Tau oligomers and aggregation in Alzheimer's disease

Department of Molecular Biomedicine, Center of Research and Advanced Studies CINVESTAV-IPN, México DF, Mexico.
Journal of Neurochemistry (Impact Factor: 4.24). 11/2009; 112(6):1353-67. DOI: 10.1111/j.1471-4159.2009.06511.x
Source: PubMed

ABSTRACT We are analyzing the physiological function of Tau protein and its abnormal pathological behavior when this protein is self-assemble into pathological filaments. These aggregates of Tau protein are the main components in many diseases such as Alzheimer's disease (AD). Recent studies suggest that Tau acquires complex oligomeric conformations which may be toxic. In this review, we emphasized the possible phenomena implicated in the formation of these oligomers. Studies with chemical inductors indicates that the microtubule-binding domain is the most important region involved in Tau aggregation and showed the requirement of a pre-arrange Tau in abnormal conformation to promote self-assembly. Transgenic animal models and AD neuropathology studies showed that post-translational modifications are also implicated in Tau aggregation and neural cell death during AD development. Therefore, we analyzed some events that could be present during Tau aggregation. Finally, we included a brief discussion of the possible relation between glucose metabolism dysfunction in AD, and data of Tau aggregation by using aggregation inhibitors. In conclusion, the process Tau aggregation deserves further investigations to design possible therapeutic targets to inhibit the toxicity of these aggregates and it is possible that could be extended to other diseases with similar etiology.

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    • "Until recently, most of the immunotherapeutic approaches had been focused on targeting extracellular protein aggregates, for example Aβ in AD, and there has been a reluctance to target intracellular proteins such as α-syn and tau. However, as mentioned above, the discovery that α-syn and tau oligomers can penetrate and accumulate in the plasma membrane and that they can be secreted and propagate extracellularly (Lee et al., 2005; Danzer et al., 2007; Angot & Brundin, 2009; Desplats et al., 2009; Meraz-Ríos et al., 2010; Jones et al., 2012; Kfoury et al., 2012) provided a clear rationale for immunotherapy. "
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    • "This abnormal process is defined as a protein cutting that could also promote aberrant aggregation (Ávila et al., 2004) In the case of Tau molecule, the lost of any of its C-and N-extremes leads to a change of properties of the molecule. The lost of the N-terminal has been proposed as an early event in Tau aggregation process because of the capability of this extreme of inhibit Tau oligomerization in vitro (Ghoshal et al., 2002; Horowitz et al., 2006) On the other hand, C-terminal proteolysis is strongly correlated with neuropathological lesions and cognitive impairment (García- Sierra et al., 2001; Meraz-Ríos et al., 2010). Latest years many reports have demonstrated the relationship between site-specific phosphorylation at sites Ser199, Ser202, Thr205, Thr212, Ser214, located in proline-rich region, and Ser396 and Ser 404, located near C-termini. "
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    ABSTRACT: Structural studies of amyloidogenic fibrils are crucial. The insolubility and stability of fibrils makes difficult to work with by conventional methods. The research has concentrated on the use of peptides for structural studies, but the information obtained is complex for the different conditions used in the assembly of amyloidogenic fibrils in Tau or AB proteins. There is a minimum sequence with amino acids partially hidrofobic that trend to form a β-sheet structure, this region nucleating amyloidogenic fibril formation and is extremely insoluble. Analysis of the amyloidogenic regions showed a high occurrence of the aromatic residues phenylalanine and tyrosine, which have a high propensity to stack the delocalized π-electron rings. Studies with short peptides have confirmed that even two consecutive phenylalanine residues are sufficient to facilitate assembly into nanotube-like structures. Protofibrils have been identified which appear to be fibrillar precursors to amyloidogenic fibril formation, and these are preceded by the appearance of small oligomers of Tau and AB. Whether these small intermediates interact directly to form protofibrils and then these elongate to form the fully formed fibril. This process can be favored by interaction with membranes rich in negative charged surface, whereas the hydrophobic interior strengthens electrostatic secondary interactions and favors monomer recruitment with increase of local concentration, resulting in aggregate nucleation and membrane disassembly. Developing techniques for directly visualizing amyloidogenic fibrils at high resolution is promising solution to answer many key questions remain to be addressed. Elucidating these questions will undoubtedly reveal novel insights into diseases pathogenesis.
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