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1.
Glia ; 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38856177

ABSTRACT

Cholesterol is crucial for the proper functioning of eukaryotic cells, especially neurons, which rely on cholesterol to maintain their complex structure and facilitate synaptic transmission. However, brain cells are isolated from peripheral cholesterol by the blood-brain barrier and mature neurons primarily uptake the cholesterol synthesized by astrocytes for proper function. This study aimed to investigate the effect of aging on cholesterol trafficking in astrocytes and its delivery to neurons. We found that aged astrocytes accumulated high levels of cholesterol in the lysosomal compartment, and this cholesterol buildup can be attributed to the simultaneous occurrence of two events: decreased levels of the ABCA1 transporter, which impairs ApoE-cholesterol export from astrocytes, and reduced expression of NPC1, which hinders cholesterol release from lysosomes. We show that these two events are accompanied by increased microR-33 in aged astrocytes, which targets ABCA1 and NPC1. In addition, we demonstrate that the microR-33 increase is triggered by oxidative stress, one of the hallmarks of aging. By coculture experiments, we show that cholesterol accumulation in astrocytes impairs the cholesterol delivery from astrocytes to neurons. Remarkably, we found that this altered transport of cholesterol could be alleviated through treatment with endocannabinoids as well as cannabidiol or CBD. Finally, according to data demonstrating that aged astrocytes develop an A1 phenotype, we found that cholesterol buildup is also observed in reactive C3+ astrocytes. Given that reduced neuronal cholesterol affects synaptic plasticity, the ability of cannabinoids to restore cholesterol transport from aged astrocytes to neurons holds significant implications in aging and inflammation.

2.
J Comp Neurol ; 531(3): 486-499, 2023 02.
Article in English | MEDLINE | ID: mdl-36453552

ABSTRACT

Cholesterol-24-hydroxylase (CYP46), a member of the cytochrome P450 superfamily of enzymes, is selectively expressed in the brain and is mainly responsible for cholesterol turnover in the central nervous system. Although increased cyp46A1 gene expression has been linked to cognitive alterations in aging and observed in neurodegenerative diseases and after traumatic brain injury, a detailed characterization of the brain regions and cell types in which CYP46 is expressed in old individuals has not been performed. Using immunohistochemistry and immunofluorescence, we investigated the specific regions and cell populations in the brain, in which cyp46A1 is expressed in 24-month-old mice. We found that CYP46 is localized in the same neuronal populations in young and old brains, mainly in the hippocampus, in cortical layers, and in Purkinje neurons of the cerebellum. No increase in CYP46 levels was found in astrocytes in old mice brains, in primary astrocyte-neuron cocultures aged in vitro, or in primary cultures of senescent astrocytes. However, interleukin-6 treatment strongly induced cyp46A1 expression in reactive astrocytes characterized by high GFAP levels but had no effect in nonactivated astrocytes. Our data suggest that cholesterol-24-hydroxylase expression is triggered in reactive astrocytes in response to proinflammatory signals, probably as part of a response mechanism to injury.


Subject(s)
Astrocytes , Brain , Cholesterol 24-Hydroxylase , Animals , Mice , Astrocytes/metabolism , Brain/metabolism , Cholesterol/metabolism , Cholesterol 24-Hydroxylase/metabolism
3.
Biochem Mol Biol Educ ; 49(2): 198-209, 2021 03.
Article in English | MEDLINE | ID: mdl-32823370

ABSTRACT

Nowadays Molecular Cell Biology (MCB) must be taught as science is practiced. Even though there are several approaches based on scientific practices, a key aspect is to define the purpose of each of these teaching strategies and, most importantly, their implementation. Our goal was to train students to acquire, understand, and communicate new scientific knowledge in the field. The main feature of our new teaching methodology was progressive training in scientific practices associated with a back-and-forward interplay between activities and assessments. The methodology was implemented over 4 years, in students attending the MCB course of the undergraduate degree in Biological Sciences. In the first two modules, the students were prepared to comprehend MCB concepts and techniques and to experience activities based on scientific practices. In the third module, the students analyzed a primary paper in-depth. They were assessed by midterm exams based on a primary paper, written laboratory reports, and the oral presentation of a scientific paper. Our teaching proposal was evaluated through the students' academic performance and by their opinion on the teaching methodology. Most students were satisfied since they improved their acquisition of concepts, their interpretation and integration of scientific knowledge, and developed skills to communicate scientific knowledge in writing and orally. The novelty of transversal interconnections and progressive training in scientific practices provides students with skills in acquiring and understanding new scientific information, even beyond the MCB course.


Subject(s)
Cell Biology/education , Educational Measurement , Molecular Biology/education , Students , Humans
4.
Dev Neurobiol ; 72(6): 766-76, 2012 Jun.
Article in English | MEDLINE | ID: mdl-21954122

ABSTRACT

Neurotrophins can influence multiple cellular functions depending on the cellular context and the specific receptors they interact with. These neurotrophic factors have been extensively studied for their ability to support neuronal survival via Trk receptors and to induce apoptosis via the p75(NTR). However, the p75(NTR) is also detected on cell populations that do not undergo apoptosis in response to neurotrophins. In particular, the authors have detected p75(NTR) expression on astrocytes during development and after seizure-induced injury. In this study, the authors investigated the role of Nerve growth factor (NGF) in regulating astrocyte proliferation and in influencing specific aspects of the cell cycle. The authors have demonstrated that NGF prevents the induction of cyclins and their association with specific cyclin-dependent kinases, and thereby prevents progression through the G1 phase of the cell cycle. Since the authors have previously shown that p75(NTR) but not TrkA, is expressed in astrocytes, these data suggest that activation of p75(NTR) promotes withdrawal of astrocytes from the cell cycle, which may have important consequences during development and after injury.


Subject(s)
Astrocytes/drug effects , Cell Cycle Checkpoints/drug effects , Nerve Growth Factor/pharmacology , Animals , Apoptosis/drug effects , Apoptosis/physiology , Astrocytes/metabolism , Cell Cycle/drug effects , Cell Cycle/physiology , Cell Cycle Checkpoints/physiology , Cells, Cultured , Cyclin-Dependent Kinases/metabolism , Epidermal Growth Factor/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Nerve Growth Factor/metabolism
5.
J Neurosci ; 30(46): 15608-15, 2010 Nov 17.
Article in English | MEDLINE | ID: mdl-21084616

ABSTRACT

Proneurotrophins and mature neurotrophins activate different signaling pathways with distinct effects on their target cells: proneurotrophins can induce apoptotic signaling via p75(NTR), whereas mature neurotrophins activate Trk receptors to influence survival and differentiation. Here, we demonstrate that the PTEN (phosphatase and tensin homolog deleted on chromosome 10) phosphatase represents a novel switch between the survival and apoptotic signaling pathways in rat CNS neurons. Simultaneous activation of p75(NTR) by proNGF and TrkB signaling by BDNF elicited apoptosis despite TrkB phosphorylation. Apoptosis induced by p75(NTR) required suppression of TrkB-induced phosphoinositide-3 kinase signaling, mediated by induction of PTEN, for apoptosis to proceed. Inhibition of PTEN restored the ability of BDNF to phosphorylate Akt and protect cultured basal forebrain neurons from proNGF-induced death. In vivo, inhibition or knockdown of PTEN after pilocarpine-induced seizures protected CNS neurons from p75(NTR)-mediated death, demonstrating that PTEN is a crucial factor mediating the balance between p75(NTR)-induced apoptotic signaling and Trk-mediated survival signaling in brain neurons.


Subject(s)
Brain/physiology , Nerve Growth Factors/physiology , PTEN Phosphohydrolase/biosynthesis , Protein Precursors/physiology , Receptor, trkB/antagonists & inhibitors , Receptor, trkB/physiology , Receptors, Nerve Growth Factor/physiology , Signal Transduction/physiology , Animals , Brain/cytology , Brain/metabolism , Cell Death/physiology , Cell Survival/physiology , Cells, Cultured , Female , Male , Nerve Tissue Proteins , Neurons/metabolism , Neurons/physiology , PTEN Phosphohydrolase/antagonists & inhibitors , PTEN Phosphohydrolase/genetics , Pregnancy , Rats , Rats, Sprague-Dawley , Receptors, Growth Factor
6.
Glia ; 57(13): 1386-92, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19229990

ABSTRACT

The p75 neurotrophin receptor has been implicated in the regulation of multiple cellular functions that differ depending on the cell context. We have observed that p75(NTR) is strongly induced on astrocytes as well as neurons in the hippocampal CA3 region after seizures; however, the function of this receptor on these glial cells has not been defined. We have employed a primary culture system to investigate the effects of neurotrophins on astrocytes. Treatment of hippocampal astrocytes with nerve growth factor (NGF) caused a reduction in cell number, but did not elicit an apoptotic response, in contrast to hippocampal neurons. Instead, activation of p75(NTR) by NGF attenuated proliferation induced by mitogens such as EGF or serum. These studies demonstrate the cell type specificity of neurotrophin functions in the brain.


Subject(s)
Astrocytes/physiology , Cell Proliferation , Hippocampus/physiology , Nerve Growth Factor/metabolism , Receptors, Nerve Growth Factor/metabolism , Animals , Apoptosis/physiology , Astrocytes/cytology , Cell Count , Cells, Cultured , Hippocampus/cytology , Male , Mitogens/metabolism , Nerve Tissue Proteins , Neurons/physiology , Pilocarpine , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Growth Factor , Seizures/chemically induced , Seizures/physiopathology
7.
Trends Neurosci ; 31(2): 99-104, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18199491

ABSTRACT

The p75 neurotrophin receptor (p75(NTR)) is expressed on many cell types and can influence a variety of cellular functions. This receptor can mediate cell survival or cell death, can promote or inhibit axonal growth and can facilitate or attenuate proliferation, depending on the cell context. The emerging picture regarding p75(NTR) indicates that it can partner with different coreceptors to dictate specific responses. It then signals by recruiting intracellular binding proteins to activate different signaling pathways. The function of p75(NTR) has mainly been studied in neurons; however, it is also expressed in a variety of glial populations, especially during development and after injury, where its roles have been poorly defined. In this review, we will examine the potential roles for p75(NTR) in glial function.


Subject(s)
Neuroglia/metabolism , Receptor, Nerve Growth Factor/physiology , Animals , Humans , Nerve Fibers, Myelinated/metabolism , Neuroglia/cytology , Pluripotent Stem Cells/cytology , Pluripotent Stem Cells/metabolism
8.
Behav Brain Res ; 153(2): 537-41, 2004 Aug 31.
Article in English | MEDLINE | ID: mdl-15265652

ABSTRACT

alpha-MSH is involved in reproductive processes and can regulate the expression of lordosis, an important component of female reproductive behavior in rats and many other species. In this study, we investigated the effects of MSH peptides on lordosis behavior when injected in medial preoptic area (POA) of ovariectomised rats primed with estradiol. The results show an increase in lordotic activity after bilateral administration of alpha-MSH and gamma-MSH. Interestingly, the treatment with the MC4 receptor antagonist HS014 did not block the stimulatory effect of alpha-MSH. Moreover, the injection of HS014 did not itself modify the lordosis quotient. Nitric oxide has been suggested to play a crucial role in the regulation of lordosis behavior via stimulation of guanylyl cyclase to synthesize cGMP. In order to determine the participation of NO in the effect of the melanocortins, another group of rats were treated with L-NAME, an inhibitor of NOS, alone or 15 min before the injection of alpha-MSH or gamma-MSH. The injection of L-NAME into the POA of E-primed rats 15 min before the test for sexual receptivity did not modify significantly the lordosis quotient at the two doses examined. The treatment with L-NAME at the lowest dose completely abolished the stimulatory effect of alpha-MSH and gamma-MSH on sexual behavior. The results indicate that the effects of MSH peptides on female sexual behavior in this area are mediated through specific MC receptor, that could be the MC3 receptor and that NO mediates the melanocortins effects.


Subject(s)
Melanocyte-Stimulating Hormones/physiology , Nitric Oxide/physiology , Preoptic Area/physiology , Receptor, Melanocortin, Type 3/physiology , Sexual Behavior, Animal/physiology , Animals , Brain Mapping , Female , Rats , Rats, Wistar , alpha-MSH/physiology , gamma-MSH/physiology
9.
Biochem Biophys Res Commun ; 313(3): 635-41, 2004 Jan 16.
Article in English | MEDLINE | ID: mdl-14697239

ABSTRACT

Ghrelin is a peptide hormone produced and secreted from the stomach. Hypothalamic injection of the peptide increases food intake but it is not known if the peptide affects other brain regions. We measured several behavioral parameters such as anxiety (elevated plus maze), memory retention (step down test), and food intake after injections of different doses of the peptide in the hippocampus, amygdala, and dorsal raphe nucleus (DRN). The injection of ghrelin in the hippocampus and DRN significantly and dose dependently increased food intake in relation to controls rats, while injections into the amygdala did not affect the food intake. We also show for the first time that ghrelin clearly and dose dependently increases memory retention in the hippocampus, amygdala, and DRN. Moreover, ghrelin at different potencies induced anxiogenesis in these brain structures while the highest dose of 3 nmol/microl was effective in all of them. The comparison of sensitivity of each brain structure indicates a specific role of them for each of the behaviors studied. The results provide new insight in to the anatomical substrate and the functional role of extrahypothalamic ghrelin targets in the CNS.


Subject(s)
Amygdala/physiology , Hippocampus/physiology , Peptide Hormones/physiology , Raphe Nuclei/physiology , Animals , Behavior, Animal , Dose-Response Relationship, Drug , Feeding Behavior , Ghrelin , Male , Maze Learning , Memory , Peptide Hormones/metabolism , Peptides/chemistry , Rats , Rats, Wistar , Substrate Specificity , Time Factors
10.
Biochem Biophys Res Commun ; 299(5): 739-43, 2002 Dec 20.
Article in English | MEDLINE | ID: mdl-12470640

ABSTRACT

Ghrelin is a peptide found in the hypothalamus and stomach that stimulates food intake and whose circulating concentrations are affected by nutritional state. Very little is known about other central behavioral effects of ghrelin, and thus, we investigated the effects of ghrelin on anxiety and memory retention. The peptide was injected intracerebroventricularly in rats and we performed open-field, plus-maze, and step-down tests (inhibitory avoidance). The administration of ghrelin increased freezing in the open field and decreased the number of entries into the open spaces and the time spent on the open arms in the plus-maze, indicating an anxiogenic effect. Moreover, the peptide increased in a dose-dependent manner the latency time in the step-down test. A rapid and prolonged increase in food intake was also observed. Our results indicate that ghrelin induces anxiogenesis in rats. Moreover, we show for the first time that ghrelin increases memory retention, suggesting that the peptide may influence processes in the hippocampus.


Subject(s)
Anxiety , Memory , Peptide Hormones/pharmacology , Animals , Appetite Regulation/drug effects , Behavior, Animal/drug effects , Dose-Response Relationship, Drug , Eating/drug effects , Ghrelin , Habituation, Psychophysiologic/drug effects , Locomotion/drug effects , Male , Memory/drug effects , Peptide Hormones/physiology , Rats , Rats, Wistar
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