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    Transparency document
    Author contributions
    Introduction Tau is a microtubule-associated protein found mainly in the neurons of vertebrates (for a review see [1]). Tau of distinct origin shows some variability in primary sequence. By splitting the tau molecule into two halves, greater variability is observed in the N-terminal than in the C-terminal half [2]. Many studies of tau have been performed using the mouse or human form, despite differences between the primary sequences of these two proteins (Fig. 1). These differences are present mainly in the N-terminal halves [3,4]. Indeed, human tau is differentiated from the mouse form by the presence of an additional peptide containing 2-NBDG from residue 17–28, inclusive. Here we sought to identify proteins with the capacity to interact with this human tau-specific domain. We found that three proteins, namely creatine kinase B (CKB), gamma enolase and glycerol-3 phosphate dehydrogenase, bound to the human peptide. One of them, CKB, did not bind when in an oxidized form. Of note, the oxidized form of CKB is present in the brains of patients with AD but not in those of controls [5,6].
    Material and methods
    Discussion Here we have examined the potential functions involving human tau peptide residues 17 to 28. A search of various data banks revealed that this sequence was not present in other proteins, and we were only able to find a motif (DXXD) that is involved in caspase cleavage [15,16]. Human tau truncation at residue 26 has been reported, and this residue is part of a DXXD motif [17]. We then tested whether the human tau peptide (residues 16–26) participates in the interaction of human tau with other brain proteins (Fig. 6). We found that three proteins: CKB, gamma-enolase and glyceraldehyde 3-phosphate dehydrogenase, bound to the human tau peptide comprising residues 16 to 26. CK-B is a brain protein that phosphorylates creatine (carbamimidoyl (methyl) amino acetic acid) in the presence of ATP [18]. Enolase is a critical enzyme in the glycolytic pathway. It has three different subunits, α, β and γ, and acts as a dimer. It is located mainly in the cytoplasm, and the dimer γγ is found mostly in mature neurons [19]. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is an oxidoreductase that catalyzes the conversion of glyceraldehyde 3 phosphate to D-glycerate 1,3 bisphosphate in one of the steps of the glycolytic pathway. These three proteins are related to energetic processes involving the production of ATP or NADH. These processes could be associated with neuronal functions like axonal transport, which seems to be impaired in neurodegenerative disorders like AD, a disease that correlates with a progressive energy deficiency in the central nervous system [20]. Additionally, due to its high energy demands, the brain is highly susceptible to oxidative imbalance and changes in the level of ATP may correlate with neurodegeneration [21]. We have focused our study mainly in CKB because the main difference between the bound proteins in control and AD extracts to human N-terminal peptide was the presence of CKB in control but not in AD samples. Human tau (16-26)-binding proteins may play a role in axonal transport. In this regard, the CKB/phosphocreatine complex could facilitate a temporal energy buffer by producing the ATP required for axonal transport [22]. Thus creatine pretreatment protects cortical axons from energy depletion in vitro [23]. Also, both, enolase and CKB can move in axons, a phenomenon associated with the component b of axonal transport [24]. Furthermore, GAPDH has been implicated in rapid axonal transport [25]. Our data can also explain the difficulty in reproducing phenomena associated with AD in mouse models. Indeed, our findings demonstrate a lower affinity of CKB for mouse tau than for human tau. These data, together with the lower affinity of the CKB observed in human samples with AD, may explain some of the phenomena associated with the disease. Furthermore, the presence of tau peptide (residues 17–28) in human could regulate the intramolecular interaction between N and C termini of the protein [26], which are modulated by microtubule interactions in living cells [27]. This interaction may compete with proteins like CKB, which bind to the tau peptide presents at the N-terminus.