المؤلفون: João D. Magalhães, A. Cristina Rego, A. Raquel Esteves, Emanuel Candeias, Diana Silva, Sandra M. Cardoso, Nuno Empadinhas, I. Luísa Ferreira, Daniela Nunes-Costa

المصدر: Journal of Neuroinflammation
Journal of Neuroinflammation, Vol 17, Iss 1, Pp 1-18 (2020)

مصطلحات موضوعية: 0301 basic medicine, Mitochondrial Turnover, Immunology, Biology, lcsh:RC346-429, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Alzheimer Disease, medicine, Cardiolipin, Animals, Neurotoxin, Neuronal innate immunity, Neurodegeneration, lcsh:Neurology. Diseases of the nervous system, Cerebral Cortex, Neurons, Innate immune system, Cyanobacteria Toxins, Research, General Neuroscience, Amino Acids, Diamino, Inflammasome, medicine.disease, Immunity, Innate, Mitochondria, Cell biology, β-N-Methylamino-l-alanine, 030104 developmental biology, Neurology, chemistry, TLR3, TLR4, Mitochondrial dysfunction, Alzheimer’s disease, 030217 neurology & neurosurgery, medicine.drug

الوصف: Background After decades of research recognizing it as a complex multifactorial disorder, sporadic Alzheimer’s disease (sAD) still has no known etiology. Adding to the myriad of different pathways involved, bacterial neurotoxins are assuming greater importance in the etiology and/or progression of sAD. β-N-Methylamino-l-alanine (BMAA), a neurotoxin produced by some microorganisms namely cyanobacteria, was previously detected in the brains of AD patients. Indeed, the consumption of BMAA-enriched foods has been proposed to induce amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), which implicated this microbial metabolite in neurodegeneration mechanisms. Methods Freshly isolated mitochondria from C57BL/6 mice were treated with BMAA and O2 consumption rates were determined. O2 consumption and glycolysis rates were also measured in mouse primary cortical neuronal cultures. Further, mitochondrial membrane potential and ROS production were evaluated by fluorimetry and the integrity of mitochondrial network was examined by immunofluorescence. Finally, the ability of BMAA to activate neuronal innate immunity was quantified by addressing TLRs (Toll-like receptors) expression, p65 NF-κB translocation into the nucleus, increased expression of NLRP3 (Nod-like receptor 3), and pro-IL-1β. Caspase-1 activity was evaluated using a colorimetric substrate and mature IL-1β levels were also determined by ELISA. Results Treatment with BMAA reduced O2 consumption rates in both isolated mitochondria and in primary cortical cultures, with additional reduced glycolytic rates, decrease mitochondrial potential and increased ROS production. The mitochondrial network was found to be fragmented, which resulted in cardiolipin exposure that stimulated inflammasome NLRP3, reinforced by decreased mitochondrial turnover, as indicated by increased p62 levels. BMAA treatment also activated neuronal extracellular TLR4 and intracellular TLR3, inducing p65 NF-κB translocation into the nucleus and activating the transcription of NLRP3 and pro-IL-1β. Increased caspase-1 activity resulted in elevated levels of mature IL-1β. These alterations in mitochondrial metabolism and inflammation increased Tau phosphorylation and Aβ peptides production, two hallmarks of AD. Conclusions Here we propose a unifying mechanism for AD neurodegeneration in which a microbial toxin can induce mitochondrial dysfunction and activate neuronal innate immunity, which ultimately results in Tau and Aβ pathology. Our data show that neurons, alone, can mount inflammatory responses, a role previously attributed exclusively to glial cells.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6ced9a98a7071a8378389392a151f92dTest

المؤلفون: Catarina R. Oliveira, Paula Agostinho, Sandra M. Cardoso, Cláudia Pereira, Paula I. Moreira

المصدر: Current Drug Target -CNS & Neurological Disorders. 4:383-403

مصطلحات موضوعية: Neurons, Pharmacology, Metal ion homeostasis, Amyloid, Amyloid beta-Peptides, biology, General Neuroscience, Neurotoxicity, P3 peptide, Neurotransmission, medicine.disease, Synaptic Transmission, Neuroprotection, Alzheimer Disease, Synapses, mental disorders, biology.protein, medicine, Animals, Humans, Senile plaques, Amyloid precursor protein secretase, Neuroscience, Neuroinflammation

الوصف: The characteristic hallmarks of Alzheimer's disease (AD), the most common form of dementia in the elderly, include senile plaques, mainly composed of beta-amyloid (Abeta) peptide, neurofibrillary tangles and selective synaptic and neuronal loss in brain regions involved in learning and memory. Genetic studies, together with the demonstration of Abeta neurotoxicity, led to the development of the amyloid cascade hypothesis to explain the AD-associated neurodegenerative process. However, a modified version of this hypothesis has emerged, the Abeta cascade hypothesis, which takes into account the fact that soluble oligomeric forms and protofibrils of Abeta and its intraneuronal accumulation also play a key role in the pathogenesis of the disease. Recent evidence posit that synaptic dysfunction triggered by non fibrillar Abeta species is an early event involved in memory decline in AD. The current understanding of the molecular mechanisms responsible for impaired synaptic function and cognitive deficits is outlined in this review, focusing on oxidative stress and disturbed metal ion homeostasis, Ca(2+) dysregulation, mitochondria and endoplasmic reticulum dysfunction, cholesterol dyshomeostasis and impaired neurotransmission. The activation of apoptotic cell death as a mechanism of neuronal loss in AD, and the prominent role of neuroinflammation in this neurodegenerative disorder, are also reviewed herein. Furthermore, we will focus on the more relevant therapeutical strategies currently used, namely those involving antioxidants, drugs for neurotransmission improvement, hormonal replacement, gamma- and beta- secretase inhibitors, Abeta clearance agents (Abeta immunization, disruption of Abeta fibrils, modulation of the cholesterol-mediated Abeta transport), non-steroidal anti-inflammatory drugs (NSAIDs), microtubules stabilizing drugs and kinase inhibitors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::785222d885df5926e573989c2f2c345cTest
https://doi.org/10.2174/1568007054546117Test

المؤلفون: Russell H. Swerdlow, A. Cristina Rego, Tice Macedo, Sandra M. Cardoso, Fernanda Borges, Catarina R. Oliveira, Teresa Cunha-Oliveira

المصدر: Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
instacron:RCAAP

مصطلحات موضوعية: medicine.medical_specialty, Programmed cell death, Cell, Amphetamine-Related Disorders, Apoptosis, Pharmacology, Mitochondrion, Membrane Potentials, Cocaine-Related Disorders, Cocaine, Internal medicine, Cell Line, Tumor, medicine, Animals, Humans, Amphetamine, Molecular Biology, Caspase, Cerebral Cortex, Neurons, biology, General Neuroscience, Neurodegeneration, Cytochromes c, medicine.disease, Mitochondria, Rats, Disease Models, Animal, Endocrinology, medicine.anatomical_structure, Electron Transport Chain Complex Proteins, Caspases, Mitochondrial Membranes, Nerve Degeneration, biology.protein, Central Nervous System Stimulants, Neurology (clinical), Neuron, Energy Metabolism, Developmental Biology, medicine.drug

الوصف: Drug abuse is associated with brain dysfunction and neurodegeneration, and various recreational drugs induce apoptotic cell death. This study examined the role of the mitochondrial apoptotic pathway in psychostimulant-induced neuronal dysfunction. Using primary neuronal cultures, we observed that amphetamine (IC50=1.40 mM) was more potent than cocaine (IC50=4.30 mM) in inducing cell toxicity. Apoptotic cell death was further evaluated using cocaine and amphetamine concentrations that moderately decreased cell reduction capacity but did not affect plasma membrane integrity. Compared to cocaine, amphetamine highly decreased the mitochondrial membrane potential, as determined using the fluorescent probe rhodamine-123, whereas both drugs decreased mitochondrial cytochrome c. In contrast to amphetamine, cocaine cytotoxicity was partly mediated through effects on the electron transport chain, since cocaine toxicity was ameliorated in mitochondrial DNA-depleted cells lacking mitochondrially encoded electron transport chain subunits. Cocaine and amphetamine induced activation of caspases-2, -3 and -9 but did not affect activity of caspases-6 or -8. In addition, amphetamine, but not cocaine, was associated with the appearance of evident nuclear apoptotic morphology. These events were not accompanied by differences in the release of the apoptosis-inducing factor (AIF) from mitochondria. Our results demonstrate that although both amphetamine and cocaine activate the mitochondrial apoptotic pathway in cortical neurons, amphetamine is more likely to promote apoptosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3c06c176d603012e702caed8d7f4bf76Test
https://pubmed.ncbi.nlm.nih.gov/16638611Test