De Ferrari GV


Full name : De Ferrari Giancarlo V

First name : Giancarlo V

Mail : P. Universidad Catolica de Chile, Alameda 340, Santiago

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Country : Chile

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Phone : 56-2-686-2720

Fax : 56-2-686-2717

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References (13)

Title : Wnt\/beta-catenin signaling stimulates the expression and synaptic clustering of the autism-associated Neuroligin 3 gene - Medina_2018_Transl.Psychiatry_8_45
Author(s) : Medina MA , Andrade VM , Caracci MO , Avila ME , Verdugo DA , Vargas MF , Ugarte GD , Reyes AE , Opazo C , De Ferrari GV
Ref : Transl Psychiatry , 8 :45 , 2018
Abstract : Synaptic abnormalities have been described in individuals with autism spectrum disorders (ASD). The cell-adhesion molecule Neuroligin-3 (Nlgn3) has an essential role in the function and maturation of synapses and NLGN3 ASD-associated mutations disrupt hippocampal and cortical function. Here we show that Wnt/beta-catenin signaling increases Nlgn3 mRNA and protein levels in HT22 mouse hippocampal cells and primary cultures of rat hippocampal neurons. We characterized the activity of mouse and rat Nlgn3 promoter constructs containing conserved putative T-cell factor/lymphoid enhancing factor (TCF/LEF)-binding elements (TBE) and found that their activity is significantly augmented in Wnt/beta-catenin cell reporter assays. Chromatin immunoprecipitation (ChIP) assays and site-directed mutagenesis experiments revealed that endogenous beta-catenin binds to novel TBE consensus sequences in the Nlgn3 promoter. Moreover, activation of the signaling cascade increased Nlgn3 clustering and co- localization with the scaffold PSD-95 protein in dendritic processes of primary neurons. Our results directly link Wnt/beta-catenin signaling to the transcription of the Nlgn3 gene and support a functional role for the signaling pathway in the dysregulation of excitatory/inhibitory neuronal activity, as is observed in animal models of ASD.
ESTHER : Medina_2018_Transl.Psychiatry_8_45
PubMedSearch : Medina_2018_Transl.Psychiatry_8_45
PubMedID: 29503438

Title : A novel functional low-density lipoprotein receptor-related protein 6 gene alternative splice variant is associated with Alzheimer's disease - Alarcon_2013_Neurobiol.Aging_34_1709 e9
Author(s) : Alarcon MA , Medina MA , Hu Q , Avila ME , Bustos BI , Perez-Palma E , Peralta A , Salazar P , Ugarte GD , Reyes AE , Martin GM , Opazo C , Moon RT , De Ferrari GV
Ref : Neurobiology of Aging , 34 :1709 e9 , 2013
Abstract : We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 (LRP6) gene are associated with Alzheimer's disease (AD). Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 (LRP6Delta3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m)RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6Delta3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/beta-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6Delta3 isoform is a novel splice variant, which shows diminished Wnt/beta-catenin signaling activity and might have a functional role in individuals with AD.
ESTHER : Alarcon_2013_Neurobiol.Aging_34_1709 e9
PubMedSearch : Alarcon_2013_Neurobiol.Aging_34_1709 e9
PubMedID: 23218566

Title : Neurodegenerative processes in Alzheimer's disease: Role of A-beta-AChE complexes and Wnt signaling -
Author(s) : Inestrosa NC , Colombres M , De Ferrari GV
Ref : In: Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects , (Inestrosa NC, Campos EO) P. Universidad Catolica de Chile-FONDAP Biomedicina :95 , 2004

Title : Poster (40) Acetylcholinesterase - amyloid beta-peptide interaction. -
Author(s) : De Ferrari GV , Inestrosa NC
Ref : In: Cholinesterases in the Second Millennium: Biomolecular and Pathological Aspects , (Inestrosa NC, Campos EO) P. Universidad Catolica de Chile-FONDAP Biomedicina :342 , 2004

Title : Neurodegenerative processes in Alzheimer?s disease. -
Author(s) : Inestrosa NC , De Ferrari GV , Opazo C , Alvarez A
Ref : Cholinergic Mechanisms, CRC Press :363 , 2004

Title : Acetylcholinesterase induces the expression of the beta-amyloid precursor protein in glia and activates glial cells in culture - von Bernhardi_2003_Neurobiol.Dis_14_447
Author(s) : Von Bernhardi R , Ramirez G , De Ferrari GV , Inestrosa NC
Ref : Neurobiol Dis , 14 :447 , 2003
Abstract : Acetylcholinesterase (AChE) activities in CNS physiopathology are increasingly diverse and range from neuritogenesis, through synaptogenesis, to enhancement of amyloid fiber assembly. In Alzheimer's disease, senile plaques and neurodegeneration specially affect regions enriched for cholinergic synapses. In this study we show an effect of AChE that could contribute to the increased deposition of Abeta in certain regions. Affinity-purified AChE induced the expression of amyloid-beta-precursor protein (beta-APP) in glial cells in a concentration-dependent manner up to 5 nM. In glia, AChE also increased inducible nitric oxide synthase (iNOS) assessed by immunocytochemistry and decreased reductive metabolism as evidence of cell activation. AChE could increase the expression of beta-APP in astrocytes and microglia as result of the activation of glial cells. As a whole, we found that AChE has additional effects that could result in an increased synthesis of Abeta, both by increasing beta-APP expression of astrocytes and by further activating glial cells.
ESTHER : von Bernhardi_2003_Neurobiol.Dis_14_447
PubMedSearch : von Bernhardi_2003_Neurobiol.Dis_14_447
PubMedID: 14678761

Title : Thioflavin T is a fluorescent probe of the acetylcholinesterase peripheral site that reveals conformational interactions between the peripheral and the acylation sites - De Ferrari_2001_J.Biol.Chem_276_23282
Author(s) : De Ferrari GV , Mallender WD , Inestrosa NC , Rosenberry TL
Ref : Journal of Biological Chemistry , 276 :23282 , 2001
Abstract : Three-dimensional structures of acetylcholinesterase (AChE) reveal a narrow and deep active site gorge with two sites of ligand binding, an acylation site at the base of the gorge, and a peripheral site near the gorge entrance. Recent studies have shown that the peripheral site contributes to catalytic efficiency by transiently binding substrates on their way to the acylation site, but the question of whether the peripheral site makes other contributions to the catalytic process remains open. A possible role for ligand binding to the peripheral site that has long been considered is the initiation of a conformational change that is transmitted allosterically to the acylation site to alter catalysis. However, evidence for conformational interactions between these sites has been difficult to obtain. Here we report that thioflavin T, a fluorophore widely used to detect amyloid structure in proteins, binds selectively to the AChE peripheral site with an equilibrium dissociation constant of 1.0 microm. The fluorescence of the bound thioflavin T is increased more than 1000-fold over that of unbound thioflavin T, the greatest enhancement of fluorescence for the binding of a fluorophore to AChE yet observed. Furthermore, when the acylation site ligands edrophonium or m-(N, N,N-trimethylammonio)trifluoroacetophenone form ternary complexes with AChE and thioflavin T, the fluorescence is quenched by factors of 2.7-4.2. The observation of this partial quenching of thioflavin T fluorescence is a major advance in the study of AChE for two reasons. First, it allows thioflavin T to be used as a reporter for ligand reactions at the acylation site. Second, it indicates that ligand binding to the acylation site initiates a change in the local AChE conformation at the peripheral site that quenches the fluorescence of bound thioflavin T. The data provide strong evidence in support of a conformational interaction between the two AChE sites.
ESTHER : De Ferrari_2001_J.Biol.Chem_276_23282
PubMedSearch : De Ferrari_2001_J.Biol.Chem_276_23282
PubMedID: 11313335

Title : A Structural Motif of Acetylcholinesterase That Promotes Amyloid beta-Peptide Fibril Formation - De Ferrari_2001_Biochemistry_40_10447
Author(s) : De Ferrari GV , Canales MA , Shin I , Weiner L , Silman I , Inestrosa NC
Ref : Biochemistry , 40 :10447 , 2001
Abstract : Acetylcholinesterase (AChE) has been found to be associated with the core of senile plaques. We have shown that AChE interacts with the amyloid beta-peptide (Abeta) and promotes amyloid fibril formation by a hydrophobic environment close to the peripheral anionic binding site (PAS) of the enzyme. Here we present evidence for the structural motif of AChE involved in this interaction. First, we modeled the docking of Abeta onto the structure of Torpedo californica AChE, and identified four potential sites for AChE-Abeta complex formation. One of these, Site I, spans a major hydrophobic sequence exposed on the surface of AChE, which had been previously shown to interact with liposomes [Shin et al. (1996) Protein Sci. 5, 42-51]. Second, we examined several AChE-derived peptides and found that a synthetic 35-residue peptide corresponding to the above hydrophobic sequence was able to promote amyloid formation. We also studied the ability to promote amyloid formation of two synthetic 24-residue peptides derived from the sequence of a Omega-loop, which has been suggested as an AChE-Abeta interacting motif. Kinetic analyses indicate that only the 35-residue hydrophobic peptide mimics the effect of intact AChE on amyloid formation. Moreover, RP-HPLC analysis revealed that the 35-residue peptide was incorporated into the growing Abeta-fibrils. Finally, fluorescence binding studies showed that this peptide binds Abeta with a K(d) = 184 microM, independent of salt concentration, indicating that the interaction is primarily hydrophobic. Our results indicate that the homologous human AChE motif is capable of accelerating Abeta fibrillogenesis.
ESTHER : De Ferrari_2001_Biochemistry_40_10447
PubMedSearch : De Ferrari_2001_Biochemistry_40_10447
PubMedID: 11523986

Title : Acetylcholinesterase-amyloid-beta-peptide interaction and Wnt signaling involvement in Abeta neurotoxicity - Inestrosa_2000_Acta.Neurol.Scand.Suppl_176_53
Author(s) : Inestrosa NC , Alvarez A , Godoy J , Reyes A , De Ferrari GV
Ref : Acta Neurologica Scandinavica Supplementum , 176 :53 , 2000
Abstract : Previous studies have indicated that acetylcholinesterase (AChE) promotes amyloid-beta-peptide (Abeta) fibril formation and AChE-Abeta complexes increase Abeta-dependent neurotoxicity. Here we present evidence for the: i) identification of the AChE motif that promotes amyloid formation, ii) in vivo effect of AChE on brain plaque formation, and iii) connection between AChE-Abeta neurotoxicity and the Wnt signal transduction pathway. Computer modeling, stereotaxic infusions and cell biological techniques were used to study the above problems. Results indicated that a 3.4 kDa AChE peptide promotes Abeta fibril formation. AChE infusion into rat hippocampus determines the appearance of anti-Abeta and thioflavine-S positive plaques, and AChE-Abeta toxicity on hippocampal cultures was blocked by lithium, an activator of the Wnt cascade. We suggest that AChE-Abeta/Abeta dependent neurotoxicity may result in loss of function of Wnt signaling components, and open the possibility that lithium may be considered as a candidate for therapeutic intervention in Alzheimer's disease pathology.
ESTHER : Inestrosa_2000_Acta.Neurol.Scand.Suppl_176_53
PubMedSearch : Inestrosa_2000_Acta.Neurol.Scand.Suppl_176_53
PubMedID: 11261806

Title : Toxic effects of acetylcholinesterase on neuronal and glial-like cells in vitro - Calderon_1998_Mol.Psychiatry_3_247
Author(s) : Calderon FH , Von Bernhardi R , De Ferrari GV , Luza S , Aldunate R , Inestrosa NC
Ref : Mol Psychiatry , 3 :247 , 1998
Abstract : Acetylcholinesterase (AChE), the enzyme involved in the hydrolysis of the neurotransmitter acetylcholine, has been implicated in non-cholinergic actions which may play a role in neurodegenerative diseases such as Alzheimer's disease. To study the potential cytotoxicity of brain AChE, the effects of affinity purified AChE were analyzed on neuronal (Neuro 2a) and glial-like (B12) cells. LDH release and MTT reduction assays showed that AChE was toxic; the toxicity was dependent on the enzyme concentration, time of incubation and cellular density. The toxic effect of AChE was not related to its catalytic activity, since the anti-cholinesterase drug BW284C51 and heat inactivation were unable to block the effects of the enzyme. When cells were incubated at 4 degrees C, toxicity was completely blocked, in contrast to cells incubated at 37 degrees C. The presence of serum in the culture medium inhibited the toxic effects of AChE. Cytoplasmic shrinkage, condensation and fragmentation of nucleus as well as DNA strand breaks detected with the TUNEL technique indicated that apoptotic cell death is involved in the effect of AChE. Considering that we have previously shown that AChE promotes the assembly of beta-amyloid peptide into neurotoxic amyloid fibrils, it is conceivable that the neurotoxicity of AChE shown here may play a role in the neuronal degeneration observed in Alzheimer's disease.
ESTHER : Calderon_1998_Mol.Psychiatry_3_247
PubMedSearch : Calderon_1998_Mol.Psychiatry_3_247
PubMedID: 9672900

Title : Responses induced by tacrine in neuronal and non-neuronal cell lines - De Ferrari_1998_J.Neurosci.Res_52_435
Author(s) : De Ferrari GV , Von Bernhardi R , Calderon FH , Luza SC , Inestrosa NC
Ref : Journal of Neuroscience Research , 52 :435 , 1998
Abstract : Alzheimer's disease (AD) is associated with a reduction in cholinergic activity as a result of specific neuronal loss. Current potential treatments for the disease include both cholinomimetic drugs and anticholinesterase inhibitors. One of the drugs approved by the FDA is tacrine (9-amine-1,2,3,4 tetrahydroacridine; THA), a strong acetylcholinesterase (AChE) inhibitor. We have studied the effects of tacrine on glial and neuronal cells in culture assessing cell survival and viability and morphology. Lactate dehydrogenase (LDH) activity and methylthiazol-diphenyl-tetrazolium (MTT) reduction were used as toxicity indicators. We found that tacrine toxicity on rat B12 glial cells and mouse Neuro 2A cells was strongly dependent on its concentration (up to 500 microM) and time of exposure. The toxic effect was not prevented by serum factors nor by bovine serum albumin. Fluorescein-conjugated phalloidin was used to examine the arrangement of actin filaments at substrate adhesion regions and cell-cell contacts. Primary events following exposure to tacrine included changes in cell morphology, disappearance of actin filament bundles, and disruption of focal adhesion contacts. At concentrations between 10 and 50 microM, tacrine induced neurite outgrowth in Neuro 2A cells, an effect that was not observed in B12 cells, suggesting that certain tacrine effects could be specific for neuronal cells. Although similar trends of response were observed for both cell types, some differences between undifferentiated and differentiated cells were apparent.
ESTHER : De Ferrari_1998_J.Neurosci.Res_52_435
PubMedSearch : De Ferrari_1998_J.Neurosci.Res_52_435
PubMedID: 9589388

Title : Molecular Interactions of Acetylcholinesterase with the Synaptic Basal Lamina and the Senile Plaques -
Author(s) : Inestrosa NC , Alarcon R , Alvarez A , Calderon FH , Campos EO , Casanueva OI , De Ferrari GV , Deprez P , Garcia-Huidobro T , Munoz FJ , Perez D , Reyes AE
Ref : In: Structure and Function of Cholinesterases and Related Proteins - Proceedings of Sixth International Meeting on Cholinesterases , (Doctor, B.P., Taylor, P., Quinn, D.M., Rotundo, R.L., Gentry, M.K. Eds) Plenum Publishing Corp. :167 , 1998

Title : Identification of an Acetylcholinesterase Fragment that Promotes Alzheimer beta-Amyloid Fibril Formation -
Author(s) : De Ferrari GV , Inestrosa NC
Ref : In: Structure and Function of Cholinesterases and Related Proteins - Proceedings of Sixth International Meeting on Cholinesterases , (Doctor, B.P., Taylor, P., Quinn, D.M., Rotundo, R.L., Gentry, M.K. Eds) Plenum Publishing Corp. :185 , 1998