PubMed Health⌕ Search

Biomedical subjects

Jesús Avila

Publications and source records attributed to Jesús Avila.

At least 19 recordsLinked to original sources
PubMed2007

Cortistatin as a therapeutic target in inflammation.

Cortistatin (CST) is a recently discovered neuropeptide from the somatostatin gene family, named after its predominantly cortical expression and ability to depress cortical activity. CST shows many remarkable structural and functional similarities to its related neuropeptide somatostatin, or somatotropin release-inhibiting factor. However, the many physiological differences between CST and somatostatin are just as remarkable as the similarities. CST-29 has recently been shown to prevent inflammation in rodent models for human diseases, raising novel therapeutic properties to this neuropeptide. In this review, the authors address a new possible role for CST in the immune system and evaluate the possible therapeutic use of CST to treat disorders associated with inflammation.

Animals↗
PubMed2006

Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert.

Glycogen synthase kinase-3 (GSK-3) has been proposed as the main kinase able to aberrantly phosphorylate tau in Alzheimer's disease (AD) and related tauopathies, raising the possibility of designing novel therapeutic interventions for AD based on GSK-3 inhibition. Lithium, a widely used drug for affective disorders, inhibits GSK-3 at therapeutically relevant concentrations. Therefore, it was of great interest to test the possible protective effects of lithium in an AD animal model based on GSK-3 overexpression. We had previously generated a double transgenic model, overexpressing GSK-3beta in a conditional manner, using the Tet-off system and tau protein carrying a triple FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation. This transgenic line shows tau hyperphosphorylation in hippocampal neurones accompanied by neurofibrillary tangles (NFTs). We used this transgenic model to address two issues: first, whether chronic lithium treatment is able to prevent the formation of aberrant tau aggregates that result from the overexpression of FTDP-17 tau and GSK-3beta; second, whether lithium is able to change back already formed NFTs in aged animals. Our data suggest that progression of the tauopathy can be prevented by administration of lithium when the first signs of neuropathology appear. Furthermore, it is still possible to partially reverse tau pathology in advanced stages of the disease, although NFT-like structures cannot be changed. The same results were obtained after shut-down of GSK-3beta overexpression, supporting the possibility that GSK-3 inhibition is not sufficient to reverse NFT-like aggregates.

Age Factors↗
PubMed2006

Extracellular tau is toxic to neuronal cells.

The degeneration of neurons in disorders such as Alzheimer's disease has an immediate consequence, the release of intracellular proteins into the extracellular space. One of these proteins, tau, has proven to be toxic when added to cultured neuronal cells. This toxicity varies according to the degree of protein aggregation. The addition of tau to cultured neuroblastoma cells provoked an increase in the levels of intracellular calcium, which is followed by cell death. We suggest that this phenomenon may be mediated by the interaction of tau with muscarinic receptors, which promotes the liberation of calcium from intracellular stores.

Alzheimer Disease↗
PubMed2006

Role of MAP1B in axonal retrograde transport of mitochondria.

The MAPs (microtubule-associated proteins) MAP1B and tau are well known for binding to microtubules and stabilizing these structures. An additional role for MAPs has emerged recently where they appear to participate in the regulation of transport of cargos on the microtubules found in axons. In this role, tau has been associated with the regulation of anterograde axonal transport. We now report that MAP1B is associated with the regulation of retrograde axonal transport of mitochondria. This finding potentially provides precise control of axonal transport by MAPs at several levels: controlling the anterograde or retrograde direction of transport depending on the type of MAP involved, controlling the speed of transport and controlling the stability of the microtubule tracks upon which transport occurs.

Animals↗
PubMed2006

In vitro tau fibrillization: mapping protein regions.

We have investigated the propensity to form fibrillar aggregates of a variety of fragments and variants of the tau protein under the influence of a tau fibrillization inducer: coenzyme Q(0). To better identify fibrillization hotspots, we compare the polymerization propensity of tau fragments containing the sequence of putative hotspots with that of tau variants with that same sequence deleted. We also investigate the effects of biologically occurring modifications such as phosphorylation and deamidation. We found that residues 305 to 335 are essential for in vitro tau fibrillization. Residues 306 to 311 facilitate in vitro assembly, but are not sufficient to mimic the in vivo fibrillization of tau. Furthermore, the propensity of the 306-311 sequence to form fibrils is highly decreased by chemical modifications of tyrosine 310 that are commonly found in vivo.

Alzheimer Disease↗
PubMed2006

Lymphocyte chemotaxis is regulated by histone deacetylase 6, independently of its deacetylase activity.

In this work, the role of HDAC6, a type II histone deacetylase with tubulin deacetylase activity, in lymphocyte polarity, motility, and transmigration was explored. HDAC6 was localized at dynamic subcellular structures as leading lamellipodia and the uropod in migrating T-cells. However, HDAC6 activity did not appear to be involved in the polarity of migrating lymphocytes. Overexpression of HDAC6 in freshly isolated lymphocytes and T-cell lines increased the lymphocyte migration mediated by chemokines and their transendothelial migration under shear flow. Accordingly, the knockdown of HDAC6 expression in T-cells diminished their chemotactic capability. Additional experiments with HDAC6 inhibitors (trichostatin, tubacin), other structural related molecules (niltubacin, MAZ-1391), and HDAC6 dead mutants showed that the deacetylase activity of HDAC6 was not involved in the modulatory effect of this molecule on cell migration. Our results indicate that HDAC6 has an important role in the chemotaxis of T-lymphocytes, which is independent of its tubulin deacetylase activity.

Acetylation↗
PubMed2006

Full reversal of Alzheimer's disease-like phenotype in a mouse model with conditional overexpression of glycogen synthase kinase-3.

Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase that is particularly abundant in the CNS. Dysregulation of GSK-3 activity is believed to play a key role in the pathogenesis of CNS chronic disorders such as Alzheimer's disease (AD), bipolar disorder, and Huntington's disease, and of metabolic disorders such as type II diabetes. Accordingly, GSK-3 inhibitors have been postulated as therapeutic tools for these diseases. Interestingly, pathophysiological and pharmacological regulation of GSK-3 is affected by an amplification mechanism that applies both to inhibition and activation. The possibility therefore exists that sustained inhibition or activation might persist after cessation of the initial trigger. Regarding AD, GSK-3 has been shown to accumulate in pretangle neurons. Furthermore, GSK-3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in PHF (paired helical filament)-tau and GSK-3 activity contributes both to beta-amyloid production and to beta-amyloid-mediated neuronal death. In good agreement, mice with conditional overexpression of GSK-3 in forebrain neurons (Tet/GSK-3beta mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis as well as spatial learning deficit. Here, we exploit the conditional system used to generate Tet/GSK-3beta mice to explore whether the biochemical, histopathological, and behavioral consequences of increased GSK-3 activity are susceptible to revert after restoration of normal GSK-3 levels. Here, we show that transgene shutdown in symptomatic mice leads to normal GSK-3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK-3 inhibitors for AD therapeutics.

Alzheimer Disease↗
PubMed2006

gamma-cleavage-independent functions of presenilin, nicastrin, and Aph-1 regulate cell-junction organization and prevent tau toxicity in vivo.

Genetic analysis of familial Alzheimer's disease has revealed that mutations in the gamma-secretase enzyme presenilin promote toxic Abeta secretion; however, presenilin mutations might also influence tau hyperphosphorylation and neurodegeneration through gamma-secretase-independent mechanisms. To address this possibility and determine whether other components of the gamma-secretase complex possess similar regulatory functions, we analyzed the roles of presenilin, nicastrin, and aph-1 in a Drosophila model for tau-induced neurodegeneration. Here, we show that presenilin and nicastrin prevent tau toxicity by modulating the PI3K/Akt/GSK3beta phosphorylation pathway, whereas aph-1 regulates aPKC/PAR-1 activities. Moreover, we found that these transmembrane proteins differentially regulate the intracellular localization of GSK3beta and aPKC at cell junctions. Inhibition of gamma-secretase activity neither interfered with these kinase pathways nor induced aberrant tau phosphorylation. These results establish new in vivo molecular functions for the three components of the gamma-secretase complex and reveal a different mechanism that might contribute to neuronal degeneration in Alzheimer's disease.

Alzheimer Disease↗
PubMed2006

Tau phosphorylation and aggregation in Alzheimer's disease pathology.

In this article I shall review how tau phosphorylation and aggregation participates in Alzheimer's disease (AD) and other tauopathies. Tau, a microtubule associated protein, is the main component, in phosphorylated form, of the aberrant paired helical filaments found in AD. Tau is present in phosphorylated and aggregated form not only in AD, but in other pathologies (tauopathies). In this review, the phosphorylation of tau, its aggregation, and the possible relation between tau phosphorylation and aggregation is, briefly, described. Also, it is discussed the toxicity of modified tau. In addition, I propose a working model detailing the progression of tau pathologies.

Alzheimer Disease↗
PubMed2006

Sodium tungstate decreases the phosphorylation of tau through GSK3 inactivation.

Tungstate treatment increases the phosphorylation of glycogen synthase kinase-3beta (GSK3beta) at serine 9, which triggers its inactivation both in cultured neural cells and in vivo. GSK3 phosphorylation is dependent on the activation of extracellular signal-regulated kinases 1/2 (ERK1/2) induced by tungstate. As a consequence of GSK3 inactivation, the phosphorylation of several GSK3-dependent sites of the microtubule-associated protein tau decreases. Tungstate reduces tau phosphorylation only in primed sequences, namely, those prephosphorylated by other kinases before GSK3beta modification, which are serines 198, 199, or 202 and threonine 231. The phosphorylation at these sites is involved in reduction of the interaction of tau with microtubules that occurs in Alzheimer's disease.

Animals↗
PubMed2006

A clonal cell line from immortalized olfactory ensheathing glia promotes functional recovery in the injured spinal cord.

Immortalized cell lines of olfactory ensheathing glia (OEG) that maintain the proregenerative properties of primary cultures provide an unlimited source of OEG for both basic and applied studies. Indeed, one specific immortalized rat OEG clonal line (TEG3) proved to be as good as primary OEG in promoting neuritogenesis and axon regeneration in culture models. Thus, we examined the capacity of TEG3 to promote axonal repair in an animal model of spinal cord injury, dorsal column crush. TEG3 cells can acquire astrocyte-like or Schwann cell-like morphology depending on the conditions under which they are cultured. In the injured spinal cord, prelabeled TEG3 survived for at least 10 weeks after grafting and they integrated into the spinal cord, adopting Schwann cell-like, astrocyte-like, or intermediate morphologies. In TEG3-transplanted animals, sensory projection axons grow into the lesion site and there was robust sprouting/axonal growth of the corticospinal tract, both into and beyond the lesion site, after crushing of the spinal cord-dorsal columns. TEG3-transplanted animals also recovered sensory and motor function in tape removal and beam walking behavioral tests. These data indicate that certain immortalized cell lines derived from a single cell can maintain the regenerative properties of primary OEG.

Animals↗
PubMed2006

Effect of acetylcholine on tau phosphorylation in human neuroblastoma cells.

Alzheimer's disease (AD) is a senile dementia characterized by a progressive loss of memory, together with cognitive and behavioral impairments. In the past it was indicated that the disease was associated with a loss of acetylcholine (ACh) in the cerebral cortex (Bowen et al., 1976; Davies and Maloney, 1976); afterward, it was indicated that the severity of dementia was correlated with the extent of cholinergic loss (Perry et al., 1981). Because one of the biochemical features of AD is modification by phosphorylation of the microtubule-associated protein tau (for review, see Avila et al., 2004), in this work we indicate the effect of ACh on tau phosphorylation at specific sites recognized by 12E8 and PThr50 antibodies in human neuroblastoma SH-SY5Y cells. Two sites in which modification might regulate the binding of tau to microtubules (Novak et al., 1991; Feijoo et al., 2004).

Acetylcholine↗
PubMed2006

Acetylcholine receptors and tau phosphorylation.

Alzheimer's disease (AD) is characterized by the presence, in the brain of the patients, of two aberrant structures: intracellular neurofibrillary tangles (NFTs), containing an abnormal hyperphosphorylated form of tau protein, and extracellular senile plaques (SPs), mainly composed by fibrillar amyloid beta peptide. Another feature of AD is the neurodegeneration and dysfunction of basal forebrain cholinergic system. A possible connection among those AD characteristics could occur. Thus, the purpose of this short review is to summarize the involvement of nicotinic (nAChR) and muscarinic (mAChR) receptors on tau phosphorylation, in a direct way, or through the previous interaction of some of these receptors with amyloid beta. Several studies have demonstrated that nAChR activation results in a significantly increase of tau phosphorylation, whereas mAChR activation, may prevent tau phosphorylation.

Amyloid beta-Peptides↗
PubMed2006

Inhibition of GSK3 dependent tau phosphorylation by metals.

One of the main pathological characteristics of Alzheimer's disease is the presence in the brain of the patients of an aberrant structure, the paired helical filaments, composed of hyperphosphorylated tau. The level of tau phosphorylation has been correlated with the capacity for tau aggregation. Thus, the mechanism for tau phosphorylation could be important to clarify those pathological features in Alzheimer's disease. Tau protein could be modified by different kinases, being GSK3 the one that could modify more sites of that protein. GSK3 activity could be modulate by the presence of metals like magnesium that can be required for the proper function of the kinase, whereas, metals like manganesum or lithium inhibit the activity of the kinase. Many works have been done to study the inhibition of GSK3 by lithium, a specific inhibitor of that kinase. More recently, it has been indicated that sodium tungstate could also inhibit GSK3 through a different mechanism. In this review, we discuss the effect of these two metals, lithium and tungstate, on GSK3 (or tau I kinase) activity.

Animals↗
PubMed2006

Characteristics of the binding of thioflavin S to tau paired helical filaments.

Binding of histological benzothiazole dye thioflavin S (ThS) to protein aggregates has been related with the presence of amyloid beta sheet structure in those protein aggregates. Paired helical filaments (PHF) from Alzheimer's disease (AD) patients, (whose main component is the microtubule associated protein, tau) bind to thioflavins. By using a novel immunofluorescence method, the binding of ThS to isolated tau filaments was tested. Also, the characteristics of this binding of ThS to PHF or to the in vitro assembled tau filaments, have been analyzed. Our results suggests that ThS binds to PHF with a higher affinity than to the straight filaments (SF), also found in AD.

Alzheimer Disease↗
PubMed2006

Tau protein, the main component of paired helical filaments.

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. 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.

Alzheimer Disease↗