scispace - formally typeset
Search or ask a question
Institution

Fundación Instituto Leloir

FacilityBuenos Aires, Argentina
About: Fundación Instituto Leloir is a facility organization based out in Buenos Aires, Argentina. It is known for research contribution in the topics: Dentate gyrus & Neurogenesis. The organization has 702 authors who have published 1052 publications receiving 39299 citations.


Papers
More filters
Journal ArticleDOI
TL;DR: This special issue is devoted to revisit the “amyloid cascade hypothesis” (ACH) in the pathogenesis of sporadic Alzheimer's disease (AD) and ask whether Aβ plays an active protective role in brain aging.
Abstract: This special issue is devoted to revisit the “amyloid cascade hypothesis” (ACH) in the pathogenesis of sporadic Alzheimer's disease (AD). Since the identification 20 years ago of the first APP mutation [1] the ACH gained enormous importance based on genetic and biochemical evidence. However the outcome of recent clinical trials aimed at reducing extracellular Aβ levels suggests that such strategy may not have the expected impact on AD progression because the role of Aβ is more complex than that of the lone driver of AD. Some of the reasons proposed for the failure may be the initiation of the trials in demented patients with serious brain damage, and unforeseen serious design flaws in the studies. These results led us to ask whether Aβ plays an active protective role in brain aging. It is also clear that regardless of whether Aβ is protective or toxic, trials focused on modulating the Aβ response will remain a major interest in AD therapeutic research. According to the amyloid cascade hypothesis, increased amounts of Aβ contribute to the development of AD [2]. Aβ peptides are generated in the amyloidogenic pathway of APP processing by sequential proteolysis by β- and γ-secretases. In the alternative nonamyloidogenic APP processing pathway, α-secretase cleaves within the Aβ peptide region and prevents Aβ generation. Increasing the α-secretase-mediated processing of APP may therefore be a therapeutic option for the treatment of AD. Since various substrates have been assigned to α-secretase-like cleavage events, putative side effects of α-secretase activators should be considered. BACE1, the catalytic component of β-secretase, is the key enzyme initiating Aβ production in vivo, making it a prime drug target for AD treatment. The past decade has shown significant progress in the understanding of BACE1 molecular and cellular properties, however, further investigation is crucial to predict side effects of BACE1 inhibition. γ-Secretase complex represents a fascinating biological machine that is assembled from at least four core proteins (presenilins 1 or 2, APH1, PEN2, and nicastrin). These proteins are sufficient for cleavage of multiple different, nonhomologous type 1 transmembrane (TM) proteins, with the cleavage occurring through the substrates' TM domains. γ-Secretase remains a target of intense interest for modulating Aβ. Nowadays, the focus has clearly shifted toward modulators that minimize effects on other substrates (in particular notch), with compounds that either shift the site of cleavage to produce shorter forms of Aβ or selectively inhibit APP processing while allowing the enzyme to continue processing notch. Compounds now under investigation may not have sufficient potency, brain penetration, or selectivity to effectively lower brain Aβ while avoiding notch-related toxicity. Recently, another secretase-mediated APP-derived catabolite called APP Intra Cellular Domain (AICD) gained relevance in the field appears to be a multifunctional factor affecting several physiological processes likely to contribute to Alzheimer's disease pathology by acting as a transcription factor that controls the expression of a series of proteins involved in control of cell death and Aβ degradation. The steady state of monomeric Aβ in the brain is the result of a tightly controlled balance between production and removal; sporadic AD may reflect defects in clearance mechanisms for Aβ rather than in the enhanced synthesis which occurs in early-onset cases. It was recently demonstrated that the kinetics of Aβ production is similar between control and late-onset AD patients, however there is an impairment in the clearance of Aβ in AD as compared to controls, indicating that Aβ clearance mechanisms may be critically important in AD [3]. Among these mechanisms, interaction of Aβ with ApoE, decreased catabolism via reduced proteolysis, impaired transport across the blood-brain barrier, and impaired CSF transport deserve special attention. Based on experimental evidence in animal models of AD, upregulation of amyloid degrading enzymes (ADEs) individually in the brain appears to be a viable strategy to reduce the amyloid burden and improve cognitive function. However, these animal models in themselves have limitations to representing the human disease. With evidence that the extent of insoluble, deposited amyloid poorly correlated with cognitive impairment, research efforts focused on soluble forms of Aβ, also referred to as Aβ oligomers. Following a decade of studies, soluble oligomeric forms of Aβ are now believed to be the most biologically active form of Aβ. Understanding the events triggered by oligomeric Aβ species has greatly improved in the past years but specific efforts are required to understand the molecular mechanism(s) of endogenous Aβ assemblies. Brain amyloid deposits contain proteins besides Aβ, such as apolipoprotein E (apoE). Significantly, inheritance of the apoE4 allele is the strongest genetic risk factor for the most common, late-onset form of AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE4 in particular is an amyloid catalyst or “pathological chaperone”. Evidence from numerous epidemiological studies indicates that type 2 diabetes, a non-insulin-dependent form of diabetes mellitus, is associated with a 2- to 3-fold increase in the relative risk for sporadic AD. Experimental evidence suggests that abnormalities in insulin metabolism in diabetic conditions could mechanistically influence the onset of AD via modulation of the synthesis and degradation of amyloidogenic Aβ peptides, providing a molecular link between metabolic dysfunction and neurodegenerative process in the elder population. In this special issue D. A. Borquez and C. Gonzalez-Billault review the potential role of multiprotein complexes between the AICD and its adapter protein Fe65 and how these complexes impact on the neurodegeneration observed in AD. G. M. Pasinetti and colleagues describe the role of insulin receptor (IR) signaling mechanisms in the onset and/or progression of AD dementia and the relevance of insulin-sensitizing therapeutic strategies to stimulate down-stream IR in nondiabetic AD patients. C. Reitz critically reviews the evidence for and against the amyloid cascade hypothesis in AD and provides suggestions for future directions. T. Wisniewski and Huntington Potter consider the scientific basis of the contrasting views of apoE's role, suggesting that these seemingly opposing views can be reconciled. A. J. Turner and colleagues critically evaluate general biochemical and physiological functions of Neprilysin, one of the relevant ADEs in the human brain, and their therapeutic relevance. We hope that this focused series of articles will provide the readers a critical overview of current understanding of Aβ deposition in AD. Laura Morelli George Perry Fabrizio Tagliavini

2 citations

Journal ArticleDOI
TL;DR: Tetraspanin1 (Tspan1) is identified as a critical regulator of TrkA signaling and neuronal differentiation induced by NGF, and knockdown of Tspan1 reduces the surface levels of TrKA by promoting its preferential sorting towards the autophagy/lysosomal degradation pathway.
Abstract: The molecular mechanisms that control the biosynthetic trafficking, surface delivery, and degradation of TrkA receptor are essential for proper nerve growth factor (NGF) function, and remain poorly understood. Here, we identify Tetraspanin1 (Tspan1) as a critical regulator of TrkA signaling and neuronal differentiation induced by NGF. Tspan1 is expressed by developing TrkA-positive dorsal root ganglion (DRG) neurons and its downregulation in sensory neurons inhibits NGF-mediated axonal growth. In addition, our data demonstrate that Tspan1 forms a molecular complex with the immature form of TrkA localized in the endoplasmic reticulum (ER). Finally, knockdown of Tspan1 reduces the surface levels of TrkA by promoting its preferential sorting towards the autophagy/lysosomal degradation pathway. Together, these data establish a novel homeostatic role of Tspan1, coordinating the biosynthetic trafficking and degradation of TrkA, regardless the presence of NGF.

2 citations

Journal ArticleDOI
TL;DR: In this paper, the authors characterized the autophagic response induced by hypoxia in Drosophila melanogaster and found that this process is essential for adaptation and survival because larvae with impaired autophagy are hypersensitive to low oxygen levels.
Abstract: Macroautophagy/autophagy, a mechanism of degradation of intracellular material required to sustain cellular homeostasis, is exacerbated under stress conditions like nutrient deprivation, protein aggregation, organelle senescence, pathogen invasion, and hypoxia, among others. Detailed in vivo description of autophagic responses triggered by hypoxia is limited. We have characterized the autophagic response induced by hypoxia in Drosophila melanogaster. We found that this process is essential for Drosophila adaptation and survival because larvae with impaired autophagy are hypersensitive to low oxygen levels. Hypoxia triggers a bona fide autophagic response, as evaluated by several autophagy markers including Atg8, LysoTracker, Lamp1, Pi3K59F/Vps34 activity, transcriptional induction of Atg genes, as well as by transmission electron microscopy. Autophagy occurs in waves of autophagosome formation and maturation as hypoxia exposure is prolonged. Hypoxia-triggered autophagy is induced cell autonomously, and different tissues are sensitive to hypoxic treatments. We found that hypoxia-induced autophagy depends on the basic autophagy machinery but not on the hypoxia master regulator sima/HIF1A. Overall, our studies lay the foundation for using D. melanogaster as a model system for studying autophagy under hypoxic conditions, which, in combination with the potency of genetic manipulations available in this organism, provides a platform for studying the involvement of autophagy in hypoxia-associated pathologies and developmentally regulated processes.Abbreviations: Atg: autophagy-related; FYVE: zinc finger domain from Fab1 (yeast ortholog of PIKfyve); GFP: green fluorescent protein; HIF: hypoxia-inducible factor; hsf: heat shock factor; Hx: hypoxia; mCh: mCherry; PtdIns: phosphatidylinositol; PtdIns3P: phosphatidylinositol-3-phosphate; Rheb: Ras homolog enriched in brain; sima: similar; Stv: Starvation; TEM: transmission electron microscopy; Tor: target of rapamycin; UAS: upstream activating sequence; Vps: vacuolar protein sorting.

2 citations

Journal Article
TL;DR: Estos resultados sugieren that el aumento en the vascularización podría ser predictivo of metástasis más agresivas, donde the expresión of MCP-1 estaría estrechamente vinculada al desarrollo of vasos a través oficiales del reclutamiento of macrófagos.
Abstract: Se analizaron biopsias de melanoma metastásico humano para elucidar la relación entre la expresión de la quimioquina MCP-1/CCL2 (monocyte chemoattractant protein-1), la angiogénesis y la agresividad del tumor. Se encontró que esta quimioquina se expresa en el 100% de los casos, con heterogeneidad en el porcentaje de células positivas dentro del tumor. Estos tumores presentaron gran cantidad de macrófagos infiltrantes, particularmente asociados a las áreas de más activa angiogénesis. Se obtuvo correlación positiva entre el porcentaje de células que expresan MCP-1 y el grado de vascularización. Asimismo, se encontró asociación entre una mayor angiogénesis y la proliferación tumoral evaluada como índice mitótico. Estos resultados sugieren que el aumento en la vascularización podría ser predictivo de metástasis más agresivas, donde la expresión de MCP-1 estaría estrechamente vinculada al desarrollo de vasos a través del reclutamiento de macrófagos.

2 citations

Journal ArticleDOI
TL;DR: In this paper, it was shown that decapentaplegic, a ligand belonging to the BMP retrograde signaling pathway required for coordinated growth during development, is recruited by a group of circadian neurons in the adult brain to trigger structural remodeling of terminals.
Abstract: Rhythmic rest-activity cycles are controlled by an endogenous clock. In Drosophila, this clock resides in ∼150 neurons organized in clusters whose hierarchy changes in response to environmental conditions. The concerted activity of the circadian network is necessary for the adaptive responses to synchronizing environmental stimuli. Thus far, work was devoted to unravel the logic of the coordination of different clusters focusing on neurotransmitters and neuropeptides. We further explored communication in the adult male brain through ligands belonging to the bone morphogenetic protein (BMP) pathway. Herein we show that the lateral ventral neurons (LNvs) express the small morphogen decapentaplegic (DPP). DPP expression in the large LNvs triggered a period lengthening phenotype, the downregulation of which caused reduced rhythmicity and affected anticipation at dawn and dusk, underscoring DPP per se conveys time-of-day relevant information. Surprisingly, DPP expression in the large LNvs impaired circadian remodeling of the small LNv axonal terminals, likely through local modulation of the guanine nucleotide exchange factor Trio. These findings open the provocative possibility that the BMP pathway is recruited to strengthen/reduce the connectivity among specific clusters along the day and thus modulate the contribution of the clusters to the circadian network.SIGNIFICANCE STATEMENT The circadian clock relies on the communication between groups of so-called clock neurons to coordinate physiology and behavior to the optimal times across the day, predicting and adapting to a changing environment. The circadian network relies on neurotransmitters and neuropeptides to fine-tune connectivity among clock neurons and thus give rise to a coherent output. Herein we show that decapentaplegic, a ligand belonging to the BMP retrograde signaling pathway required for coordinated growth during development, is recruited by a group of circadian neurons in the adult brain to trigger structural remodeling of terminals on a daily basis.

2 citations


Authors

Showing all 707 results

Network Information
Related Institutions (5)
Laboratory of Molecular Biology
24.2K papers, 2.1M citations

91% related

European Bioinformatics Institute
10.5K papers, 999.6K citations

91% related

Salk Institute for Biological Studies
13.1K papers, 1.6M citations

91% related

Wellcome Trust Sanger Institute
9.6K papers, 1.2M citations

91% related

Howard Hughes Medical Institute
34.6K papers, 5.2M citations

90% related

Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
202210
2021107
202099
201986
201865
201781