Abstract: Introduction: TAU isoforms as disease mediators: The microtubule-associated protein TAU is predominantly present in the axons of neurons under physiological conditions. In Alzheimer’s disease (AD) and related tauopathies, TAU also mislocalizes (“TAU missorting”) to the soma and the dendrites, where it eventually forms aggregates, the so-called neurofibrillary tangles (for review see Zimmer-Bensch and Zempel, 2021; Zempel, 2023). Alternative splicing of the TAU encoding MAPT gene results in eight major TAU isoforms, six of which are expressed in the human brain, while only three are present in the adult rodent brain (Goedert et al., 1989; Bullmann et al., 2009). The axodendritic distribution of the different TAU isoforms is strikingly different in neurons. The longest and least expressed (< 10% of the whole TAUom in the human central nervous system (CNS)) isoform of TAU, 2N4R-TAU, e.g., is partially retained in the somatodendritic compartment, where it induces enhanced dendritic outgrowth and spine maturation (Zempel et al., 2017; Bachmann et al., 2021). Amyloid-beta oligomers (AβO) induce pathological TAU missorting and the loss of dendritic spines, a sensitive measure of synaptic health and function. Interestingly, TAU depletion in mice, primary rodent neurons, and induced pluripotent stem cell (iPSC)-derived human neurons protects them from AβO toxicity, spine loss, and consequential neuronal dysfunction (Roberson et al., 2007; Zempel et al., 2013; Buchholz et al., 2022).