Publications by authors named "Sandra I Mota"

10 Publications

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The Sigma-1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models.

Neurotherapeutics 2021 Apr 1. Epub 2021 Apr 1.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Pridopidine is a selective Sigma-1 receptor (S1R) agonist in clinical development for Huntington disease (HD) and amyotrophic lateral sclerosis. S1R is a chaperone protein localized in mitochondria-associated endoplasmic reticulum (ER) membranes, a signaling platform that regulates Ca signaling, reactive oxygen species (ROS) and mitochondrial fission. Here, we investigate the protective effects of pridopidine on various mitochondrial functions in human and mouse HD models. Pridopidine effects on mitochondrial dynamics were assessed in primary neurons from YAC128 HD mice expressing the mutant human HTT gene. We observe that pridopidine prevents the disruption of mitochondria-ER contact sites and improves the co-localization of inositol 1,4,5-trisphosphate receptor (IPR) and its chaperone S1R with mitochondria in YAC128 neurons, leading to increased mitochondrial activity, elongation, and motility. Increased mitochondrial respiration is also observed in YAC128 neurons and in pridopidine-treated HD human neural stem cells (hNSCs). ROS levels were assessed after oxidative insult or S1R knockdown in pridopidine-treated YAC128 neurons, HD hNSCs, and human HD lymphoblasts. All HD models show increased ROS levels and deficient antioxidant response, which are efficiently rescued with pridopidine. Importantly, pridopidine treatment before HO-induced mitochondrial dysfunction and S1R presence are required for HD cytoprotection. YAC128 mice treated at early/pre-symptomatic age with pridopidine show significant improvement in motor coordination, indicating a delay in symptom onset. Additionally, in vivo pridopidine treatment reduces mitochondrial ROS levels by normalizing mitochondrial complex activity. In conclusion, S1R-mediated enhancement of mitochondrial function contributes to the neuroprotective effects of pridopidine, providing insight into its mechanism of action and therapeutic potential.
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http://dx.doi.org/10.1007/s13311-021-01022-9DOI Listing
April 2021

Chronic hyperglycemia impairs hippocampal neurogenesis and memory in an Alzheimer's disease mouse model.

Neurobiol Aging 2020 08 15;92:98-113. Epub 2020 Apr 15.

CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine of the University of Coimbra (FMUC), Coimbra, Portugal. Electronic address:

During aging, lifestyle-related factors shape the brain's response to insults and modulate the progression of neurodegenerative pathologies such as Alzheimer's disease (AD). This is the case for chronic hyperglycemia associated with type 2 diabetes, which reduces the brain's ability to handle the neurodegenerative burden associated with AD. However, the mechanisms behind the effects of chronic hyperglycemia in the context of AD are not fully understood. Here, we show that newly generated neurons in the hippocampal dentate gyrus of triple transgenic AD (3xTg-AD) mice present increased dendritic arborization and a number of synaptic puncta, which may constitute a compensatory mechanism allowing the animals to cope with a lower neurogenesis rate. Contrariwise, chronic hyperglycemia decreases the complexity and differentiation of 3xTg-AD newborn neurons and reduces the levels of β-catenin, a key intrinsic modulator of neuronal maturation. Moreover, synaptic facilitation is depressed in hyperglycemic 3xTg-AD mice, accompanying the defective hippocampal-dependent memory. Our data suggest that hyperglycemia evokes cellular and functional alterations that accelerate the onset of AD-related symptoms, namely memory impairment.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.003DOI Listing
August 2020

Shaping the Nrf2-ARE-related pathways in Alzheimer's and Parkinson's diseases.

Ageing Res Rev 2019 09 12;54:100942. Epub 2019 Aug 12.

Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address:

A failure in redox homeostasis is a common hallmark of Alzheimer's Disease (AD) and Parkinson's Disease (PD), two age-dependent neurodegenerative disorders (NDD), causing increased oxidative stress, oxidized/damaged biomolecules, altered neuronal function and consequent cell death. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a redox-regulated transcription factor, results in upregulation of cytoprotective and antioxidant enzymes/proteins, protecting against oxidative stress. Nrf2 regulation is achieved by various proteins and pathways, at both cytoplasmatic and nuclear level; however, the elaborate network of mechanisms involved in Nrf2 regulation may restrain Nrf2 pathway normal activity. Indeed, altered Nrf2 activity is involved in aging and NDD, such as AD and PD. Therefore, understanding the diversity of Nrf2 control mechanisms and regulatory proteins is of high interest, since more effective NDD therapeutics can be identified. In this review, we first introduce Keap1-Nrf2-ARE structure, function and regulation, with a special focus on the several pathways involved in Nrf2 positive and negative modulation, namely p62, PKC, PI3K/Akt/GSK-3β, NF-kB and p38 MAPK. We then briefly describe the evidences for oxidative stress and Nrf2 pathway deregulation in different stages of NDDs. Finally, we discuss the potential of Nrf2-related pathways as potential therapeutic targets to possibly prevent or slowdown NDD progression.
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http://dx.doi.org/10.1016/j.arr.2019.100942DOI Listing
September 2019

c-Src regulates Nrf2 activity through PKCδ after oxidant stimulus.

Biochim Biophys Acta Mol Cell Res 2019 04 24;1866(4):686-698. Epub 2019 Jan 24.

Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address:

Nrf2 is the main transcription factor involved in expression of cell defense enzymes, which is altered in several oxidant-related disorders. Cytosolic Nrf2 activation is modulated through phosphorylation by PKCδ, an enzyme controlled by Src tyrosine kinases. Of relevance, Src family members are involved in numerous cellular processes and regulated by hydrogen peroxide (HO). In this study we analysed the activation of cell survival-related signaling proteins, c-Src and Nrf2, and the influence of c-Src kinase on Nrf2 regulation after exposure to HO. Acute exposure of HT22 mouse hippocampal neural cells to HO increased c-Src and Nrf2 phosphorylation/activation at Tyr416 and Ser40, respectively. Nrf2 phosphorylation at Ser40, its nuclear accumulation and transcriptional activity involving heme oxygenase-1 (HO-1) expression were dependent on c-Src kinase activation. Moreover, modulation of Nrf2 activity by c-Src occurred through PKCδ phosphorylation at Tyr311. We demonstrate, for the first time, c-Src-mediated regulation of Nrf2 transcriptional activity, via PKCδ activation, following an acute HO stimulus. This work supports that the c-Src/PKCδ/Nrf2 pathway may constitute a novel signaling pathway stimulated by HO and a potential target for the treatment of diseases involving redox deregulation.
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http://dx.doi.org/10.1016/j.bbamcr.2019.01.011DOI Listing
April 2019

biomass increases dendritic arborization of newly-generated neurons in mouse hippocampal dentate gyrus.

Oncotarget 2018 Aug 31;9(68):32929-32942. Epub 2018 Aug 31.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Brain cognitive reserve refers to the ability of the brain to manage different challenges that arise throughout life, making it resilient to neuropathology. Hippocampal adult neurogenesis has been considered to be a relevant contributor for brain cognitive reserve and brain plasticity. (CV), a common healthful mushroom, has been receiving increasing attention by its antitumoral, anti-inflammatory, antioxidant, antibacterial, and immunomodulatory properties, including in the hippocampus. Herein, we evaluated whether CV biomass oral administration for 2.5 months enhances hippocampal neurogenic reserve under normal/physiological conditions, by quantifying hippocampal dentate gyrus (DG) granular cell layer (GCL) and subgranular zone (SGZ) volumes, proliferation, number and dendritic complexity features of hippocampal newly-generated neurons. We also analyzed β-catenin levels in DG newly-generated immature neurons, because it plays a major role in neurogenesis. Although no differences were observed in the volume of GCL and SGZ layers, in proliferation and in the number of newly-generated neurons of controls and CV-administered mice, we found that CV administration promotes a significant increase in dendritic length and branching and total dendritic volume of immature neurons, suggesting a positive effect of oral CV administration in the hippocampal neurogenic reserve. We also observed that β-catenin levels are increased both in the nucleus and cytoplasm of DG immature neurons, suggesting that Wnt/β-catenin signalling may play an important role in the CV positive effect on the differentiation of these cells. These data unveil a so far unexplored neurogenic potential of CV supplementation, which emerges as a possible preventive strategy for different neurological conditions.
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http://dx.doi.org/10.18632/oncotarget.25978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152478PMC
August 2018

Assessing Mitochondrial Function in In Vitro and Ex Vivo Models of Huntington's Disease.

Methods Mol Biol 2018 ;1780:415-442

CNC-Center for Neuroscience and Cell Biology, University of Coimbra-polo I, Coimbra, Portugal.

Mitochondrial dysfunction has gained a preponderant role in the pathogenesis of Huntington's disease (HD). Mutant huntingtin (mHTT) directly interacts with mitochondria in a deleterious manner. As the central hub of the cell, not only mitochondrial bioenergetics is affected but there is also diminished mitochondrial membrane potential (Δψ ) and altered production of reactive oxygen species (ROS). Restoration of mitochondrial function has proven to be a major player in the search and establishment of therapeutics for HD patients. As such, performing an overall study of mitochondrial function is crucial. In this chapter, we describe some methodologies used to study mitochondrial function by determining the oxygen consumption, changes in Δψ , mitochondrial calcium handling, and levels of mitochondrial ROS. Here we focus on biological samples derived from HD versus control cells and/or animal models, namely functional isolated brain mitochondria, an ex vivo animal model, and cultured cells, including cell lines and primary neural cultures, as in vitro models.
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http://dx.doi.org/10.1007/978-1-4939-7825-0_19DOI Listing
February 2019

Oxidative stress involving changes in Nrf2 and ER stress in early stages of Alzheimer's disease.

Biochim Biophys Acta 2015 Jul 6;1852(7):1428-41. Epub 2015 Apr 6.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal. Electronic address:

Oxidative stress and endoplasmic reticulum (ER) stress have been associated with Alzheimer's disease (AD) progression. In this study we analyzed whether oxidative stress involving changes in Nrf2 and ER stress may constitute early events in AD pathogenesis by using human peripheral blood cells and an AD transgenic mouse model at different disease stages. Increased oxidative stress and increased phosphorylated Nrf2 (p(Ser40)Nrf2) were observed in human peripheral blood mononuclear cells (PBMCs) isolated from individuals with mild cognitive impairment (MCI). Moreover, we observed impaired ER Ca2+ homeostasis and increased ER stress markers in PBMCs from MCI individuals and mild AD patients. Evidence of early oxidative stress defense mechanisms in AD was substantiated by increased p(Ser40)Nrf2 in 3month-old 3xTg-AD male mice PBMCs, and also with increased nuclear Nrf2 levels in brain cortex. However, SOD1 protein levels were decreased in human MCI PBMCs and in 3xTg-AD mice brain cortex; the latter further correlated with reduced SOD1 mRNA levels. Increased ER stress was also detected in the brain cortex of young female and old male 3xTg-AD mice. We demonstrate oxidative stress and early Nrf2 activation in AD human and mouse models, which fails to regulate some of its targets, leading to repressed expression of antioxidant defenses (e.g., SOD-1), and extending to ER stress. Results suggest markers of prodromal AD linked to oxidative stress associated with Nrf2 activation and ER stress that may be followed in human peripheral blood mononuclear cells.
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http://dx.doi.org/10.1016/j.bbadis.2015.03.015DOI Listing
July 2015

Impaired Src signaling and post-synaptic actin polymerization in Alzheimer's disease mice hippocampus--linking NMDA receptors and the reelin pathway.

Exp Neurol 2014 Nov 13;261:698-709. Epub 2014 Aug 13.

Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address:

Early cognitive deficits in Alzheimer's disease (AD) have been related to deregulation of N-methyl-d-aspartate receptors (NMDARs) and synaptic dysfunction in response to amyloid-beta peptide. NMDAR anchorage to post-synaptic membrane depends in part on Src kinase, which is also implicated in NMDAR activation and actin cytoskeleton stabilization, two processes relevant for normal synaptic function. In this study we analyzed the changes in GluN2B subunit phosphorylation and the levels of proteins involved in Src related signaling pathways linking the Tyr kinase to actin cytoskeleton polymerization, namely reelin, disabled-1 (Dab1) and cortactin, in hippocampal and cortical homogenates obtained from the triple transgenic mouse model of AD (3xTg-AD) that shows progression of pathology as a function of age versus age-matched wild-type mice. Moreover, we evaluated regional post-synaptic actin polymerization using phalloidin labeling in hippocampal slices. Young (3month-old) 3xTg-AD male mice hippocampus exhibited decreased GluN2B Tyr1472 phosphorylation and reduced Src activity. In the cortex, decreased Src activity correlated with reduced levels of reelin and Dab1, implicating changes in the reelin pathway. We also observed diminished phosphorylated Dab1 and cortactin protein levels in the hippocampus and cortex of young 3xTg-AD male mice. Concordantly with the recognized role of these proteins in actin stabilization, we detected a significant decrease in post-synaptic F-actin in 3month-old 3xTg-AD male CA1 and CA3 hippocampal regions. These data suggest deregulated Src-dependent signaling pathways involving GluN2B-composed NMDARs and post-synaptic actin cytoskeleton depolymerization in the hippocampus in early stages of AD.
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http://dx.doi.org/10.1016/j.expneurol.2014.07.023DOI Listing
November 2014

Dysfunctional synapse in Alzheimer's disease - A focus on NMDA receptors.

Neuropharmacology 2014 Jan 22;76 Pt A:16-26. Epub 2013 Aug 22.

CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal. Electronic address:

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly. Alterations capable of causing brain circuitry dysfunctions in AD may take several years to develop. Oligomeric amyloid-beta peptide (Aβ) plays a complex role in the molecular events that lead to progressive loss of function and eventually to neurodegeneration in this devastating disease. Moreover, N-methyl-D-aspartate (NMDA) receptors (NMDARs) activation has been recently implicated in AD-related synaptic dysfunction. Thus, in this review we focus on glutamatergic neurotransmission impairment and the changes in NMDAR regulation in AD, following the description on the role and location of NMDARs at pre- and post-synaptic sites under physiological conditions. In addition, considering that there is currently no effective ways to cure AD or stop its progression, we further discuss the relevance of NMDARs antagonists to prevent AD symptomatology. This review posits additional information on the role played by Aβ in AD and the importance of targeting the tripartite glutamatergic synapse in early asymptomatic and possible reversible stages of the disease through preventive and/or disease-modifying therapeutic strategies. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.
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http://dx.doi.org/10.1016/j.neuropharm.2013.08.013DOI Listing
January 2014

Amyloid-beta peptide 1-42 causes microtubule deregulation through N-methyl-D-aspartate receptors in mature hippocampal cultures.

Curr Alzheimer Res 2012 Sep;9(7):844-56

Faculty of Medicine, and Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marques de Pombal, 3004-517 Coimbra, Portugal.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder among the elderly. Nmethyl- D-aspartate receptor (NMDAR) overactivation has been implicated in early synaptic dysfunction that precedes late neurodegeneration in AD. Moreover, oligomers of amyloid-beta peptide (Aβ) 1-42 are considered the most synaptotoxic forms, responsible for early cognitive deficits in AD. In this work we evaluate the role of NMDARs on Aβ-evoked neuronal dysfunction and cell death through changes in microtubule polymerization in mature hippocampal cultures. Exposure to Aβ 1-42 caused a decrease in total and polymerized levels of beta-III tubulin and polymerized alpha-tubulin, suggesting microtubule disassembly. Moreover, Aβ induced DNA fragmentation in both neuronal and non-neuronal cells. Indeed, the effects of Aβ on beta-III tubulin polymerization were significantly correlated with reduced neurite length and neuronal DNA fragmentation. Interestingly, these effects were prevented by MK-801 and memantine, suggesting a role for extrasynaptic NMDARs in Aβ toxicity, and by ifenprodil, further indicating the involvement of GluN2B-containing NMDARs. Nevertheless, exposure to Aβ did not potentiate the effects caused by selective activation of NMDARs. Data largely suggest that Aβ-induced hippocampal neuronal dysfunction occurs through NMDAR-dependent microtubule disassembly associated to neurite retraction and DNA fragmentation in mature hippocampal cells.
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http://dx.doi.org/10.2174/156720512802455322DOI Listing
September 2012