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: 4.28). 11/2009; 112(6):1353-67. DOI: 10.1111/j.1471-4159.2009.06511.x
Source: PubMed


J. Neurochem. (2010) 112, 1353–1367.
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.

Download full-text


Available from: Karla Isabel Lira-De León
  • Source
    • "The cytoskeleton is a cellular structure that provides neuronal morphology and whose essential components are the microtubules. The cytoskeleton is important in the formation of axon and dendrites, which are involved both in transport and neurotransmission [24]. Tubulin is the major building block of microtubules dynamic cytoskeletal structures involved in crucial cellular functions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aim. The aim of the present study was to investigate the effect of cornel iridoid glycoside (CIG) on tau hyperphosphorylation induced by wortmannin (WT) and GF-109203X (GFX) and the underlying mechanisms. Methods. Human neuroblastoma SK-N-SH cells were preincubated with CIG (50, 100, and 200 µg/ml, resp.) for 24 h and then exposed to 10 µM WT and 10 µM GFX for 3 h after washing out CIG. Immunohistochemistry was used to observe the microtubular cytoskeleton of the cultured cells. Western blotting was used to measure the phosphorylation level of tau protein, glycogen synthase kinase 3 β (GSK-3 β ), and protein phosphatase 2A (PP2A). The activity of PP2A was detected by a biochemical assay. Results. Preincubation of CIG significantly attenuated the WT/GFX-induced tau hyperphosphorylation at the sites of Thr205, Thr212, Ser214, Thr217, Ser396, and PHF-1 and improved the damage of morphology and microtubular cytoskeleton of the cells. CIG did not prevent the decrease in p-AKT-ser473 and p-GSK-3 β -ser9 induced by WT/GFX. However, CIG significantly elevated the activity of PP2A by reducing the demethylation of PP2A catalytic subunit (PP2Ac) at Leu309 and the ratio of PME-1/LCMT in the WT/GFX-treated cells. The results suggest that CIG may be beneficial to the treatment of AD.
    Full-text · Article · Dec 2013 · Evidence-based Complementary and Alternative Medicine
  • Source
    • "While a toxicity of the Aβ plaques is still under debate, their soluble precursors of non-aggregated Aβ proteins are toxic in various ways also by the formation of NFTs as a result of aggregation of a hyperphosporylated and misfolded tau protein as will be discussed later (Mattson, 2004; Pakaski and Kalman, 2008; Mohandas et al., 2009; Piau et al., 2011). Such tau protein can no longer support the intracellular transport mediated by the microtubules and with the loss of neuronal function the cell is dedicated to undergo apoptosis (Iqbal and Grundke-Iqbal, 2008; Marco et al., 2010). Protein kinases are known to mainly contribute to these toxic events as they play a central role in the cellular pathways of regulated cell function and division. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Present Alzheimer's disease (AD) therapies suffer from inefficient effects on AD symptoms like memory or cognition, especially in later states of the disease. Used acteylcholine esterase inhibitors or the NMDA receptor antagonist memantine address one target structure which is involved in a complex, multifactorial disease progression. So the benefit for patients is presently poor. A more close insight in the AD progression identified more suggested target structures for drug development. Strategies of AD drug development concentrate on novel target structures combined with the established ones dedicated for combined therapy regimes, preferably by the use of one drug which may address two target structures. Protein kinases have been identified as promising target structures because they are involved in AD progression pathways like pathophysiological tau protein phosphorylations and amyloid β toxicity. The review article will shortly view early inhibitors of single protein kinases like glycogen synthase kinase (gsk3) β and cyclin dependent kinase 5. Novel inhibitors will be discussed which address novel AD relevant protein kinases like dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A). Moreover, multitargeting inhibitors will be presented which target several protein kinases and those which are suspected in influencing other AD relevant processes. Such a multitargeting is the most promising strategy to effectively hamper the multifactorial disease progression and thus gives perspective hopes for a future better patient benefit.
    Full-text · Article · Nov 2013 · Frontiers in Cellular Neuroscience
  • Source
    • "The structure and function of microtubules are impaired as a consequence of the abnormal hyperphosphorylation of Tau protein, which precludes its ability to stabilize the monomers of alpha- and beta-tubulin14. Hyperphosphorylated Tau aggregates into oligomers to form PHFs to further originate NFTs15. Several protein kinases are involved in this process, namely glycogen synthase kinase-3 beta (GSK3β), cyclin-dependent kinase-5 (CDK5), and extracellular signal-related kinase-2 (ERK2)16; these enzymes may also be regarded as potential targets for disease-modification, upon their inhibition by specific drugs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease, and corresponds to the most common cause of dementia worldwide. Although not fully understood, the pathophysiology of AD is largely represented by the neurotoxic events triggered by the beta-amyloid cascade and by cytoskeletal abnormalities subsequent to the hyperphosphorylation of microtubule-associated Tau protein in neurons. These processes lead respectively to the formation of neuritic plaques and neurofibrillary tangles, which are the pathological hallmarks of the disease. Clinical benefits of the available pharmacological treatment for AD with antidementia drugs (namely cholinesterase inhibitors and memantine) are unquestionable, although limited to a temporary, symptomatic support to cognitive and related functions. Over the past decade, substantial funding and research have been dedicated to the search and development of new pharmaceutical compounds with disease-modifying properties. The rationale of such approach is that by tackling key pathological processes in AD it may be possible to attenuate or even change its natural history. In the present review, we summarize the available evidence on the new therapeutic approaches that target amyloid and Tau pathology in AD, focusing on pharmaceutical compounds undergoing phase 2 and phase 3 randomized controlled trials.
    Full-text · Article · Oct 2013 · The Indian Journal of Medical Research
Show more