that inflammatory forms of cell death may help drive this selective loss. One such pathway, called necroptosis, is a highly inflammatory type of programmed cell death controlled by the proteins RIPK1 and RIPK3. Markers of necroptosis are elevated in AD brains and are found in the same vulnerable neurons that accumulate tau, yet scientists do not yet understand whether these processes are directly connected.
Dr. Louros’ project explores the possibility that tau and the necroptosis machinery physically interact. Both tau and RIPK proteins assemble into highly ordered structures known as amyloid fibrils. Previous work has shown that different amyloid-forming proteins can sometimes “cross-seed,” meaning they directly bind to one another and influence each other’s aggregation. Specific regions of RIPK proteins share structural similarities with the parts of tau that drive its aggregation. This raises the possibility that tau and RIPK proteins may bind together, potentially linking tau buildup to the activation of inflammatory cell death pathways. Based on this, their project tests the hypothesis that tau and necrosome components (RIPK1 and RIPK3) can form mixed assemblies that promote the spread of tau in cells and connect tau aggregation to inflammatory necroptotic cell death.
They will investigate this hypothesis using two experimental aims. First, they will define how tau and RIPK proteins interact at the molecular level, including whether they directly co-assemble and what the structural and stability properties of these assemblies are. Second, they will determine whether these interactions promote tau propagation in cellular systems and characterize the conformational and proteomic signatures of these assemblies, including validation in human iPSC-derived neurons.
If successful, this work will uncover a direct molecular link between tau pathology and inflammatory cell death in AD. By elucidating whether and how tau aggregation is associated with necroptosis, the study could help explain why certain neurons are especially vulnerable and identify new therapeutic opportunities to interrupt the harmful interplay between protein aggregation and inflammation.
