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Authors: Avila, Jesús

Article Type: Review Article

Abstract: Tau protein, which was discovered in Prof. Kirschner’s laboratory in 1975, has been the focus of my research over the last 40 years. In this issue of the Journal of Alzheimer ’s Disease commemorating its 20th year of publication, I will provide a short review of some of the features of my relationship with tau.

Keywords: Alzheimer’s disease, microtubules, neurons, tau

DOI: 10.3233/JAD-170600

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1277-1285, 2018

Authors: Avila, Jesús

Article Type: Research Article

Abstract: In this volume we commemorate the centennial of Alois Alzheimer's discovery of what was later known as Alzheimer's disease, named by Alzheimer's mentor, Emil Kraepelin [1]. In a much more low level, our group remember in this issue a paper published twenty years ago. In that paper it was described that tau can self-polymerize and, at that time, it suggested that tau was not only a component of Alzheimer paired helical filaments, as indicated some months earlier during that year, 1986, but that it was the main component of Alzheimer paired helical filaments.

Keywords: Alzheimer disease, paired helical filament, phosphorylation, tau

DOI: 10.3233/JAD-2006-9S320

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 171-175, 2006

Authors: Sayas, C.L. | Ávila, Jesús

Article Type: Review Article

Abstract: During neuronal development, spherical neuroblasts differentiate into mature neurons through the extension of a long axon and several shorter dendrites. Morphological changes that underlie neuronal differentiation are mostly driven by the microtubular cytoskeleton. Regulation of microtubule dynamics and stability during axon and dendrite extension relies on the action of different families of microtubular proteins, such as classical microtubule-associated proteins (MAPs) and microtubule plus-end tracking proteins (+TIPs). This review article addresses recent research on the crosstalk between the main axonal MAPs, tau and MAP1B, and end binding proteins (EBs), the core +TIPs, during axon outgrowth in developing neuronal cells. Furthermore, we …discuss the potential implications of the dysregulation of the interplay between tau and EBs in neurodegenerative disorders such as Alzheimer's disease. Show more

Keywords: Alzheimer's disease, axon outgrowth, MAPs, MAP1B, microtubule dynamics, neurodegeneration, neuronal development, tau, +TIPs

DOI: 10.3233/JAD-132315

Citation: Journal of Alzheimer's Disease, vol. 40, no. s1, pp. S17-S22, 2014

Authors: Medina, Miguel | Avila, Jesús

Article Type: Editorial

DOI: 10.3233/JAD-140755

Citation: Journal of Alzheimer's Disease, vol. 40, no. s1, pp. S1-S3, 2014

Authors: Avila, Jesús | Perry, George

Article Type: Article Commentary

Abstract:  Memory consolidation related to the hippocampal-cortex connection takes place during sleep. This connection may involve at least two steps— one in the NREM phase of sleep (transmission) and the other in the REM phase (consolidation). In this brief report, we comment on the role of tau protein in these two phases of sleep. The absence of tau decreases δ waves in NREM, whereas the overexpression of modified (phosphorylated and/or mutated) tau alters θ waves in REM.

Keywords: Alzheimer’s disease, delta waves, memory, NREM phase, sleep, tau

DOI: 10.3233/JAD-230230

Citation: Journal of Alzheimer's Disease, vol. 94, no. 2, pp. 491-495, 2023

Authors: Hernández, Félix | Avila, Jesús

Article Type: Research Article

Abstract: There is controversy in some neurodegenerative disorders whether the presence of aberrant aggregates in a neuron could have a toxic or a protective effect. In some disorders like in encephalopathies (prion disease), protein aggregates are toxic for the neuron. In other disorders, like Huntington disease, a protective role has been suggested for the aggregates of huntingtin. In this paper, we review the role of tau aggregation and hypothesize that tau aggregates could have an insufficient protective role in damaged neurons.

Keywords: GSK3, tau aggregation, tau phosphorylation, tauopathology

DOI: 10.3233/JAD-2008-14414

Citation: Journal of Alzheimer's Disease, vol. 14, no. 4, pp. 449-452, 2008

Authors: Lorío, Gretchen | Avila, Jesús | Díaz-Nido, Javier

Article Type: Research Article

Abstract: Accumulation of hyperphosphorylated tau protein and progressive neuronal loss are among the major hallmarks of certain neurodegenerative disorders including Alzheimer's disease. However, the relationship between tau phosphorylation and neuronal cell death remains unclear. Here we have analyzed tau modifications during two forms of neuronal death, apoptosis and necrosis, using primary cultures of cerebellar granule neurons as a simple model system. Induction of neuronal apoptosis by inhibition of phosphatidylinositol 3-kinase results in a rapid increase in the phosphorylation of tau, which is followed by the dephosphorylation and cleavage of the protein. In contrast, necrosis triggered by high salt shock or glutamate …treatment leads to a rapid dephosphorylation and an almost complete proteolysis of tau. These data suggests that a transient tau hyperphosphorylation occurs at an early stage of apoptosis, whereas tau is dephosphorylated and cleaved during the late phase of apoptosis as well as in necrotic neurons. Show more

DOI: 10.3233/JAD-2001-3607

Citation: Journal of Alzheimer's Disease, vol. 3, no. 6, pp. 563-575, 2001

Authors: Hernandez, Felix | Lucas, Jose J. | Avila, Jesus

Article Type: Review Article

Abstract: Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed serine/threonine kinase that plays a key role in the pathogenesis of Alzheimer's disease (AD). GSK3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in paired helical filaments, and GSK3 activity contributes both to amyloid-β production and amyloid-β-mediated neuronal death. Thus, mice generated in our laboratory with conditional overexpression of GSK3 in forebrain neurons (Tet/GSK3β mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis, as well as spatial learning deficit. In this review, we describe recent contributions of our group showing that transgene shutdown …in that animal model leads to normal GSK3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK3 inhibitors for AD therapeutics. In addition, we have combined transgenic mice overexpressing the enzyme GSK3β with transgenic mice expressing tau with a triple FTDP-17 mutation that develop prefibrillar tau-aggregates. Our data suggest that progression of the tauopathy can be prevented by administration of lithium when the first signs of neuropathology appear. Further, it is possible to partially reverse tau pathology in advanced stages of the disease, although the presence of already assembled neurofibrillary tangle-like structures cannot be reversed. Show more

Keywords: Alzheimer's disease, GSK3, tau

DOI: 10.3233/JAD-2012-129025

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S141-S144, 2013

Authors: Hernández, Félix | García-García, Esther | Avila, Jesús

Article Type: Research Article

Abstract: Inge Grundke-Iqbal and Khalid Iqbal found a connection between microtubule associated tau and Alzheimer's disease. They described that abnormally phosphorylated tau is a component of the paired helical filaments found in the disease. Afterwards they described that tau hyperphosphorylation prevents microtubule assembly. Now trying to complement the relationship between microtubules and tau phosphorylation, we have commented on the effect of microtubule disassembly on tau phosphorylation. In this study, we investigated the role of microtubule depolymerization induced by nocodazole on tau phosphorylation in human neuroblastoma SH-SY5Y cells. Our results indicate that nocodazole provokes tau phosphorylation mediated by GSK3, as determined by …using AT-8 or Tau-1 antibodies. Interestingly, total GSK3β and GSK3β phosphorylation on Ser-9 are not altered during nocodazole treatment. In addition, microtubule stabilization with taxol had similar effects, likely because taxol and tau compete for the same binding sites on microtubules, and in the presence of taxol, tau could be detached from microtubules. Thus, unbound tau from microtubles can be phosphorylated by GSK3, even if the activity of GSK3 is not altered, probably because tau unbound to microtubules could be a better substrate for the kinase than microtubule-associated tau. These findings suggest that microtubule depolymerization can be a primary event in neurodegenerative disorders like Alzheimer's disease and that tau phosphorylation takes place afterwards. Show more

Keywords: Disassembly, GSK3, microtubules, phosphorylation, tau

DOI: 10.3233/JAD-130545

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 507-513, 2013

Authors: Goñi-Oliver, Paloma | Avila, Jesús | Hernández, Félix

Article Type: Research Article

Abstract: Deregulation of glycogen synthase kinase-3 (GSK-3) activity is believed to play a key role in the pathogenesis of Alzheimer's disease (AD). GSK-3 activity is regulated by phosphorylation and through interaction with GSK-3-binding proteins. Previously, we demonstrated that calpain activation produces a truncation of GSK-3. In this study, we show that calpain-mediated GSK-3 truncation, induced by N-methyl-D-aspartic acid (NMDA), depends on extracellular calcium. Primary cultures of cortical neurons treated with NMDA reduce GSK-3 levels up to 75%, although the truncated form of GSK-3 does not accumulate, suggesting that a short-lived product is formed. The data obtained with human AD samples suggest …that, although a great variability exists at least in postmortem samples, truncated GSK-3 does not accumulate. However, memantine, a non-competitive NMDA receptor which has been approved for the treatment of moderate to severe AD, is able to inhibit GSK-3 truncation induced by NMDA in primary cultures of cortical neurons in a dose-dependent manner. Thus, memantine modulates GSK-3 signaling, which might explain its protective role in AD. Overall, our data reinforces the important relationship between NMDA receptors and GSK-3 and their involvement as one of the first steps in neurodegenerative diseases such as AD. Show more

Keywords: Alzheimer's disease, calpain, glycogen synthase kinase-3 (GSK-3), N-methyl-D-aspartic acid (NMDA), proteolysis

DOI: 10.3233/JAD-2009-1190

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 843-848, 2009