Microtubule-Tau Interaction as a Therapeutic Target for Alzheimer’s Disease

Ivashko-Pachima, Yanina; Zhou, Liu-yao; Lei, Peng; Gozes, Illana

doi:10.1007/s12031-016-0715-x

Cited by 10 publications

(6 citation statements)

References 131 publications

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“…Overall, Tau implication in neurodegenerative diseases, and other diseases where MTs play an important role, clearly shows the interest of the Tau/MTs interaction as a potential target for intervention (Pachima et al, 2016; Das and Ghosh, 2019). Many advances have been made in the understanding of Tau functions as a MAP, and in the structural aspects of the Tau/MTs interaction.…”

Section: Perspectivesmentioning

confidence: 99%

Role of Tau as a Microtubule-Associated Protein: Structural and Functional Aspects

Barbier

Zejneli

Martinho

et al. 2019

Front. Aging Neurosci.

386

248

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Microtubules (MTs) play a fundamental role in many vital processes such as cell division and neuronal activity. They are key structural and functional elements in axons, supporting neurite differentiation and growth, as well as transporting motor proteins along the axons, which use MTs as support tracks. Tau is a stabilizing MT associated protein, whose functions are mainly regulated by phosphorylation. A disruption of the MT network, which might be caused by Tau loss of function, is observed in a group of related diseases called tauopathies, which includes Alzheimer’s disease (AD). Tau is found hyperphosphorylated in AD, which might account for its loss of MT stabilizing capacity. Since destabilization of MTs after dissociation of Tau could contribute to toxicity in neurodegenerative diseases, a molecular understanding of this interaction and its regulation is essential.

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Section: Perspectivesmentioning

confidence: 99%

Role of Tau as a Microtubule-Associated Protein: Structural and Functional Aspects

Barbier

Zejneli

Martinho

et al. 2019

Front. Aging Neurosci.

386

248

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“…NAP protects against ADNP deficiencies in mice (Vulih‐Shultzman et al, ), which is extended to SKIP (Amram et al, ). NAP (davunetide) has shown efficacy in the clinical setting, enhancing cognitive scores in amnestic MCI patients and daily functional activities in schizophrenia patients (Gozes et al, ; Javitt et al, ; Jarskog et al, ; Morimoto et al, ; Magen et al, ; Gozes, ; Pachima et al, ). Focusing on sexual differences, future clinical studies will highlight the sex effect on personalized brain protection.…”

Section: Replacement Therapiesmentioning

confidence: 99%

Sexual divergence in activity‐dependent neuroprotective protein impacting autism, schizophrenia, and Alzheimer's disease

Gozes

2016

J of Neuroscience Research

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Discovered in our laboratory, activity-dependent neuroprotective protein (ADNP) interacts with key regulatory proteins, including the chromatin remodeling complex SWI/SNF, proteins associated with RNA splicing, RNA translation, microtubule dynamics, and autophagy. ADNP regulates > 400 genes during mouse embryonic development and is essential for neural tube closure. ADNP key functions extend from mice to men, with mutations causing ADNP-related ID/autism syndrome, also known as the Helsmoortel-Van der Aa syndrome. ADNP mRNA increases in lymphocytes derived from schizophrenia patients and in patients suffering from mild cognitive impairment (MCI) and further increases in Alzheimer's disease patients compared with controls. Serum ADNP levels correlate with IQ. NAP (davunetide), an ADNP snippet drug candidate, protects cognition in patients suffering from amnestic MCI preceding Alzheimer's disease and significantly enhances functional daily activities in schizophrenia patients toward future development. It is important to note that ADNP is sexually regulated in the brains of birds, mice, and men and in lymphocytes of patients suffering from schizophrenia. ADNP haploinsufficiency in mice results in significantly decreased axonal transport (with male-female differences) changes in gene expression in a sex-dependent manner, including key regulatory mechanisms during brain and heart development and function and behavioral outcomes. These findings pave the path for better understanding of brain function through the prism of sex differences. © 2016 Wiley Periodicals, Inc.

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“…Therefore, it is believed that tau detachment from MTs [16,17] and abnormalities in axonal transport precede NFT formation as well as any clinical symptoms of the disease [18]. The study of tau transport in axons and its interaction with MTs could help to find preventive and therapeutic measures against AD, especially as recent research identified tau interaction with MTs as a possible therapeutic target in AD [19,20].…”

Section: Introductionmentioning

confidence: 99%

Simulating tubulin-associated unit transport in an axon: using bootstrapping for estimating confidence intervals of best-fit parameter values obtained from indirect experimental data

Кузнецов

2017

Proc. R. Soc. A.

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In this paper, we first develop a model of axonal transport of tubulin-associated unit (tau) protein. We determine the minimum number of parameters necessary to reproduce published experimental results, reducing the number of parameters from 18 in the full model to eight in the simplified model. We then address the following questions: Is it possible to estimate parameter values for this model using the very limited amount of published experimental data? Furthermore, is it possible to estimate confidence intervals for the determined parameters? The idea that is explored in this paper is based on using bootstrapping. Model parameters were estimated by minimizing the objective function that simulates the discrepancy between the model predictions and experimental data. Residuals were then identified by calculating the differences between the experimental data and model predictions. New, surrogate ‘experimental’ data were generated by randomly resampling residuals. By finding sets of best-fit parameters for a large number of surrogate data the histograms for the model parameters were produced. These histograms were then used to estimate confidence intervals for the model parameters, by using the percentile bootstrap. Once the model was calibrated, we applied it to analysing some features of tau transport that are not accessible to current experimental techniques.

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Microtubule-Tau Interaction as a Therapeutic Target for Alzheimer’s Disease

Cited by 10 publications

References 131 publications

Role of Tau as a Microtubule-Associated Protein: Structural and Functional Aspects

Role of Tau as a Microtubule-Associated Protein: Structural and Functional Aspects

Sexual divergence in activity‐dependent neuroprotective protein impacting autism, schizophrenia, and Alzheimer's disease

Simulating tubulin-associated unit transport in an axon: using bootstrapping for estimating confidence intervals of best-fit parameter values obtained from indirect experimental data

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