alejandra alvarez - Academia.edu (original) (raw)

Papers by alejandra alvarez

Frontiers in Cell and Developmental Biology, 2022

Niemann-Pick type A (NPA) disease is a fatal lysosomal neurodegenerative disorder caused by the d... more Niemann-Pick type A (NPA) disease is a fatal lysosomal neurodegenerative disorder caused by the deficiency in acid sphingomyelinase (ASM) activity. NPA patients present severe and progressive neurodegeneration starting at an early age. Currently, there is no effective treatment for this disease and NPA patients die between 2 and 3 years of age. NPA is characterized by an accumulation of sphingomyelin in lysosomes and dysfunction in the autophagy-lysosomal pathway. Recent studies show that c-Abl tyrosine kinase activity downregulates autophagy and the lysosomal pathway. Interestingly, this kinase is also activated in other lysosomal neurodegenerative disorders. Here, we describe that c-Abl activation contributes to the mechanisms of neuronal damage and death in NPA disease. Our data demonstrate that: 1) c-Abl is activated in-vitro as well as in-vivo NPA models; 2) imatinib, a clinical c-Abl inhibitor, reduces autophagy-lysosomal pathway alterations, restores autophagy flux, and lower...

Biomaterials Science, 2021

The development and use of nanosystems is an emerging strategy for the diagnosis and treatment of... more The development and use of nanosystems is an emerging strategy for the diagnosis and treatment of a broad number of diseases, such as Alzheimer's disease (AD).

Frontiers in Cellular Neuroscience, 2019

Spine pathology has been implicated in the early onset of Alzheimer's disease (AD), where Aβ-Olig... more Spine pathology has been implicated in the early onset of Alzheimer's disease (AD), where Aβ-Oligomers (AβOs) cause synaptic dysfunction and loss. Previously, we described that pharmacological inhibition of c-Abl prevents AβOs-induced synaptic alterations. Hence, this kinase seems to be a key element in AD progression. Here, we studied the role of c-Abl on dendritic spine morphological changes induced by AβOs using c-Abl null neurons (c-Abl-KO). First, we characterized the effect of c-Abl deficiency on dendritic spine density and found that its absence increases dendritic spine density. While AβOs-treatment reduces the spine number in both wild-type (WT) and c-Abl-KO neurons, AβOs-driven spine density loss was not affected by c-Abl. We then characterized AβOs-induced morphological changes in dendritic spines of c-Abl-KO neurons. AβOs induced a decrease in the number of mushroom spines in c-Abl-KO neurons while preserving the populations of immature stubby, thin, and filopodia spines. Furthermore, synaptic contacts evaluated by PSD95/Piccolo clustering and cell viability were preserved in AβOs-exposed c-Abl-KO neurons. In conclusion, our results indicate that in the presence of AβOs c-Abl participates in synaptic contact removal, increasing susceptibility to AβOs damage. Its deficiency increases the immature spine population reducing AβOs-induced synapse elimination. Therefore, c-Abl signaling could be a relevant actor in the early stages of AD.

Cells, 2021

Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC... more Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1−/− mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n =...

Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology, 2021

Background Brain metastases (BM) occur in almost one third of patients with systemic malignancies... more Background Brain metastases (BM) occur in almost one third of patients with systemic malignancies. Only a small number of studies focus on infratentorial location and whole brain radiotherapy (WBRT) as the main non-surgical management. The aim of the study was to compare the prognosis of patients treated with WBRT among patients with supra- or infratentorial lesions. Materials and methods At a single center, 263 patients with either breast (BC) or lung (LC) cancer, that had developed BM and received treatment with WBRT, were analyzed during an 8-year period. Results A total of 152 patients with BC and 111 with LC were analyzed, median age at the time of BM was 50.7 years, systemic activity other than BM was detected in 91%. Newly diagnosed BM were supratentorial in 40%, infratentorial in 10% and 51% in both locations. Median overall survival was 13 months (95% CI: 11.1-14.8 months), without significant difference between supra- or infratentorial location. WBRT alone was administered...

Cancer, 2020

The current study was performed to identify factors that are present at the time of breast cancer... more The current study was performed to identify factors that are present at the time of breast cancer (BC) diagnosis that are associated with a higher rate of central nervous system metastasis (CNSm).

Background: Brain metastases (BM) occur in almost one third of patients with solid tumors. The ai... more Background: Brain metastases (BM) occur in almost one third of patients with solid tumors. The aim of the study was to compare the prognosis of patients treated with whole brain radiotherapy (WBRT) among patients with supra- or infratentorial lesions.Material and Methods: At a single center, 263 patients with either breast (BC) or lung (LC) cancer, that developed BM and received treatment with WBRT, were analyzed during an 8-year period.Results: A total of 152 patients with BC and 111 with LC were analyzed, median age at the time of BM was 50.7 years, systemic activity other than BM was detected in 91%. Newly diagnosed BM were supratentorial and infratentorial in 133 patients (51%); exclusively supratentorial in 105 patients (40%); and exclusively infratentorial in 10%. Globally, 238 patients (90%) had supratentorial lesions, and 158 (60%) had infratentorial lesions. Median overall survival was 13 months (95%CI 11.1-14.8 months), without significant difference between supra- or infr...

iScience, 2020

HIGHLIGHTS c-Abl is a TFEB regulator that mediates its tyr phosphorylation c-Abl inhibition promo... more HIGHLIGHTS c-Abl is a TFEB regulator that mediates its tyr phosphorylation c-Abl inhibition promotes TFEB activity independently of mTORC1 c-Abl inhibition reduces cholesterol accumulation in NPC1 models

Nature Communications, 2020

The molecular connections between homeostatic systems that maintain both genome integrity and pro... more The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1α signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1α endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1α to catalyze RIDD. The protective role of IRE1α under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways th...

Nanomaterials, 2020

The early detection of the amyloid beta peptide aggregates involved in Alzheimer’s disease is cru... more The early detection of the amyloid beta peptide aggregates involved in Alzheimer’s disease is crucial to test new potential treatments. In this research, we improved the detection of amyloid beta peptide aggregates in vitro and ex vivo by fluorescence combining the use of CRANAD-2 and gold nanorods (GNRs) by the surface enhancement fluorescence effect. We synthetized GNRs and modified their surface with HS-PEG-OMe and HS-PEG-COOH and functionalized them with the D1 peptide, which has the capability to selectively bind to amyloid beta peptide. For an in vitro detection of amyloid beta peptide, we co-incubated amyloid beta peptide aggregates with the probe CRANAD-2 and GNR-PEG-D1 observing an increase in the intensity of the fluorescence signal attributed to surface enhancement fluorescence. Furthermore, the surface enhancement fluorescence effect was observed in brain slices of transgenic mice with Alzheimer´s disease co-incubated with CRANAD-2 and GNR-PEG-D1. An increase in the fluo...

Revista Colombiana de Gastroenterología, 2014

Introducción: el esófago de Barrett (EB) con displasia tiene un reconocido potencial maligno. Ni ... more Introducción: el esófago de Barrett (EB) con displasia tiene un reconocido potencial maligno. Ni la supresión ácida, ni la cirugía antirreflujo producen una regresión consistente o completa del epitelio metaplásico o displásico. La termoablación endoscópica a través de la coagulación con argón plasma (APC) ofrece la posibilidad de su erradicación (ablación), pero los posibles factores que pueden influir en el desenlace de la terapia aún no han sido evaluados consistentemente. Objetivo: evaluar la eficacia de la APC en la erradicación del EB con displasia y los factores que influencian su desenlace inmediato y tras por lo menos un año de seguimiento. Métodos: A 33 pacientes con EB y displasia (19 hombres-58%), con una media de edad de 56,9±6,35 años (rango 45 a 69 años) con una longitud media del EB de 4,1 cm (rango de 2-8 cm), se les practicó terapia con APC a intervalos de cada 4-6 semanas, hasta lograr la erradicación del EB, mientras estaban recibiendo terapia con doble dosis de ...

Computational and Structural Biotechnology Journal, 2019

Alzheimer's disease (AD) is a neurodegenerative process characterized by the accumulation of extr... more Alzheimer's disease (AD) is a neurodegenerative process characterized by the accumulation of extracellular deposits of amyloid β-peptide (Aβ), which induces neuronal death. Monomeric Aβ is not toxic but tends to aggregate into β-sheets that are neurotoxic. Therefore to prevent or delay AD onset and progression one of the main therapeutic approaches would be to impair Aβ assembly into oligomers and fibrils and to promote disaggregation of the preformed aggregate. Albumin is the most abundant protein in the cerebrospinal fluid and it was reported to bind Aβ impeding its aggregation. In a previous work we identified a 35-residue sequence of clusterin, a wellknown protein that binds Aβ, that is highly similar to the C-terminus (CTerm) of albumin. In this work, the docking experiments show that the average binding free energy of the CTerm-Aβ 1-42 simulations was significantly lower than that of the clusterin-Aβ 1-42 binding, highlighting the possibility that the CTerm retains albumin's binding properties. To validate this observation, we performed in vitro structural analysis of soluble and aggregated 1 μM Aβ 1-42 incubated with 5 μM CTerm, equimolar to the albumin concentration in the CSF. Reversed-phase chromatography and electron microscopy analysis demonstrated a reduction of Aβ 1-42 aggregates when the CTerm was present. Furthermore, we treated a human neuroblastoma cell line with soluble and aggregated Aβ 1-42 incubated with CTerm obtaining a significant protection against Aβ-induced neurotoxicity. These in silico and in vitro data suggest that the albumin CTerm is able to impair Aβ aggregation and to promote disassemble of Aβ aggregates protecting neurons.

World Journal of Gastroenterology, 2007

Clinical Kidney Journal, 2019

BackgroundReliable determination of glomerular filtration rate (GFR) is crucial in the evaluation... more BackgroundReliable determination of glomerular filtration rate (GFR) is crucial in the evaluation of living kidney donors. Although some guidelines recommend the use of measured GFR (mGFR), many centres still rely on estimated GFR (eGFR) obtained through equations or 24-h creatinine clearance. However, eGFR is neither accurate nor precise in reflecting real renal function. We analysed the impact of eGFR errors on evaluation and decision making regarding potential donors.MethodsWe evaluated 103 consecutive living donors who underwent mGFR via iohexol plasma clearance and eGFR by 51 creatinine- and/or cystatin C–based equations. The cut-off for living donation in our centre is GFR > 80 mL/min for donors >35 years of age or 90 mL/min for those <35 years of age. We analysed the misclassification of donors based on the cut-off for donation-based eGFR.ResultsNinety-three subjects (90.3%) had mGFR values above (donors) and 10 [9.7% (95% confidence interval 5.4–17)] below (non-dono...

The Journal of Neuroscience, 1998

Brain acetylcholinesterase (AChE) forms stable complexes with amyloid-β peptide (Aβ) during its a... more Brain acetylcholinesterase (AChE) forms stable complexes with amyloid-β peptide (Aβ) during its assembly into filaments, in agreement with its colocalization with the Aβ deposits of Alzheimer’s brain. The association of the enzyme with nascent Aβ aggregates occurs as early as after 30 min of incubation. Analysis of the catalytic activity of the AChE incorporated into these complexes shows an anomalous behavior reminiscent of the AChE associated with senile plaques, which includes a resistance to low pH, high substrate concentrations, and lower sensitivity to AChE inhibitors. Furthermore, the toxicity of the AChE–amyloid complexes is higher than that of the Aβ aggregates alone. Thus, in addition to its possible role as a heterogeneous nucleator during amyloid formation, AChE, by forming such stable complexes, may increase the neurotoxicity of Aβ fibrils and thus may determine the selective neuronal loss observed in Alzheimer’s brain.

Kidney International Reports, 2018

Introduction: Despite the high incidence of posttransplant diabetes mellitus (PTDM) among high-ri... more Introduction: Despite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization. Methods: We conducted an open-label, multicenter, randomized trial testing whether a tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) or cyclosporine A (CsA) with steroid minimization (SM) (CsA-SM), decreased the incidence of PTDM compared with tacrolimus with SM (Tac-SM). All arms received basiliximab and mycophenolate mofetil. High risk was defined by age >60 or >45 years plus metabolic criteria based on body mass index, triglycerides, and high-density lipoprotein-cholesterol levels. The primary endpoint was the incidence of PTDM after 12 months. Results: The study comprised 128 de novo renal transplant recipients without pretransplant diabetes (Tac-SW: 44, Tac-SM: 42, CsA-SM: 42). The 1-year incidence of PTDM in each arm was 37.8% for Tac-SW, 25.7% for Tac-SM, and 9.7% for CsA-SM (relative risk [RR] Tac-SW vs. CsA-SM 3.9 [1.2-12.4; P ¼ 0.01]; RR Tac-SM vs. CsA-SM 2.7 [0.8-8.9; P ¼ 0.1]). Antidiabetic therapy was required less commonly in the CsA-SM arm (P ¼ 0.06); however, acute rejection rate was higher in CsA-SM arm (Tac-SW 11.4%, Tac-SM 4.8%, and CsA-SM 21.4% of patients; cumulative incidence P ¼ 0.04). Graft and patient survival, and graft function were similar among arms. Conclusion: In high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence.

Journal of nanobiotechnology, Jan 10, 2018

Stable and non-toxic fluorescent markers are gaining attention in molecular diagnostics as powerf... more Stable and non-toxic fluorescent markers are gaining attention in molecular diagnostics as powerful tools for enabling long and reliable biological studies. Such markers should not only have a long half-life under several assay conditions showing no photo bleaching or blinking but also, they must allow for their conjugation or functionalization as a crucial step for numerous applications such as cellular tracking, biomarker detection and drug delivery. We report the functionalization of stable fluorescent markers based on nanodiamonds (NDs) with a bifunctional peptide. This peptide is made of a cell penetrating peptide and a six amino acids long β-sheet breaker peptide that is able to recognize amyloid β (Aβ) aggregates, a biomarker for the Alzheimer disease. Our results indicate that functionalized NDs (fNDs) are not cytotoxic and can be internalized by the cells. The fNDs allow ultrasensitive detection (at picomolar concentrations of NDs) of in vitro amyloid fibrils and amyloid ag...

Nanomedicine : nanotechnology, biology, and medicine, Jan 30, 2017

The properties of nanometric materials make nanotechnology a promising platform for tackling prob... more The properties of nanometric materials make nanotechnology a promising platform for tackling problems of contemporary medicine. In this work, gold nanorods were synthetized and stabilized with polyethylene glycols and modified with two kinds of peptides. The D1 peptide that recognizes toxic aggregates of Aβ, a peptide involved in Alzheimer's disease (AD); and the Angiopep 2 that can be used to deliver nanorods to the mammalian central nervous system. The nanoconjugates were characterized using absorption spectrophotometry, dynamic light scattering, and transmission electron microscopy, among other techniques. We determined that the nanoconjugate does not affect neuronal viability; it penetrates the cells, and decreases aggregation of Aβ peptide in vitro. We also showed that when we apply our nanosystem to a Caenorhabditis elegans AD model, the toxicity of aggregated Aβ peptide is decreased. This work may contribute to the development of therapies for AD based on metallic nanopar...

Redox Biology, 2017

MLN64 is a late endosomal cholesterol-binding membrane protein that has been implicated in choles... more MLN64 is a late endosomal cholesterol-binding membrane protein that has been implicated in cholesterol transport from endosomal membranes to the plasma membrane and/or mitochondria, in toxin-induced resistance, and in mitochondrial dysfunction. Down-regulation of MLN64 in Niemann-Pick C1 deficient cells decreased mitochondrial cholesterol content, suggesting that MLN64 functions independently of NPC1. However, the role of MLN64 in the maintenance of endosomal cholesterol flow and intracellular cholesterol homeostasis remains unclear. We have previously described that hepatic MLN64 overexpression increases liver cholesterol content and induces liver damage. Here, we studied the function of MLN64 in normal and NPC1deficient cells and we evaluated whether MLN64 overexpressing cells exhibit alterations in mitochondrial function. We used recombinant-adenovirus-mediated MLN64 gene transfer to overexpress MLN64 in mouse liver and hepatic cells; and RNA interference to down-regulate MLN64 in NPC1-deficient cells. In MLN64overexpressing cells, we found increased mitochondrial cholesterol content and decreased glutathione (GSH) levels and ATPase activity. Furthermore, we found decreased mitochondrial membrane potential and mitochondrial fragmentation and increased mitochondrial superoxide levels in MLN64-overexpressing cells and in NPC1-deficient cells. Consequently, MLN64 expression was increased in NPC1-deficient cells and reduction of its expression restore mitochondrial membrane potential and mitochondrial superoxide levels. Our findings suggest that MLN64 overexpression induces an increase in mitochondrial cholesterol content and consequently a decrease in mitochondrial GSH content leading to mitochondrial dysfunction. In addition, we demonstrate that MLN64 expression is increased in NPC cells and plays a key role in cholesterol transport into the mitochondria.

Journal of Alzheimer's disease : JAD, Oct 26, 2016

One of the pathological hallmarks of Alzheimer's disease (AD) is the presence of amyloid plaq... more One of the pathological hallmarks of Alzheimer's disease (AD) is the presence of amyloid plaques, which are deposits of misfolded and aggregated amyloid-beta peptide (Aβ). The role of the c-Abl tyrosine kinase in Aβ-mediated neurodegeneration has been previously reported. Here, we investigated the therapeutic potential of inhibiting c-Abl using imatinib. We developed a novel method, based on a technique used to detect prions (PMCA), to measure minute amounts of misfolded-Aβ in the blood of AD transgenic mice. We found that imatinib reduces Aβ-oligomers in plasma, which correlates with a reduction of AD brain features such as plaques and oligomers accumulation, neuroinflammation, and cognitive deficits. Cells exposed to imatinib and c-Abl KO mice display decreased levels of β-CTF fragments, suggesting that an altered processing of the amyloid-beta protein precursor is the most probable mechanism behind imatinib effects. Our findings support the role of c-Abl in Aβ accumulation an...