Caspase-cleaved tau is senescence-associated and induces a toxic gain of function by putting a brake on axonal transport

Abstract

The microtubule-associated protein tau plays a central role in tauopathies such as Alzheimer’s disease (AD). The exact molecular mechanisms underlying tau toxicity are unclear, but aging is irrefutably the biggest risk factor. This raises the question of how cellular senescence affects the function of tau as a microtubule regulator. Here we report that the proportion of tau that is proteolytically cleaved at the caspase-3 site (TauC3) doubles in the hippocampus of senescent mice. TauC3 is also elevated in AD patients. Through quantitative live-cell imaging, we show that TauC3 has a drastically reduced dynamics of its microtubule interaction. Single-molecule tracking of tau confirmed that TauC3 has a longer residence time on axonal microtubules. The reduced dynamics of the TauC3-microtubule interaction correlated with a decreased transport of mitochondria, a reduced processivity of APP-vesicle transport and an induction of region-specific dendritic atrophy in CA1 neurons of the hippocampus. The microtubule-targeting drug Epothilone D normalized the interaction of TauC3 with microtubules and modulated the transport of APP-vesicles dependent on the presence of overexpressed human tau. The results indicate a novel toxic gain of function, in which a post-translational modification of tau changes the dynamics of the tau-microtubule interaction and thus leads to axonal transport defects and neuronal degeneration. The data also introduce microtubule-targeting drugs as pharmacological modifiers of the tau-microtubule interaction with the potential to restore the physiological interaction of pathologically altered tau with microtubules.

Super-resolution imaging and quantitative analysis of microtubule arrays in model neurons show that epothilone D increases the density but decreases the length and straightness of microtubules in axon-like processes

“…3 A, E). Such a shift in microtubule array property may explain the negative effect of EpoD on microtubule-based axonal transport as we previously reported in the same cell system ( Conze et al, 2022 ). Molecular motor proteins use the microtubules as tracks for the transport of vesicles and organelles, and the length of the cargo run correlates with the length of the individual microtubules.…”

“…Critical events during neurodegenerative conditions and diseases are changes in microtubule regulation, dynamics, and organization that affect vital microtubule-dependent processes such as transport ( Brandt and Bakota, 2017 , Dubey et al, 2015 , Millecamps and Julien, 2013 ). The microtubule organization in terms of polymer lengths, microtubule number, the spatial distribution of individual microtubules as well as the axial distribution of cytoskeletal intersections contribute to the efficiency and regulation of neuronal transport in an interplay with other factors such as post-translational modifications (PTMs) or interactions with MAPs ( Balint et al, 2013 , Conze et al, 2022 ).…”

Tau and α-synuclein shape microtubule organization and microtubule-dependent transport in neuronal dendrites

“…Therefore, we analyzed whether the lack of tau protein would affect the dynamics of dendritic microtubules, which could influence arbor formation. To determine possible changes in microtubule dynamics, we used a previously established photoactivation assay (Conze et al, 2022). Viral mediated expression of photoactivatable GFP-tagged α-tubulin was performed in primary hippocampal cell cultures prepared from control or Tau KO mice (Fig.…”

Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule regulation

“…Treatment of the cells was performed 20 hours prior to live imaging by addition of the respective compound (or DMSO for carrier control) in the desired concentration. Live cell imaging for photoactivation experiments was essentially performed as described previously (Conze et al, 2022) using a laser scanning microscope (Nikon Eclipse Ti2-E (Nikon, Japan)) equipped with a LU-N4 laser unit with 488-nm and 405-nm lasers and a Fluor 60× ultraviolet-corrected objective lens (NA 1.4) enclosed in an incubation chamber maintaining 37°C and 5% CO 2 . Photoactivation of a 6 μm long neurite segment was performed with a 405-nm laser.…”

“…Mechanisms of toxicity are also controversial, but prefibrillar tau oligomers and soluble tau with disease-like modifications can be toxic species (Fath et al, 2002; Patterson et al, 2011). Furthermore, disruption of the physiological function of tau, particularly its dynamic interaction with axonal microtubules, can be a crucial contributor to the disease (Conze et al, 2022).…”