Person: Palmer, Charlotte
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First Name
Charlotte
Last Name
Palmer
Institution
ISCIII
Centrre
ISCIII::Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)
CNIC Organization
CNIO Organization
Institute
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Publication Oligomeric and Fibrillar Species of Aβ42 Diversely Affect Human Neural Stem Cells.(Multidisciplinary Digital Publishing Institute (MDPI), 2021-09-02) Bernabeu-Zornoza, Adela; Coronel Lopez, Raquel; Palmer, Charlotte; López-Alonso, Victoria; Liste-Noya, Isabel; Ministerio de Ciencia e Innovación (España); Ministerio de Economía y Competitividad (España); Comunidad de Madrid (España)Amyloid-β 42 peptide (Aβ1-42 (Aβ42)) is well-known for its involvement in the development of Alzheimer's disease (AD). Aβ42 accumulates and aggregates in fibers that precipitate in the form of plaques in the brain causing toxicity; however, like other forms of Aβ peptide, the role of these peptides remains unclear. Here we analyze and compare the effects of oligomeric and fibrillary Aβ42 peptide on the biology (cell death, proliferative rate, and cell fate specification) of differentiating human neural stem cells (hNS1 cell line). By using the hNS1 cells we found that, at high concentrations, oligomeric and fibrillary Aβ42 peptides provoke apoptotic cellular death and damage of DNA in these cells, but Aβ42 fibrils have the strongest effect. The data also show that both oligomeric and fibrillar Aβ42 peptides decrease cellular proliferation but Aβ42 oligomers have the greatest effect. Finally, both, oligomers and fibrils favor gliogenesis and neurogenesis in hNS1 cells, although, in this case, the effect is more prominent in oligomers. All together the findings of this study may contribute to a better understanding of the molecular mechanisms involved in the pathology of AD and to the development of human neural stem cell-based therapies for AD treatment.Publication Physiological and pathological effects of amyloid-β species in neural stem cell biology(Medknow Publications, 2019-12) Bernabeu-Zornoza, Adela; Coronel Lopez, Raquel; Palmer, Charlotte; Monteagudo, Maria; Zambrano, Alberto; Liste-Noya, Isabel; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (España); Comunidad de Madrid (España)Although amyloid-β peptide is considered neurotoxic, it may mediate several physiological processes during embryonic development and in the adult brain. The pathological function of amyloid-β peptide has been extensively studied due to its implication in Alzheimer's disease, but its physiological function remains poorly understood. Amyloid-β peptide can be detected in non-aggregated (monomeric) and aggregated (oligomeric and fibrillary) forms. Each form has different cytotoxic and/or physiological properties, so amyloid-β peptide and its role in Alzheimer's disease need to be studied further. Neural stem cells and neural precursor cells are good tools for the study on neurodegenerative diseases and can provide future therapeutic applications in diseases such as Alzheimer's disease. In this review, we provide an outline of the effects of amyloid-β peptide, in monomeric and aggregated forms, on the biology of neural stem cells/neural precursor cells, and discuss the controversies. We also describe the possible molecular targets that could be implicated in these effects, especially GSK3β. A better understanding of amyloid-β peptide (both physiological and pathological), and the signaling pathways involved are essential to advance the field of Alzheimer's disease.Publication Neurogenesis Is Increased in Human Neural Stem Cells by Aβ40 Peptide(Multidisciplinary Digital Publishing Institute (MDPI), 2022-05-22) Bernabeu-Zornoza, Adela; Coronel Lopez, Raquel; Palmer, Charlotte; Martin, Alberto; López-Alonso, Victoria; Liste-Noya, Isabel; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Comunidad de Madrid (España)Amyloid-β 40 peptides [Aβ1-40 (Aβ40)] are present within amyloid plaques in the brains of patients with Alzheimer's disease (AD). Even though Aβ peptides are considered neurotoxic, they can mediate many biological processes, both in adult brains and throughout brain development. However, the physiological function of these Aβ peptides remains poorly understood, and the existing data are sometimes controversial. Here, we analyze and compare the effects of monomeric Aβ40 on the biology of differentiating human neural stem cells (human NSCs). For that purpose, we used a model of human NSCs called hNS1. Our data demonstrated that Aβ40 at high concentrations provokes apoptotic cellular death and the damage of DNA in human NSCs while also increasing the proliferation and favors neurogenesis by raising the percentage of proliferating neuronal precursors. These effects can be mediated, at least in part, by β-catenin. These results provide evidence of how Aβ modulate/regulate human NSC proliferation and differentiation, suggesting Aβ40 may be a pro-neurogenic factor. Our data could contribute to a better understanding of the molecular mechanisms involved in AD pathology and to the development of human NSC-based therapies for AD treatment, since these results could then be used in diagnosing the disease at early stages and be applied to the development of new treatment options.Publication Effects of lung and airway epithelial maturation cocktail on the structure of lung bud organoids(BioMed Central (BMC), 2018) Magro-Lopez, Esmeralda; Palmer, Charlotte; Manso, Joana; Liste-Noya, Isabel; Zambrano, Alberto; Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (España)Organoids from human pluripotent stem cells are becoming suitable models for studies of organ development, drug screening, regenerative medicine, and disease modeling. Three-dimensional minilungs in Matrigel culture have recently been generated from human embryonic stem cells. These particular organoids, named lung bud organoids, showed branching airway and early alveolar structures resembling those present in lungs from the second trimester of human gestation. We show here that the treatment of such organoids with a lung and airway epithelial maturation cocktail containing dexamethasone drives lung bud organoids to the formation of paddle-racquet like structures. This strategy may help to increase the versatility of lung organoids and to generate structures more advanced than the original branching texture.Publication Role of Amyloid Precursor Protein (APP) and Its Derivatives in the Biology and Cell Fate Specification of Neural Stem Cells(Springer, 2018-09) Coronel Lopez, Raquel; Bernabeu-Zornoza, Adela; Palmer, Charlotte; Muñiz-Moreno, Mar; Zambrano, Alberto; Cano, Eva; Liste-Noya, Isabel; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Comunidad de Madrid (España)Amyloid precursor protein (APP) is a member of the APP family of proteins, and different enzymatic processing leads to the production of several derivatives that are shown to have distinct biological functions. APP is involved in the pathology of Alzheimer's disease (AD), the most common neurodegenerative disorder causing dementia. Furthermore, it is believed that individuals with Down syndrome (DS) have increased APP expression, due to an extra copy of chromosome 21 (Hsa21), that contains the gene for APP. Nevertheless, the physiological function of APP remains unclear. It is known that APP plays an important role in neural growth and maturation during brain development, possibly by influencing proliferation, cell fate specification and neurogenesis of neural stem cells (NSCs). Proteolytic cleavage of APP occurs mainly via two mutually exclusive pathways, the non-amyloidogenic pathway or the amyloidogenic pathway. Other alternative pathways (η-secretase, δ-secretase and meprin pathways) have also been described for the physiological processing of APP. The different metabolites generated from these pathways, including soluble APPα (sAPPα), soluble APPβ (sAPPβ), β-amyloid (Aβ) peptides and the APP intracellular domain (AICD), have different functions determined by their structural differences, equilibrium and concentration with respect to other fragments derived from APP. This review discusses recent observations regarding possible functions of APP and its proteolytic derivatives in the biology and phenotypic specification of NSCs. This can be important for a better understanding of the pathogenesis and the development of future therapeutic applications for AD and/or DS, diseases in which alterations in neurogenesis have been described.Publication Aβ42 Peptide Promotes Proliferation and Gliogenesis in Human Neural Stem Cells(Springer, 2019-06) Bernabeu-Zornoza, Adela; Coronel Lopez, Raquel; Palmer, Charlotte; Calero, Miguel; Martínez-Serrano, A; Cano, Eva; Zambrano, Alberto; Liste-Noya, Isabel; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Comunidad de Madrid (España)Amyloid-β 42 [Aβ1-42 (Aβ42)] is one of the main Aβ peptide isoforms found in amyloid plaques of brains with Alzheimer's disease (AD). Although Aβ42 is associated with neurotoxicity, it might mediate several normal physiological processes during embryonic brain development and in the adult brain. However, due to the controversy that exists in the field, relatively little is known about its physiological function. In the present work, we have analyzed the effects of different concentrations of monomeric Aβ42 on cell death, proliferation, and cell fate specification of human neural stem cells (hNSCs), specifically the hNS1 cell line, undergoing differentiation. Our results demonstrate that at higher concentrations (1 μM), Aβ42 increases apoptotic cell death and DNA damage, indicating that prolonged exposure of hNS1 cells to higher concentrations of Aβ42 is neurotoxic. However, at lower concentrations, Aβ42 significantly promotes cell proliferation and glial cell specification of hNS1 cells by increasing the pool of proliferating glial precursors, without affecting neuronal differentiation, in a concentration-dependent manner. At the molecular level, these effects could be mediated, at least in part, by GSK3β, whose expression is increased by treatment with Aβ42 and whose inhibition prevents the glial specification induced by Aβ42. Since the cellular and molecular effects are known to appear decades before the first clinical symptoms, these types of studies are important in discovering the underlying pathophysiological processes involved in the development of AD. This knowledge could then be used in diagnosing the disease at early stages and be applied to the development of new treatment options.Publication Physiological effects of amyloid precursor protein and its derivatives on neural stem cell biology and signaling pathways involved(Medknow Publications, 2019-10) Coronel Lopez, Raquel; Palmer, Charlotte; Bernabeu-Zornoza, Adela; Monteagudo, Maria; Rosca, Andreea; Zambrano, Alberto; Liste-Noya, Isabel; Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (España); Comunidad de Madrid (España)The pathological implication of amyloid precursor protein (APP) in Alzheimer's disease has been widely documented due to its involvement in the generation of amyloid-β peptide. However, the physiological functions of APP are still poorly understood. APP is considered a multimodal protein due to its role in a wide variety of processes, both in the embryo and in the adult brain. Specifically, APP seems to play a key role in the proliferation, differentiation and maturation of neural stem cells. In addition, APP can be processed through two canonical processing pathways, generating different functionally active fragments: soluble APP-α, soluble APP-β, amyloid-β peptide and the APP intracellular C-terminal domain. These fragments also appear to modulate various functions in neural stem cells, including the processes of proliferation, neurogenesis, gliogenesis or cell death. However, the molecular mechanisms involved in these effects are still unclear. In this review, we summarize the physiological functions of APP and its main proteolytic derivatives in neural stem cells, as well as the possible signaling pathways that could be implicated in these effects. The knowledge of these functions and signaling pathways involved in the onset or during the development of Alzheimer's disease is essential to advance the understanding of the pathogenesis of Alzheimer's disease, and in the search for potential therapeutic targets.Publication Amyloid Precursor Protein (APP) Regulates Gliogenesis and Neurogenesis of Human Neural Stem Cells by Several Signaling Pathways(Multidisciplinary Digital Publishing Institute (MDPI), 2023-08-19) Coronel Lopez, Raquel; Bernabeu-Zornoza, Adela; Palmer, Charlotte; González-Sastre, Rosa; Rosca, Andreea; Mateos-Martínez, Patricia; López-Alonso, Victoria; Liste-Noya, Isabel; Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); University of Alcalá (España)Numerous studies have focused on the pathophysiological role of amyloid precursor protein (APP) because the proteolytic processing of APP to β-amyloid (Aβ) peptide is a central event in Alzheimer's disease (AD). However, many authors consider that alterations in the physiological functions of APP are likely to play a key role in AD. Previous studies in our laboratory revealed that APP plays an important role in the differentiation of human neural stem cells (hNSCs), favoring glial differentiation (gliogenesis) and preventing their differentiation toward a neuronal phenotype (neurogenesis). In the present study, we have evaluated the effects of APP overexpression in hNSCs at a global gene level by a transcriptomic analysis using the massive RNA sequencing (RNA-seq) technology. Specifically, we have focused on differentially expressed genes that are related to neuronal and glial differentiation processes, as well as on groups of differentially expressed genes associated with different signaling pathways, in order to find a possible interaction between them and APP. Our data indicate a differential expression in genes related to Notch, Wnt, PI3K-AKT, and JAK-STAT signaling, among others. Knowledge of APP biological functions, as well as the possible signaling pathways that could be related to this protein, are essential to advance our understanding of AD.