Alzheimer’s disease and similar neurodegenerative diseases involve aggregation of the protein Tau and disruption of cell structural networks. The protein HDAC6 helps clear Tau aggregates and regulate the cytoskeleton, thus exerting neuroprotective effects. HDAC6’s catalytic domains mediate some of these functions, but the roles of another domain, the zinc finger ubiquitin-binding domain (ZnF UBP), are less understood. A recent study investigated the effects of purified HDAC6 ZnF UBP on cultured neuronal cells. The researchers found that HDAC6 ZnF UBP was nontoxic to cells, and cell imaging showed that it promoted reorganization of the cytoskeletal components actin and tubulin in ways that likely support neuron growth and migration. Localization of the protein ApoE in cell nuclei was increased, indicating improved neuronal health. HDAC6 ZnF UBP also reduced Tau phosphorylation, a key event in Alzheimer’s disease pathogenesis and reduced the activity of the enzyme GSK-3β, which phosphorylates Tau, by increasing the proportion of inactivated enzyme. Although the exact mechanisms of these effects are unclear, and studies in animal models are needed, the findings reveal that HDAC6 ZnF UBP contributes to various neuroprotective effects of HDAC6 and suggest that it may be useful as a treatment for Alzheimer’s disease and related conditions.