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  • We found that three proteins CKB gamma enolase and glycerald


    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 Glpbio KRN 7000 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. Our study adds new proteins able to bind N-terminal human tau end. Thus, it has been recently published that deletion of amino acids studied here from longest human tau isoform alters binding of proteins as synapsin-1, synaptotagmin-1, some 14-3-3 proteins and Annexin A5, having the human form more affinity than the deleted form [28]. Proteins here described able to bind N-terminal end of human tau (residues 16–26) have been described to be involved in AD. AD may be caused by a progressive energy deficiency syndrome in the central nervous system [20]. In AD, CKB [5,6], enolase [29] and GAPDH [30] are modified by oxidation. In the case of GAPDH (a protein that interacts with APP), its enzymatic activity shows a significant decrease in this disease, as a result of oxidative modification [30] resulting in higher susceptibility of cells bearing oxidatively modified GAPDH.
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    Introduction Alzheimer's disease (AD) is the leading cause of dementia in the elderly population, affecting approximately 40 million people worldwide [1,2]. This neurodegenerative disease is the result of progressive neurodegenerative changes in the human brain, which lead to a progressive decline in memory, language and attention [3]. From a neuropathological point of view, the AD brain exhibits the presence of two distinctive pathological hallmarks: the extracellular deposition of amyloid-β (Aβ) peptide in senile plaques and the intracellular accumulation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein [4]. Additional features include microgliosis and a widespread and progressive loss of neurons, synapses and white matter [1,5]. Cognitive and behavioral symptoms constitute only the “tip of the iceberg”, since the disruption of brain structure and function and consequent neuronal loss precede the clinical signs of the disease by 20–30 years [6]. Within this scenario, defective cerebral metabolism has gained attention as a possible initial cause of this neurodegenerative disease, particularly for the sporadic cases of AD, where aging and metabolic disorders are main risk factors [7,8]. In fact, compelling evidence revealed that regional brain hypometabolism occurs prior to the occurrence of senile plaques and NFTs in both genetic and sporadic AD [[9], [10], [11], [12], [13], [14]] suggesting impaired glucose metabolism may be an upstream event in AD progression.