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

ArticleinThe EMBO Journal 32(22) · September 2013with50 Reads
DOI: 10.1038/emboj.2013.207 · Source: PubMed
Abstract
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.
    • "Hyperphosphorylated-tau is released from axons and aggregates in the soma and dendrites of neurons [39]. Such somato-dendritic accumulation of tau has been suggested to underlie the toxic effects of Aβ [28, 38,[40][41][42] . Interestingly, similar somato-dendritic accumulation of hyperphosphorylated tau has been shown in AICD-Tg mice [16]. "
    [Show abstract] [Hide abstract] ABSTRACT: Amyloid precursor protein (APP) is cleaved by gamma-secretase to simultaneously generate amyloid beta (Aβ) and APP Intracellular Domain (AICD) peptides. Aβ plays a pivotal role in Alzheimer’s disease (AD) pathogenesis but recent studies suggest that amyloid-independent mechanisms also contribute to the disease. We previously showed that AICD transgenic mice (AICD-Tg) exhibit AD-like features such as tau pathology, aberrant neuronal activity, memory deficits and neurodegeneration in an age-dependent manner. Since AD is a tauopathy and tau has been shown to mediate Aβ–induced toxicity, we examined the role of tau in AICD-induced pathological features. We report that ablating endogenous tau protects AICD-Tg mice from deficits in adult neurogenesis, seizure severity, short-term memory deficits and neurodegeneration. Deletion of tau restored abnormal phosphorylation of NMDA receptors, which is likely to underlie hyperexcitability and associated excitotoxicity in AICD-Tg mice. Conversely, overexpression of wild-type human tau aggravated receptor phosphorylation, impaired adult neurogenesis, memory deficits and neurodegeneration. Our findings show that tau is essential for mediating the deleterious effects of AICD. Since tau also mediates Aβ-induced toxic effects, our findings suggest that tau is a common downstream factor in both amyloid-dependent and–independent pathogenic mechanisms and therefore could be a more effective drug target for therapeutic intervention in AD.
    Full-text · Article · Jul 2016
    • "For example, abnormal tau, either in the form of soluble protein or in the form of abnormal filaments, is known to produce toxicity that could theoretically contribute to microtubule loss via Tau's phosphatase-activating domain (Kanaan et al., 2012). When tau abnormally enters dendrites during Alzheimer's disease, recent evidence suggests that dendritic microtubules degrade because they become more polyglutamylated and hence more sensitive to spastin (Zempel et al., 2013). Loss-of-function and gain-of-function mechanisms may apply to various neurodegenerative disorders in which loss of microtubule mass or a change in microtubule dynamics or stability has been observed, including Amyotrophic Lateral Sclerosis, Hereditary Spastic Paraplegia, Parkinson's disease, and others (Fanara et al., 2007; Solowska et al., 2014; Coyne et al., 2014; Cappelletti et al., 2015). "
    [Show abstract] [Hide abstract] ABSTRACT: Microtubules are essential for the development and maintenance of axons and dendrites throughout the life of the neuron, and are vulnerable to degradation and disorganization in a variety of neurodegenerative diseases. Microtubules, polymers of tubulin heterodimers, are intrinsically polar structures with a plus end favored for assembly and disassembly and a minus end less favored for these dynamics. In the axon, microtubules are nearly uniformly oriented with plus ends out, whereas in dendrites, microtubules have mixed orientations. Microtubules in developing neurons typically have a stable domain toward the minus end and a labile domain toward the plus end. This domain structure becomes more complex during neuronal maturation when especially stable patches of polyaminated tubulin become more prominent within the microtubule. Microtubules are the substrates for molecular motor proteins that transport cargoes toward the plus or minus end of the microtubule, with motor-driven forces also responsible for organizing microtubules into their distinctive polarity patterns in axons and dendrites. A vast array of microtubule-regulatory proteins impart direct and indirect changes upon the microtubule arrays of the neuron, and these include microtubule-severing proteins as well as proteins responsible for the stability properties of the microtubules. During neurodegenerative diseases, microtubule mass is commonly diminished, and the potential exists for corruption of the microtubule polarity patterns and microtubule-mediated transport. These ill effects may be a primary causative factor in the disease or may be secondary effects, but regardless, therapeutics capable of correcting these microtubule abnormalities have great potential to improve the status of the degenerating nervous system.
    Full-text · Article · Jun 2016
    • "The prominence of ribosomal proteins in the brain TIA1 network combined with the presence of RBPs important for RNA transport, such as HNRNPR, SYNCRIP, and EWSR1, emphasizes an important role for tau in regulating RNA transport and translation during stress. Under basal conditions, tau is present in dendrites only at low levels but localizes to the somatodendritic compartment during stress (Frandemiche et al., 2014; Hoover et al., 2010; Zempel et al., 2013; Zempel and Mandelkow, 2014). Tau might function in this context to slow RNA granule transport and regulate the interaction of TIA1 with other SG proteins, which would facilitate SG formation and the translational stress response. "
    [Show abstract] [Hide abstract] ABSTRACT: Dendritic mislocalization of microtubule associated protein tau is a hallmark of tauopathies, but the role of dendritic tau is unknown. We now report that tau interacts with the RNA-binding protein (RBP) TIA1 in brain tissue, and we present the brain-protein interactome network for TIA1. Analysis of the TIA1 interactome in brain tissue from wild-type (WT) and tau knockout mice demonstrates that tau is required for normal interactions of TIA1 with proteins linked to RNA metabolism, including ribosomal proteins and RBPs. Expression studies show that tau regulates the distribution of TIA1, and tau accelerates stress granule (SG) formation. Conversely, TIA1 knockdown or knockout inhibits tau misfolding and associated toxicity in cultured hippocampal neurons, while overexpressing TIA1 induces tau misfolding and stimulates neurodegeneration. Pharmacological interventions that prevent SG formation also inhibit tau pathophysiology. These studies suggest that the pathophysiology of tauopathy requires an intimate interaction with RNA-binding proteins.
    Full-text · Article · May 2016
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