title: Pseudophosphorylation of Tau at distinct epitopes or the presence of the P301L mutation targets the microtubule-associated protein Tau to dendritic spines.
abstract: Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ) and Tau in the brain. In mature neurons, Tau is concentrated in the axon and found at lower levels in the dendrite where it is required for targeting Fyn to the spines. Here Fyn mediates Aβ toxicity, which is vastly abrogated when Tau is either deleted or a truncated form of Tau (Tau(1-255)) is co-expressed. Interestingly, MAP2, a microtubule-binding protein with mainly dendritic localization that shares Fyn-binding motifs with Tau, does not mediate Aβ's synaptic toxicity in the absence of Tau. Here we show in hippocampal neurons that endogenous Tau enters the entire spine, albeit at low levels, whereas MAP2 only enters its neck or is restricted to the dendritic shaft. Based on an extensive mutagenesis study, we also reveal that the spine localization of Tau is facilitated by deletion of the microtubule-binding repeat domain. When distinct phosphorylation sites (AT180-T231/S235, 12E8-S262/S356, PHF1-S396/S404) were pseudophosphorylated (with glutamic acid, using alanine replacements as controls), Tau targeting to spines was markedly increased, whereas the pseudophosphorylation of the late phospho-epitope S422 had no effect. In determining the role physiological Fyn has in the spine localization of Tau, we found that neither were endogenous Tau levels reduced in Fyn knockout compared with wild-type synaptosomal brain fractions nor was the spine localization of over-expressed pseudophosphorylated or P301L Tau. This demonstrates that although Fyn targeting to the spine is Tau dependent, elevated levels of phosphorylated Tau or P301L Tau can enter the spine in a Fyn-independent manner.
authors.affiliation: Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), The University of Queensland, Australia.
authors.forename: Di
authors.initials: D
authors.lastname: Xia
authors.affiliation: Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), The University of Queensland, Australia.
authors.forename: Chuanzhou
authors.initials: C
authors.lastname: Li
authors.affiliation: Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute (QBI), The University of Queensland, Australia. Electronic address: j.goetz@uq.edu.au.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Götz
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism*; D000939:Epitopes / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D020125:Mutation, Missense; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport / Q000235:genetics; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000939:Epitopes; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D016875:tau Proteins; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn
keywords: Alzheimer's disease; Frontotemporal dementia; Fyn; PSD95; Phosphorylation; Tau