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  • Our study adds new proteins able to bind


    Our study adds new proteins able to bind N-terminal human tau end. Thus, it has been recently published that deletion of 2-NBDG 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 Regulation of protein function most often occurs by some type of post-translational modification (PTM), the principal one being protein phosphorylation [1]. Two major types of kinases, serine/threonine- and tyrosine-kinases, catalyze phosphorylation of serine and threonine and tyrosine residues, respectively. Such protein PTMs can have significant effects on protein structure, hence, regulating the protein function. For example, if a Ser or Thr located near a Glu or Asp residue in the protein, the negative charges of the phosphate group and the negatively charged amino acids will drive the groups apart, markedly changing the localized structure of the protein (Fig. 1). In contrast, if Ser or Thr near a Lys or Arg group is phosphorylated, the negatively charged phosphate group will be attracted to the positive amino acids, again significantly changing the localized structure of the protein (Fig. 1). In the case of Tyr phosphorylation, Tyr kinases, either alone or as a receptor-activated Tyr kinase, are often involved in processes associated with signal transduction following ligand binding to a specific receptor [2]. Any modification of the phenolic ring of Tyr that sterically blocks access of the Tyr OH group would lead to decreased receptor-tyrosine kinase signaling, clearly detrimental to cell survival. Along with kinases, protein phosphatases that remove protein-bound phosphate groups are involved in phosphorylation of proteins, and, consequently, also contribute to regulation of protein function [3]. About 500 kinases and 100 phosphatases are in the human genome [4]. Their complex interactions among various kinases and phosphatases regulate the dynamics of critical cellular processes [5]. Often these kinases and phosphatases are themselves regulated, certainly by other kinases and phosphatases, but also for example by the cis-trans prolyl isomerase, Pin1 [6,7], which in Alzheimer disease (AD) is oxidatively dysfunctional [8,9]. This, together with differential expression or post-translational modification of kinases and phosphatases, cause loss of regulation of these kinases and phosphatases, resulting in compromised cellular processes. Such is the case in AD brain as discussed further below based on results of phosphoproteomics.
    Alzheimer disease The major age-related neurodegenerative disorder in humans, AD is characterized clinically by age-related anosmia (loss of smell), cognitive decline (decreased ability to think, reason, and perform complex mental tasks, ultimately leading to dementia), often difficult personality changes, and very commonly eventual verbal aphasia (inability to speak). Pathologically, AD is characterized by the presence of senile plaques (composed mostly of aggregated amyloid β-peptide (Aβ) and dystrophic neurites), neurofibrillary tangles (NFT, composed of aggregated hyperphosphorylated tau protein), and loss of synapses, and many scientists believe also loss of neurons [10]. Since both plaques and tangles are observable in brain of AD patients using PET scanning [11,12] and/or detection of both Aβ40 and Aβ42 and phosphorylated tau in CSF specimens [10], newer diagnostic criteria are more biochemical/pathological-centered and less on clinical symptoms, which can occur due to conditions other than AD.