Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin

DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany.
The EMBO Journal (Impact Factor: 10.43). 09/2013; 32(22). DOI: 10.1038/emboj.2013.207
Source: PubMed


Mislocalization and aggregation of Aβ and Tau combined with loss of synapses and microtubules (MTs) are hallmarks of Alzheimer disease. We exposed mature primary neurons to Aβ oligomers and analysed changes in the Tau/MT system. MT breakdown occurs in dendrites invaded by Tau (Tau missorting) and is mediated by spastin, an MT-severing enzyme. Spastin is recruited by MT polyglutamylation, induced by Tau missorting triggered translocalization of TTLL6 (Tubulin-Tyrosine-Ligase-Like-6) into dendrites. Consequences are spine loss and mitochondria and neurofilament mislocalization. Missorted Tau is not axonally derived, as shown by axonal retention of photoconvertible Dendra2-Tau, but newly synthesized. Recovery from Aβ insult occurs after Aβ oligomers lose their toxicity and requires the kinase MARK (Microtubule-Affinity-Regulating-Kinase). In neurons derived from Tau-knockout mice, MTs and synapses are resistant to Aβ toxicity because TTLL6 mislocalization and MT polyglutamylation are prevented; hence no spastin recruitment and no MT breakdown occur, enabling faster recovery. Reintroduction of Tau re-establishes Aβ-induced toxicity in TauKO neurons, which requires phosphorylation of Tau's KXGS motifs. Transgenic mice overexpressing Tau show TTLL6 translocalization into dendrites and decreased MT stability. The results provide a rationale for MT stabilization as a therapeutic approach.

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    • "Dendra2-protein tagging has been previously used in the context of protein trafficking in neurons. For instance, photoswitchable fluorescent proteins have been used to track the protein Tau along axons (Zempel et al., 2013), to follow the actin dynamics in presynaptic termini (Flynn et al., 2009), or to visualize the subcellular distribution and real-time transport of the ionotropic ATP-gated P2X7 receptors in rat hippocampal neurons (Shrivastava et al., 2013). More recently, the expression of Dendra2-tagged proteins has been used to target mitochondria and to analyze their transport and morphology in sensory axons of living mice (Bolea et al., 2014). "
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    ABSTRACT: Spines are small protrusions on dendritic membranes receiving inputs from axonal termini. They consist in a head connected to the dendritic shaft by a narrow neck and contain multiple synaptic proteins that interact in a coordinated manner to allow for synaptic communication. This process involves many proteins that are moving in and out spines. However, comparing this synaptodendritic movement in basal and stimulated conditions is very challenging. Here we describe an elegant method to measure the activity-dependent diffusion of synaptic proteins using Dendra2 photoconversion. We provide a successful method to obtain Dendra2-photoconverted images and a step-by-step procedure to analyze the data. This live-imaging approach may also apply to investigate the diffusion of proteins across other subcellular compartments or organelles including but not restricted to, nucleus, nucleolus, ER, or vesicular structures. Once the imaging system is set up, data can be acquired in 1-30 min and analyzed in approximately 1-4 h.
    Full-text · Article · Sep 2015 · Frontiers in Cellular Neuroscience
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    • "We have shown previously that in the presence of elevated levels of (phosphorylated) human tau, Aβ toxicity is exaggerated, most likely because, under these conditions, more Fyn enters the spine (Ittner et al., 2010; Ittner and Götz, 2011). In the presence of oligomeric Aβ tau not only changes its phosphorylation status but also alters its subcellular localization (Zempel et al., 2010, 2013). A role for tau phosphorylation specifically at the 12E8 epitope Ser262/Ser356 has been shown to be required for Aβ-mediated spine loss mediated via the CaMK2-AMPK signaling pathway (Mairet-Coello et al., 2013). "
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    ABSTRACT: The kinase Fyn, the microtubule-associated protein tau and the peptide amyloid-β (Aβ) constitute a toxic triad in Alzheimer's disease (AD). Tau's subcellular localization is mainly regulated by phosphorylation whereas Fyn's localization is dictated by palmitoylation targeting it to the plasma membrane in a reversible manner. We have previously shown that tau is required for Fyn to be targeted to the dendritic spine. We had also shown that a truncated form of tau (Δtau) that accumulates in the cell soma is capable of trapping Fyn and preventing it from entering the spine. Here we determined that palmitoylation is required for Fyn's membrane and spine localization. We further evaluated the functional consequences of neuronal over-expression of the constitutively active Y531F mutant form of Fyn (FynCA) in transgenic mice. We found that the FynCA transgenic mice displayed a reduced weight, a massively reduced lifespan and a high level of hyperactivity. The lifespan of the FynCA mice was only slightly extended by crossing them with Δtau transgenic mice, possibly reflecting differences in expression patterns of the transgenes and high levels of transgenic FynCA compared to endogenous Fyn. Analysis of synaptosomes revealed that FynCA accumulated at high levels in the spine, resulting in increased levels of the NMDA receptor subunit NR2b phosphorylated at residue Y1472. Tau was strongly phosphorylated at the AT8 epitope S202/T205 as shown by Western blot and immunohistochemistry indicating that an increased tyrosine kinase activity of Fyn has down-stream consequences for serine/threonine-directed phosphorylation.
    Full-text · Article · May 2014 · Frontiers in Molecular Neuroscience
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    • "Since polyglutamylases are expressed at high levels in the brain, Ttlls that elongate glutamate side chains and activate spastin may serve as potential drug targets. Interestingly, recent findings also implicate tubulin polyglutamylation-induced spastin activation in the loss of MTs in Alzheimer's disease [18]. "
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    ABSTRACT: Polyglutamylation of tubulin and other non-tubulin substrates is a reversible posttranslational modification brought about by tubulin tyrosine-like ligases. Altered polyglutamylation is linked to tumorigenesis and resistance to chemotherapeutic drugs that target the microtubule, and therefore is a potential pharmacological target in cancer therapy. Despite the large amount of research focused on the development of anticancer agents, only a small number of well-characterized inhibitors of polyglutamylases have been identified, including the phosphinic acid-based inhibitors of Ttll7. In this minireview, we summarize the role of polyglutamylation in cancer, and draw attention to the largely unexplored area of polyglutamylase inhibition in the treatment of cancer.
    Full-text · Article · May 2014 · Cancer letters
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