Amyloid-β and tau differentially control lateral trapping of fyn in the dendritic shafts and spines — ASN Events
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  2. Session 14: Imaging Workshop 2
  3. Amyloid-β and tau differentially control lateral trapping of fyn in the dendritic shafts and spines

Amyloid-β and tau differentially control lateral trapping of fyn in the dendritic shafts and spines (#51)

Ramon Martinez-Marmol 1 , Di Xia 1 , Jurgen Gotz 1 , Frederic Meunier 1
  1. Queensland Brain Institute, The University of Queensland, St Lucia, QUEENSLAND, Australia

Aims: Deposits of amyloid-β (Aβ) and hyperphosphorylated Tau protein constitute the histological hallmark lesions of Alzheimer’s disease. A cross-talk has been established for these two molecules, with the Src kinase Fyn having assumed a critical role mediating the Aβ dendritic toxicity (Larson et al., 2012). Fyn activity is affected by oligomeric Aβ and its localisation to dendritic spines depends on Tau protein (Ittner et al., 2010). How Tau and Aβ control Fyn’s nanoscale organisation and targeting to spines remains unclear.

Methods: We used a combination of conventional confocal and nanoscale imaging to investigate the potential role of Tau in controlling dendritic Fyn targeting and establish its nanoscale organisation. We have performed dSTORM (direct stochastic optical reconstruction) microscopy (van de Linde et al., 2011)to study nanocluster organization of Fyn in hippocampal dendrites, and sptPALM (single particle tracking photo-activated localization microscopy) (Manley et al., 2008) in live neurons to analyse Fyn mobility in dendritic branches and in spines.

Results: Using dSTORM we demonstrate that Fyn is organised in nanoclusters in hippocampal dendritic shafts and spines. sptPALM experiments reveal that Fyn mobility in wild-type neurons is significantly lower in spines compared to dendritic shafts (0.0038mm2.s and 0.0067mm2.s, respectively, p-value<0.0001). However, in Tau-/- neurons Fyn mobility is markedly increased specifically in spines where tripled the values obtained in wild-type conditions (0.0078 mm2.s). This result suggest that Tau controls the lateral trapping of Fyn in this subcellular compartment. Interestingly, incubation of Tau-/- neurons with oligomeric preparations of Aβ preferentially rescues Fyn nanocluster trapping in dendritic shafts but not in spines.

Conclusions: Tau controls Fyn nanocluster organisation in different dendritic compartments by lateral trapping. Aβ-induced ectopic immobilisation of Fyn outside spines may elucidate, in part, the neuroprotective effect afforded by Tau-/-.

  1. Ittner, L.M., Ke, Y.D., Delerue, F., Bi, M., Gladbach, A., van Eersel, J., Wolfing, H., Chieng, B.C., Christie, M.J., Napier, I.A., Eckert, A., Staufenbiel, M., Hardeman, E., and Götz, J. (2010). Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 142, 387-397.
  2. Larson, M., Sherman, M.A., Amar, F., Nuvolone, M., Schneider, J.A., Bennett, D.A., Aguzzi, A., and Lesne, S.E. (2012). The complex PrP(c)-Fyn couples human oligomeric Abeta with pathological tau changes in Alzheimer's disease. J Neurosci 32, 16857-16871a.
  3. Manley, S., Gillette, J.M., Patterson, G.H., Shroff, H., Hess, H.F., Betzig, E., and Lippincott-Schwartz, J. (2008). High-density mapping of single-molecule trajectories with photoactivated localization microscopy. Nat Methods 5, 155-157.
  4. van de Linde, S., Löschberger, A., Klein, T., Heidbreder, M., Wolter, S., Heilemann, M., Sauer, M. (2011). Direct stochastic optical reconstruction microscopy with standard fluorescent probes. Nat Protocols 6, 991-1009.