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

Abstract

Mislocalization and aggregation of Ab and Tau combined with loss of synapses and microtubules (MTs) are hallmarks of Alzheimer disease. We exposed mature primary neurons to Ab 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 Ab insult occurs after Ab oligomers lose their toxicity and requires the kinase MARK (Microtubule-AffinityRegulating-Kinase). In neurons derived from Tau-knockout mice, MTs and synapses are resistant to Ab 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 Ab-induced toxicity in TauKO IntroductionAlzheimer disease (AD) is characterized by two types of abnormal protein aggregates in the brain, 'amyloid plaques' made up of Ab peptides, and 'neurofibrillary tangles' assembled from Tau protein Mucke and Selkoe, 2012). In familial AD, genetic evidence points to a master role of Ab aggregation, leading to downstream events including Tau hyperphosphorylation and aggregation (Haass and Selkoe, 2007;Karran et al, 2011). On the other hand, the distribution of Tau aggregates in the brain correlates better with the clinical progression of AD (Braak stages; Braak and Braak, 1991), and experiments with transgenic mice suggest a critical role for Tau in mediating Ab-induced toxicity.A key to understand the normal and toxic roles of Tau lies in the neuronal cytoskeleton, notably microtubules (MTs), the tracks of intracellular transport, and their interaction partners. Tau changes during development include (i) a shift from shorter fetal to longer adult isoforms, (ii) decreased phosphorylation (from a higher fetal to a lower adult level), and (iii) changed intracellular distribution (from ubiquitous to axonal) (Mandell and Banker, 1995;Bullmann et al, 2009). Notably, the early cytoskeletal changes in AD, such as lower MT stability, hyperphosphorylation, and missorting of Tau to the somatodendritic compartment, are reminiscent of the fetal state. In TauKO mice, the lack of Tau during development can be compensated by upregulation of other neuronal microtubule associated proteins (MAPs), for example, MAP1A (Harada et al, 1994), which may explain the mild phenotype. Depending on experimental conditions, the absence of Tau may have detrimental effects (inefficient axon outgrowth and neurodegeneration; Dawson et al, 2001;Dawson et al, 2010), or beneficial ones (reduction in Ab and excitotoxicity; King et al, 2006;Roberson et al, 2007;Ittner et al, 2010). In neuronal cell culture, ...

Amyloid beta1-42 peptide regulates microtubule stability independently of tau

“…By contrast, a recent paper suggests that early MT loss by Ab is caused by tau-mediated TTLL6 mislocalization and polyglutamylation of dendritic MTs (Zempel et al, 2013). The severing enzyme spastin would then be recruited to MTs through the poly-glutamylation, eventually leading to spine loss, mitochondria and neurofilament mislocalization (Zempel et al, 2013). Interestingly, an opposite role for tau in protecting MTs from being disassembled by katanin, another MT-severing enzyme, has also been shown (Qiang et al, 2006).…”

“…Surprisingly, whether the behavior of tau protein in AD could be mediated by changes of MT post-translational modifications induced by Ab has not been explored yet. By contrast, a recent paper suggests that early MT loss by Ab is caused by tau-mediated TTLL6 mislocalization and polyglutamylation of dendritic MTs (Zempel et al, 2013). The severing enzyme spastin would then be recruited to MTs through the poly-glutamylation, eventually leading to spine loss, mitochondria and neurofilament mislocalization (Zempel et al, 2013).…”

Microtubule nucleation and organization in dendrites

“…40,42,43 Spatial regulation of microtubule-severing enzyme activity in neurons is controlled by mechanisms such as the binding of the microtubule-associated protein Tau to microtubules in hippocampal neuron axons 44 and the post-translational modification of dendrite microtubules (polyglutamylation). 45 g-tubulin and microtubule-severing pathways interact in nonneuronal cells, for example to organize meiotic spindle microtubules in C. elegans. 46 The extent to which microtubule-severing pathways contribute to dendrite microtubule nucleation and furthermore how g-tubulin and microtubule-severing pathways interact to shape dendrites remain unclear and require further investigation.…”

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

“…Current models suggest that tau mislocalization recruits the MT polyglutamylation enzyme TTLL6 (tubulin-tyrosine ligase-like-6) into dendrites. Enhanced polyglutamylation of dendritic MTs may subsequently recruit spastin and induces MT breakdown in dendrites (Lacroix et al 2010;Zempel et al 2013). …”