Abstract: TAU is a neuronal microtubule-associated protein preferentially located in axons. In a battery of neurodegenerattve diseases termed “tauopathies,” including Alzheimer’s disease (AD), TAU is missorted and abnormally phosphorylated, leading to fflamentous accumulattons of hyperphosphorylated TAU, a pathological hallmark and potenttal disease driver of AD and related tauopathies (Zempel, 2024). The other hallmark of AD is the aberrant production of amyloid-β (Aβ), which accumulates in extracellular plaques. The axon initial segment (AIS) is a 20 to 60 µM long neuronal compartment separattng the axon from the axon hillock and cell body. Its molecular organization is characterized by a complex protein scaffold, consisting of transmembrane proteins, Ankyrin G (ANKG), spectrins, acttn structures (rings/patches composed of filamentous actin (F-actin), microtubules, and microtubule-associated proteins (Leterrier, 2018). Alterations of the AIS structure have been observed as a result of Aβ exposure: F-acttn is lost at the AIS after exposure to amyloid-β-oligomers (AβO; AD-like stress), likely due to aberrant activation of the F-actin severing enzyme cofilin (actin depolymerizing factor). Subsequent rapid remodeling and repolarization of F-actin might induce TAU missorttng by blocking the physiological anterograde sorting of TAU into the axon (Zempel et al., 2017, Bell-Simons et al., 2023, Buchholz and Zempel, 2024). Recently, we also provided evidence for a cluster of mitochondria in the proximal AIS, which has a functional role in the maintenance of TAU sorting: While mitochondria show relative absence in the central AIS, they cluster at the proximal AIS. The mitochondria in this cluster are largely immobile and only sparsely participate in axonal mitochondria-trafficking. Importantly, (local) impairment of this AIS-mitochondria-cluster (AMC) leads to detectable increases of somatic TAU, resembling AD-like TAU missorting (Tjiang and Zempel, 2022). While it is thus clear that both proper maintenance of F-acttn in the AIS, as well as proper functton of AIS-based mitochondria, may be crucial for neuronal function and maintenance of TAU sorttng and functton, the effect of AD-like stress on mitochondria in the AIS is underexplored.