Connecting the dots between tau dysfunction and neurodegeneration

•Downstream mechanisms of tau neurotoxicity are discussed.•Tau drives cytoskeletal, mitochondrial, chromatin, and cell cycle dysfunction.•Processes connecting tau dysfunction to apoptosis are potential therapeutic targets.

Tauopathies are devastating and ultimately fatal neurodegenerative diseases, which are histopathologically defined by insoluble filamentous deposits of abnormally phosphorylated tau protein within neurons and glia. Identifying the causes of abnormal tau phosphorylation and subsequent aggregation has been the focus of much research, and is currently a major target for the development of therapeutic interventions for tauopathies, including Alzheimer's disease (AD). Much has recently been learned about the sequence of events that lead from tau dysfunction to neuronal death. This review focuses on the cascade of events that are catalyzed by pathological tau, and highlights current and potential therapeutic strategies to target this pathway.