JCB_201701045 3161..3178

The presence of amyloid plaques and hyperphosphorylated tauloaded neurofibrillary tangles (NFTs) in the brain are invariant features of Alzheimer’s disease (AD). There is compelling evidence that soluble oligomeric Amyloid β1–42 (Aβ) plays a critical neurotoxic and synaptotoxic role during the early stages of AD (Nimmrich and Ebert, 2009; Pozueta et al., 2013a), and it has been proposed that the microtubule (MT)-associated protein (MAP) tau mediates the effects of Aβ in dendrites and axons (LaFerla, 2010; Ittner and Götz, 2011; Mairet-Coello et al., 2013; Sherman et al., 2016; Wang et al., 2016). Hyperphosphorylation of tau decreases its binding to MTs, and multiple studies support a role for Aβ in up-regulating tau phosphorylation (Busciglio et al., 1995; Zheng et al., 2002; Zempel et al., 2010; Jin et al., 2011; Mairet-Coello et al., 2013; Muratore et al., 2014). It was thus initially hypothesized that Aβ overproduction causes neurotoxicity through destabilization of the axonal MT cytoskeleton as a result of accumulation of insoluble hyperphosphorylated tau. Alternatively, neuronal injury may originate through Aβ-mediated mislocalization of soluble hyperphosphorylated tau to dendritic spines (Zempel et al., 2010), where it induces loss of glutamate receptors (Hoover et al., 2010), PrPC-mediated neurotoxicity by transporting Fyn kinase to dendritic spines (Ittner et al., 2010), and MT severing (Zempel et al., 2013). More recently, a role for pathological tau mutants and hyperphosphorylated tau has been further uncovered in presynaptic dysfunction (Zhou et al., 2017). Although these mechanisms may each contribute to synaptic injury and cell death in AD, the molecular nature of the link between Aβ and hyperphosphorylated tau remains poorly understood. We hypothesized that a primary activity of Aβ is to activate pathways that alter MT behavior and/or tubulin posttranslational modifications (PTMs) associated with MT stability and that these changes trigger a cellular stress response that leads to tau hyperphosphorylation in an attempt to restore normal MT function. In support of this model, recent evidence has shown a neurotoxic role for Aβ in acute induction of tubulin polyglutamylation (Zempel et al., 2013) and acetylation (Tsushima et al., 2015) in hippocampal neurons. These are compelling results given the implication of tubulin PTMs in the ubiquitous regulation of MT plus end–tracking proteins (+TIPs), MAPs, MT motors (Janke and Kneussel, 2010; Janke and Bulinski, 2011; Janke, 2014; Chakraborti et al., 2016), and in the case of tubulin polyglutamylation, synaptic vesicle transport (Maas et al., 2009), MT severing (Lacroix et al., 2010), and Purkinje cell degeneration (Rogowski et al., 2010). Emerging studies from several groups indicate that dynamic MTs, typically deprived of tubulin PTMs, play key roles Oligomeric Amyloid β1–42 (Aβ) plays a crucial synaptotoxic role in Alzheimer’s disease, and hyperphosphorylated tau facilitates Aβ toxicity. The link between Aβ and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aβ acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by Aβ. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in Aβ-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau-mediated neuronal damage. Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ1–42 synaptotoxicity