Francisco Wandosell - Academia.edu (original) (raw)

Papers by Francisco Wandosell

FEBS Letters, Mar 19, 2007

The mechanisms that underlie axon formation are still poorly understood. GSK3 has been recently i... more The mechanisms that underlie axon formation are still poorly understood. GSK3 has been recently implicated in establishing the axon and in its elongation. We have used four different GSK3 inhibitors to determine the role of GSK3 activity in hippocampal neurons at different periods of time. Inhibition of GSK3 activity impairs axon formation. The ''critical period'' of this activity of GSK3 is at least the first 24 h since afterwards the inhibition of GSK3 does not compromise the process of elongation, although it exacerbates axon branching. Moreover, interference RNAs impeding the expression of the GSK3 alpha or beta isoforms in hippocampal neurons prevents an axon from forming.

Background: The accumulation of extracellular amyloid-beta (Aß) peptide and intracellular neurofi... more Background: The accumulation of extracellular amyloid-beta (Aß) peptide and intracellular neurofibrillary tangles in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). For the analysis of Aß-peptide aggregation, different mouse models (single or double transgenic mice) have been used to follow the evolution of AD-amyloidosis, and to test potential treatments. So far, cerebellum tissue has not been deeply analyzed to check the amyloidosis in these transgenic models. Besides, sex influence hasn't been systematically studied in these models, even it has been described important gender differences in the evolution of AD in human population. We have checked whether the progression of amyloidosis in a double transgenic mouse, APP/PS1, is susceptible to aging and differentially affects males and females. Methods: Aß levels were measured by ELISA in plasma and tissue samples. Cortex and cerebellum tissue of transgenic males and females from 6 to 15 months of age were processed to be analyzed. In addition, fixed hemibrains brain were coronally sectioned and used to perform immunohistochemistry and immunofluorescence studies. Results: Peripheral levels of Aß presented different levels at 15months-old, being significantly higher in females. This divergence is observed in cerebellum analysis too. The accumulation of amyloid in the cerebellum was 10 fold higher in the females at 15 months. However, cortex results didn't show such differences between sexes. Immunohistochemistry and immunofluorescence analysis confirm ELISA results. Furthermore, the distribution of reactive glial cells showed important differences between cortex and cerebellum. The levels of astrocytes in the molecular layer of the cerebellum were significantly reduced. Conclusions: The cerebellum tissue should be deeply analyzed to follow its implications in the evolution of the disease and the developed pathology. Moreover, gender differences could be crucial for a complete understanding of this disease. We suggest that human population could be studied in this way. In addition, sex specific treatment strategies could be developed, even more, differential response after any therapeutic approach could be observed too.

Journal of Neuroscience Research, Jan 15, 1997

Frontiers research topics, 2019

John Wiley & Sons, Inc. eBooks, Sep 12, 2006

Biochimica Et Biophysica Acta: Molecular Basis Of Disease, Apr 1, 1998

The b-amyloid peptide A b or A4 is produced by proteolytic cleavage from amyloid precursor protei... more The b-amyloid peptide A b or A4 is produced by proteolytic cleavage from amyloid precursor protein APP. The progressive cerebral deposition of this peptide is one of the most important features of Alzheimer's disease. From the study of normal and transfected cells, two APP processing pathways have been proposed as physiological alternatives. One of these can produce A b or amyloidogenic peptides, whereas the second does not. However, it is not completely clear how APPs are post-translationally modified, proteolytically processed and metabolized in the brain. We report here that APPs Ž. also exist as proteoglycan, chondroitin-sulfate ChS. We have identified in normal rat brain a complex pool of 8 to 130 Ž. kDa ChS-core proteins. The main portion of these proteoglycan PGs APPs contains complete amyloidogenic sequence, suggesting a novel proteolytic processing of APP from the amino-terminal to the transmembrane region. This population appears augmented after brain damage. These findings may have significant implications in understanding the initial deposition and kinetics of amyloid aggregation in a pathological situation like Alzheimer's disease.

Frontiers in Molecular Neuroscience, 2011

Glycogen synthase kinase-3 (GSK-3) is ubiquitously expressed and unusually active in resting, non... more Glycogen synthase kinase-3 (GSK-3) is ubiquitously expressed and unusually active in resting, non-stimulated cells. In mammals, at least three proteins (α, β1, and β2), generated from two different genes, gsk-3α and gsk-3β, are widely expressed at both the RNA and protein levels although some tissues show preferential expression of some of the three proteins. Control of GSK-3 activity occurs by complex mechanisms that depend on specific signaling pathways, often controlling the inhibition of the kinase activity. GSK-3 appears to integrate different signaling pathways from a wide selection of cellular stimuli. The unique position of GSK-3 in modulating the function of a diverse series of proteins and its association with a wide variety of human disorders has attracted significant attention as a therapeutic target and as a means to understand the molecular basis of brain disorders. Different neurodegenerative diseases including frontotemporal dementia, progressive supranuclear palsy, and Alzheimer's disease, present prominent tau pathology such as tau hyperphosphorylation and aggregation and are collectively referred to as tauopathies. GSK-3 has also been associated to different neuropsychiatric disorders, like schizophrenia and bipolar disorder. GSK-3β is the major kinase to phosphorylate tau both in vitro and in vivo and has been proposed as a target for therapeutic intervention. The first therapeutic strategy to modulate GSK-3 activity was the direct inhibition of its kinase activity. This review will focus on the signaling pathways involved in the control of GSK-3 activity and its pathological deregulation. We will highlight different alternatives of GSK-3 modulation including the direct pharmacological inhibition as compared to the modulation by upstream regulators.

International Journal of Molecular Sciences, Jan 17, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Current Neuropharmacology, Apr 1, 2022

Brain ischemia, also known as ischemic stroke, occurs when there is a lack of blood supply into t... more Brain ischemia, also known as ischemic stroke, occurs when there is a lack of blood supply into the brain. When an ischemic insult appears, both neurons and glial cells can react in several ways that will determine the severity and prognosis. This high heterogeneity of responses has been a major obstacle in developing effective treatments or preventive methods for stroke. Although white matter pathophysiology has not been deeply assessed in stroke, its remodelling can greatly influence the clinical outcome and the disability degree. Oligodendrocytes, the unique cell type implied in CNS myelination, are sensible to ischemic damage. Loss of myelin sheaths can compromise axon survival, so new Oligodendrocyte Precursor Cells are required to restore brain function. Stroke can, therefore, enhance oligodendrogenesis to regenerate those new oligodendrocytes that will ensheath the damaged axons. Given that myelination is a highly complex process that requires coordination of multiple pathways such as Sonic Hedgehog, RTKs or Wnt/β-catenin, we will analyse new research highlighting their importance after brain ischemia. In addition, oligodendrocytes are not isolated cells inside the brain, but rather form part of a dynamic environment of interactions between neurons and glial cells. For this reason, we will put some context into how microglia and astrocytes react against stroke and influence oligodendrogenesis to highlight the relevance of remyelination in the ischemic brain. This will help to guide future studies to develop treatments focused on potentiating the ability of the brain to repair the damage.

Pharmaceutical Research, Feb 6, 2018

Purpose The induction of autophagy has recently been explored as a promising therapeutic strategy... more Purpose The induction of autophagy has recently been explored as a promising therapeutic strategy to combat Alzheimer's disease. Among many other factors, there is evidence that ceramides/dihydroceramides act as mediators of autophagy, although the exact mechanisms underlying such effects are poorly understood. Here, we describe how two dihydroceramide desaturase inhibitors (XM461 and XM462) trigger autophagy and reduce amyloid secretion by neurons. Methods Neurons isolated from wild-type and APP/PS1 transgenic mice were exposed to the two dihydroceramide desaturase inhibitors to assess their effect on these cell's protein and lipid profiles. Results Both dihydroceramide desaturase inhibitors increased the autophagic vesicles in wild-type neurons, reflected as an increase in LC3-II, and this was correlated with the accumulation of dihydroceramides and dihydrosphingomyelins. Exposing APP/PS1 transgenic neurons to these inhibitors also produced a 50% reduction in amyloid secretion and/or production. The lipidomic defects triggered by these dihydroceramide desaturase inhibitors were correlated with a loss of S6K activity, witnessed by the changes in S6 phosphorylation, which strongly suggested a reduction of mTORC1 activity. Conclusions The data obtained strongly suggest that dihydroceramide desaturase 1 activity may modulate autophagy and mTORC1 activity in neurons, inhibiting amyloid secretion and S6K activity. As such, it is tantalizing to propose that dihydroceramide desaturase 1 may be an important therapeutic target to combat amyloidosis.

PubMed, Jan 15, 1997

The effects of beta-amyloid (25-35) (betaA) on cultured astrocytes from rat cortex were studied a... more The effects of beta-amyloid (25-35) (betaA) on cultured astrocytes from rat cortex were studied and compared with those of a scrambled peptide and with untreated cultures. Single addition (from 5 to 200 microg/ml) of betaA peptide induced a marked morphological change in astrocytes, changing their flat polygonal shape into stellate process-bearing morphology. The changes induced by betaA were concentration and time-dependent. The addition of the scrambled peptide did not alter cell viability in comparison with untreated astrocyte cultures. However, cell viability was dose-dependently decreased by betaA. A subpopulation of betaA-treated astrocytes showed an increase in glial fibrillary acidic protein (GFAP) and Vimentin (Vim) immunostaining while other reactive astrocyte markers such as S100beta, MAP2, and ApoE remained unaltered or undetectable. The morphological changes in betaA-treated astrocytes appeared to be mainly due to a cytoskeletal reorganization, since the total amounts of GFAP and Vim proteins were not essentially modified. These results strongly suggest that astrocytes are another cellular target of the effects of betaA and this may be relevant to understanding the neuropathology of Alzheimer's disease.

Biochimica et biophysica acta. Molecular cell research, May 1, 2013

International Journal of Alzheimer's Disease, 2011

Glycogen synthase kinase-3 (GSK-3) unique position in modulating the function of a diverse series... more Glycogen synthase kinase-3 (GSK-3) unique position in modulating the function of a diverse series of proteins in combination with its association with a wide variety of human disorders has attracted significant attention to the protein both as a therapeutic target and as a means to understand the molecular basis of these disorders. GSK-3 is ubiquitously expressed and, unusually, constitutively active in resting, unstimulated cells. In mammals, GSK-3α and β are each expressed widely at both the RNA and protein levels although some tissues show preferential levels of some of the two proteins. Neither gene appears to be acutely regulated at the transcriptional level, whereas the proteins are controlled posttranslationally, largely through protein-protein interactions or by posttranslational regulation. Control of GSK-3 activity thus occurs by complex mechanisms that are each dependent upon specific signalling pathways. Furthermore, GSK-3 appears to be a cellular nexus, integrating several signalling systems, including several second messengers and a wide selection of cellular stimulants. This paper will focus on the different ways to control GSK-3 activity (phosphorylation, protein complex formation, truncation, subcellular localization, etc.), the main signalling pathways involved in its control, and its pathological deregulation.

Journal of Alzheimer's Disease, Aug 11, 2010

One important aspect of studies carried out at the Center for Molecular Biology "Severo Ochoa" is... more One important aspect of studies carried out at the Center for Molecular Biology "Severo Ochoa" is focused on basic aspects of Alzheimer's disease, mainly the search for suitable therapeutic targets for this disorder. Several groups at the Center are involved in these studies, and, in this spotlight, the work they are carrying out will be described.

concesión: 16.09.2003 k 45 Fecha de publicación del folleto de patente: 16.09.2003 k 74 Agente: N... more concesión: 16.09.2003 k 45 Fecha de publicación del folleto de patente: 16.09.2003 k 74 Agente: No consta k 54 Título: Inhibidores heterocíclicos del enzima GSK 3útiles en el tratamiento de procesos neurodegenerativos e hiperproliferativos. Aviso: Se puede realizar consulta prevista por el art. 37.3.8 LP.

Neuroscience Letters, Nov 1, 2001

Fibronectin appears to be present in Senile Plaques of Alzheimer's disease brains. These senile o... more Fibronectin appears to be present in Senile Plaques of Alzheimer's disease brains. These senile or neuritic plaques are surrounded by dystrophic neurites, activated microglia and reactive astrocytes. The purpose of this work was to establish if a direct correlation exists between the production of Fibronectin (FN) by astrocytes and the presence of amyloid, analysing the modification of this protein produced after the treatment of cultured astrocytes with amyloid peptide (25-35). Our data showed that the addition of previously polymerised Ab-peptide to cultured astrocytes induced a marked increase in FN immunoreactivity that is in part dependent on phosphatases 2A or phosphatase 1, since was partially inhibited by okadaic acid. The increased amount of FN did not appear to be associated to any specific single isoform of which are mainly present in the rat brain. Our data suggest that in vivo FN accumulated in senile plaques may be the result, at least in part, of the response of reactive astrocyte to the presence of amyloid peptide. The importance of FN upregulation in vivo, as part of a 'positive' response of the astrocytes to produce molecules that favours neurite outgrowth, is discussed.

PLOS Pathogens, Jan 22, 2015

Herpes simplex virus type 1 (HSV-1) and HSV-2 are highly prevalent viruses that cause a variety o... more Herpes simplex virus type 1 (HSV-1) and HSV-2 are highly prevalent viruses that cause a variety of diseases, from cold sores to encephalitis. Both viruses establish latency in peripheral neurons but the molecular mechanisms facilitating the infection of neurons are not fully understood. Using surface plasmon resonance and crosslinking assays, we show that glycoprotein G (gG) from HSV-2, known to modulate immune mediators (chemokines), also interacts with neurotrophic factors, with high affinity. In our experimental model, HSV-2 secreted gG (SgG2) increases nerve growth factor (NGF)-dependent axonal growth of sympathetic neurons ex vivo, and modifies tropomyosin related kinase (Trk)A-mediated signaling. SgG2 alters TrkA recruitment to lipid rafts and decreases TrkA internalization. We could show, with microfluidic devices, that SgG2 reduced NGF-induced TrkA retrograde transport. In vivo, both HSV-2 infection and SgG2 expression in mouse hindpaw epidermis enhance axonal growth modifying the termination zone of the NGF-dependent peptidergic free nerve endings. This constitutes, to our knowledge, the discovery of the first viral protein that modulates neurotrophins, an activity that may facilitate HSV-2 infection of neurons. This dual function of the chemokine-binding protein SgG2 uncovers a novel strategy developed by HSV-2 to modulate factors from both the immune and nervous systems.

Scientific Reports

The most accepted hypothesis in Alzheimer’s disease (AD) is the amyloid cascade which establishes... more The most accepted hypothesis in Alzheimer’s disease (AD) is the amyloid cascade which establishes that Aβ accumulation may induce the disease development. This accumulation may occur years before the clinical symptoms but it has not been elucidated if this accumulation is the cause or the consequence of AD. It is however, clear that Aβ accumulation exerts toxic effects in the cerebral cells. It is important then to investigate all possible associated events that may help to design new therapeutic strategies to defeat or ameliorate the symptoms in AD. Alterations in the mitochondrial physiology have been found in AD but it is not still clear if they could be an early event in the disease progression associated to amyloidosis or other conditions. Using APP/PS1 mice, our results support published evidence and show imbalances in the mitochondrial dynamics in the cerebral cortex and hippocampus of these mice representing very early events in the disease progression. We demonstrate in cel...

International Journal of Molecular Sciences, 2022

Since the optic nerve is one of the most myelinated tracts in the central nervous system (CNS), m... more Since the optic nerve is one of the most myelinated tracts in the central nervous system (CNS), many myelin diseases affect the visual system. In this sense, our laboratory has recently reported that the GTPases R-Ras1 and R-Ras2 are essential for oligodendrocyte survival and maturation. Hypomyelination produced by the absence of one or both proteins triggers axonal degeneration and loss of visual and motor function. However, little is known about R-Ras specificity and other possible roles that they could play in the CNS. In this work, we describe how a lack of R-Ras1 and/or R-Ras2 could not be compensated by increased expression of the closely related R-Ras3 or classical Ras. We further studied R-Ras1 and R-Ras2 expression within different CNS anatomical regions, finding that both were more abundant in less-myelinated regions, suggesting their expression in non-oligodendroglial cells. Finally, using confocal immunostaining colocalization, we report for the first time that R-Ras2 is...