Biomedical subjects

Alberto Gómez-Ramos

Publications and source records attributed to Alberto Gómez-Ramos.

9 recordsLinked to original sources

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

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

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↗

PubMed2005

Characterization of Alzheimer paired helical filaments by electron microscopy.

We show how electron microscopy can be used to answer several critical issues in neurodegenerative disorders that course with the formation of aberrant filamentous structures. Thus, electron microscopy is a useful technique to study in vitro assembly of pathogenic proteins, to map the regions involved in filament formation, as well as to detect by immunoelectron microscopy which proteins bind to the filaments. Furthermore, electron microscopy is the main technique used to discover if an animal model develops fibrillar pathology and if those filaments are similar to those found in human patients. This review focuses on Alzheimer's disease and related tauopathies, although similar studies have been done with other neurodegenerative disorders as, for example, Huntington's disease.

Alzheimer Disease↗

PubMed2004

Expression of an altered form of tau in Sf9 insect cells results in the assembly of polymers resembling Alzheimer's paired helical filaments.

Tau is the main component of the paired helical filaments (PHFs), aberrant structures that develop in the brain of Alzheimer's disease (AD) patients and other tauopathies like frontotemporal dementia and parkinsonism associated to chromosome 17 (FTDP-17). Previous work has shown that tau overexpression in Sf9 insect cells results in the formation of long cytoplasmatic extensions as a consequence of microtubule stabilization and bundling. Throughout this work, we have taken studies in this system further by overexpression of an altered form of tau characteristic of FTDP-17, which includes three mutations (G272V, P301L and R406W) and biochemically behaves as a hyperphosphorylated form of the protein, with the aim of developing an in vitro model which would favour the formation of tau aggregates. Our results indicate that filaments resembling PHFs assemble when Sf9 cells overexpress FTDP-17 tau. The amount of these polymers is reduced in lithium treated cells which suggests that phosphorylation of FTDP-17 tau by GSK3 induces a conformational change favouring the formation of fibrillar polymers.

Actin Cytoskeleton↗

PubMed2004

Assembly in vitro of tau protein and its implications in Alzheimer's disease.

Tau is a microtubule associated protein that is also the main component of the aberrant filaments that form aberrant structures like the neuropil threads or the neurofibrillary tangles, found in the brain of Alzheimer's disease patients. The assembly of tau aberrant filaments could be reproduced in vitro by using a high concentration of tau protein or, at lower protein concentrations, by adding some compounds like polyanions, fatty acids (and derivates), and others. In this mini-review a descriptive analysis of the different conditions needed for in vitro tau polymerization are summarized.

Alzheimer Disease↗

PubMed2004

Tau phosphorylation and assembly.

Neurofibrillary tangles, one of the aberrant structures found in the brain of Alzheimer's disease patients are mainly composed of tau in hyperphosphorylated form. Thus, a possible relation between phosphorylation and assembly of tau proteins has been analysed. By doing in vitro studies we have observed that in certain conditions, where compounds from oxidative stress are present, the capacity of tau for self assembly increases upon phosphorylation.

Alzheimer Disease↗

PubMed2003

Effect of the lipid peroxidation product acrolein on tau phosphorylation in neural cells.

A hallmark of several neurodegenerative disorders, including Alzheimer's disease and tauopathies, is the hyperphosphorylation of the microtubule-associated protein tau. Tau phosphorylation by proline-directed and non-proline-directed protein kinases has been tested using antibodies PHF1 and 12E8, respectively. The effect of the lipid peroxidation product acrolein on these modes of phosphorylation has been assayed. We have found that acrolein, a peroxidation product from arachidonic acid, increases the phosphorylation of tau at the site recognized by PHF-1 both in human neuroblastoma cells and in primary cultures of mouse embryo cortical neurons. Whereas the basal phosphorylation of tau protein at the PHF1 site seems to be largely mediated by glycogen synthase kinase-3 (which is also activated in response to Abeta peptide), the acrolein-induced tau hyperphosphorylation at the same site is also due to p38 stress-activated kinase. These results support the view that oxidative stress and subsequent formation of lipid peroxidation products may contribute to tau protein phosphorylation in Alzheimer's disease and tauopathies.

Acrolein↗

PubMed2002

Formation of aberrant phosphotau fibrillar polymers in neural cultured cells.

Here we show, for the first time, the in vitro formation of filamentous aggregates of phosphorylated tau protein in SH-SY5Y human neuroblastoma cells. The formation of such aberrant aggregates, similar to those occurring in vivo in Alzheimer's disease and other tauopathies, requires okadaic acid, a phosphatase inhibitor, to increase the level of phosphorylated tau, and hydroxynonenal, a product of oxidative stress that selectively adducts and modifies phosphorylated tau. Our findings suggest that both phosphorylation and oxidative modification are required for tau filament formation. Importantly, the in vitro formation of intracellular tau aggregates could be used as a model of tau polymerization and facilitate the development of novel therapeutic approaches.

Aldehydes↗