Endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which are key events in the init... more Endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which are key events in the initiation and/or progression of several diseases, are correlated with alterations at ER-mitochondria contact sites, the so-called "Mitochondria-Associated Membranes" (MAMs). These intracellular structures are also implicated in NLRP3 inflammasome activation which is an important driver of sterile inflammation, however, the underlying molecular basis remains unclear. This work aimed to investigate the role of ER-mitochondria communication during ER stress-induced NLRP3 inflammasome activation in both peripheral and central innate immune systems, by using THP-1 human monocytes and BV2 microglia cells, respectively, as in vitro models. Markers of ER stress, mitochondrial dynamics and mass, as well as NLRP3 inflammasome activation were evaluated by Western Blot, IL-1β secretion was measured by ELISA, and ER-mitochondria contacts were quantified by transmission electron microscopy. Mitochondrial Ca2+ uptake and polarization were analyzed with fluorescent probes, and measurement of aconitase and SOD2 activities monitored mitochondrial ROS accumulation. ER stress was demonstrated to activate the NLRP3 inflammasome in both peripheral and central immune cells. Studies in monocytes indicate that ER stress-induced NLRP3 inflammasome activation occurs by a Ca2+-dependent and ROS-independent mechanism, which is coupled with upregulation of MAMs-resident chaperones, closer ER-mitochondria contacts, as well as mitochondrial depolarization and impaired dynamics. Moreover, enhanced ER stress-induced NLRP3 inflammasome activation in the immune system was found associated with pathological conditions since it was observed in monocytes derived from bipolar disorder (BD) patients, supporting a pro-inflammatory status in BD. In conclusion, by demonstrating that ER-mitochondria communication plays a key role in the response of the innate immune cells to ER stress, this work contributes to elucidate the molecular mechanisms underlying NLRP3 inflammasome activation under stress conditions, and to disclose novel potential therapeutic targets for diseases associated with sterile inflammation.
Medical and scientific communities have been striving to disentangle the complexity of neurodegen... more Medical and scientific communities have been striving to disentangle the complexity of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), in order to develop a cure or effective treatment for these diseases. Along this journey, it has become important to identify the early events occurring in the prodromal phases of these diseases and the disorders that increase the risk of neurodegeneration highlighting common pathological features. This strategy has led to a wealth of evidence identifying diabetes, mainly type 2 diabetes mellitus (T2DM) as a main risk factor for the onset and progression of AD and PD. Impaired glucose metabolism, insulin resistance, and mitochondrial dysfunction are features common to both type 2 diabetes mellitus (T2DM), and AD and PD, and they appear before clinical diagnosis of the two neurodegenerative diseases. These could represent the strategic nodes of therapeutic intervention. Following this line of thought, a conceivable approach is to repurpose antidiabetic drugs as valuable agents that may prevent or reduce the risk of cognitive decline and neurodegeneration. This review summarizes the past and current findings that link AD and PD with T2DM, emphasizing the common pathological mechanisms. The efficacy of antidiabetic drugs, namely intranasal insulin, metformin, and thiazolidinediones, in the prevention and/or treatment of AD and PD is also discussed.
A diverse range of N-terminally truncated and modified forms of amyloid-β (Aβ) oligomers have bee... more A diverse range of N-terminally truncated and modified forms of amyloid-β (Aβ) oligomers have been discovered in Alzheimer’s disease brains, including the pyroglutamate-Aβ (AβpE3). AβpE3 species are shown to be more neurotoxic when compared with the full-length Aβ peptide. Findings visibly suggest that glutaminyl cyclase (QC) catalyzed the generation of cerebral AβpE3, and therapeutic effects are achieved by reducing its activity. In recent years, efforts to effectively develop QC inhibitors have been pursued worldwide. The inhibitory activity of current QC inhibitors is mainly triggered by zinc-binding groups that coordinate Zn2+ ion in the active site and other common features. Herein, we summarized the current state of discovery and evolution of QC inhibitors as a potential Alzheimer’s disease-modifying strategy.
Alzheimer's disease (AD) is the most common form of dementia in the elderly and, despite the ... more Alzheimer's disease (AD) is the most common form of dementia in the elderly and, despite the tremendous efforts researchers have put into AD research, there are no effective options for prevention and treatment of the disease. The best way to reach this goal is to clarify the mechanisms involved in the onset and progression of AD. In the last few years the views about the drivers of AD have been changing and nowadays it is believed that neuroinflammation takes center stage in disease pathogenesis. Herein, we provide an overview about the role of neuroinflammation in AD describing the role of microglia and astroglia is this process. Then, we will debate the NLRP3 inflammasome putting the focus on its activation through the canonical, non-canonical and alternative pathways and the triggers involved herein namely endoplasmic reticulum stress, mitochondrial dysfunction, reactive oxygen species and amyloid β peptide. Data supporting the hypothesis that inflammasome-mediated peripheral inflammation may contribute to AD pathology will be presented. Finally, a brief discussion about the therapeutic potential of NLRP3 inflammasome modulation is also provided.
Since the first clinical case reported more than 100 years ago, it has been a long and winding ro... more Since the first clinical case reported more than 100 years ago, it has been a long and winding road to demystify the initial pathological events underling the onset of Alzheimer's disease (AD). Fortunately, advanced imaging techniques extended the knowledge regarding AD origin, being well accepted that a decline in brain glucose metabolism occurs during the prodromal phases of AD and is aggravated with the progression of the disease. In this sense, in the last decades, the post-translational modification O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) has emerged as a potential causative link between hampered brain glucose metabolism and AD pathology. This is not surprising taking into account that this dynamic post-translational modification acts as a metabolic sensor that links glucose metabolism to normal neuronal functioning. Within this scenario, the present review aims to summarize the current understanding on the role of O-GlcNAcylation in neuronal physiology and A...
The loss of endothelial cells (ECs) homeostasis is a trigger for cerebrovascular dysfunction that... more The loss of endothelial cells (ECs) homeostasis is a trigger for cerebrovascular dysfunction that is a common event in several neurodegenerative disorders such as Alzheimer's disease (AD). The present work addressed the role of phosphatase 2A (PP2A) in cytoskeleton rearrangement, endoplasmic reticulum (ER) homeostasis, ER-mitochondria communication and mitochondrial dynamics in brain ECs. For this purpose, rat brain endothelial (RBE4) cells were exposed to okadaic acid, a well-known inhibitor of PP2A activity. An increase in the levels of tau phosphorylated on Ser396 and Thr181 residues was observed upon PP2A inhibition, concomitantly with the rearrangement of microtubules and actin cytoskeleton. Under these conditions, an increase in the levels of ER stress markers, namely GRP78, XBP1, p-eIF2α(Ser51), and ERO1α, was observed. Moreover, PP2A inhibition upregulated the Sigma-1 receptor, an ER chaperone located at the ER-mitochondria interface, and enhanced inter-organelle Ca(2+) ...
We here investigate the effects of two exercise modalities (endurance treadmill training-TM and v... more We here investigate the effects of two exercise modalities (endurance treadmill training-TM and voluntary free-wheel activity-FW) on the brain cortex and cerebellum mitochondrial bioenergetics, permeability transition pore (mPTP), oxidative stress, as well as on proteins involved in mitochondrial biogenesis, apoptosis, and quality control. Eighteen male rats were assigned to sedentary-SED, TM and FW groups. Behavioral alterations and ex vivo brain mitochondrial function endpoints were assessed. Proteins involved in oxidative phosphorylation (OXPHOS, including the adenine nucleotide translocator), oxidative stress markers and regulatory proteins (SIRT3, p66shc, UCP2, carbonyls, MDA, -SH, aconitase, Mn-SOD), as well as proteins involved in mitochondrial biogenesis (PGC1α, TFAM) were evaluated. Apoptotic signaling was measured through quantifying caspase 3, 8 and 9-like activities, Bax, Bcl2, CypD, and cofilin expression. Mitochondrial dynamics (Mfn1/2, OPA1 and DRP1) and auto(mito)phagy (LC3II, Beclin1, Pink1, Parkin, p62)-related proteins were also measured by Western blotting. Only the TM exercise group showed increased spontaneous alternation and exploratory activity. Both exercise regimens improved mitochondrial respiratory activity, increased OXPHOS complexes I, III and V subunits in both brain subareas and decreased oxidative stress markers. Increased resistance to mPTP and decreased apoptotic signaling were observed in the brain cortex from TM and in the cerebellum from TM and FW groups. Also, exercise increased the expression of proteins involved in mitochondrial biogenesis, autophagy and fusion, simultaneous with decreased expression of mitochondrial fission-related protein DRP1. In conclusion, physical exercise improves brain cortex and cerebellum mitochondrial function, decreasing oxidative stress and apoptotic related markers. It is also possible that favorable alterations in mitochondrial biogenesis, dynamics and autophagy signaling induced by exercise contributed to increased mitochondrial plasticity leading to a more robust phenotype.
Mitochondria are highly dynamic organelles involved in a multitude of cellular events. Disturbanc... more Mitochondria are highly dynamic organelles involved in a multitude of cellular events. Disturbances of mitochondrial function and dynamics are associated with cells degeneration and death. Neurons, perhaps more than any other cell, depend on mitochondria for their survival. In fact, accumulating evidence reveals that mitochondria take center stage in several neurodegenerative diseases. Here we will give an overview of the mechanisms involved in the maintenance of a healthy mitochondrial pool in neuronal cells and how disturbances in these processes underlie the pathophysiology of three common neurodegenerative disorders, Alzheimer, Parkinson and Huntington diseases. Additionally, we will discuss the role of sirtuins in neurodegeneration and how mitohormesis and vitagenes activation may counteract neurodegenerative events.
: Mitochondria are the powerhouse of the cell. Their primary physiological function is to generat... more : Mitochondria are the powerhouse of the cell. Their primary physiological function is to generate ATP through oxidative phosphorylation via the electron transport chain. Reactive oxygen radicals generated from mitochondria have been implicated in acute brain injuries, like stroke and neurodegeneration. Recent studies have shown that mitochondrially formed oxidants are mediators of molecular signaling and have implicated mitochondria‐dependent apoptosis involving pro‐ and antiapoptotic protein binding, the release of cytochrome c and Smac, the activation of downstream caspase‐9 and ‐3, and the fragmentation of DNA. Oxidative stress and the redox state are also implicated in the survival signaling pathway that involves phosphatidylinositol 3‐kinase (PI3‐K)/Akt and downstream signaling molecular bindings like Bad/Bcl‐XL and phosphorylated Bad/14‐3‐3. Genetically modified mice (SOD1, SOD2) or rats that overexpress or are deficient in superoxide dismutase have provided strong evidence in support of the role of mitochondrial dysfunction and oxidative stress as determinants of neuronal death/survival after stroke and neurodegeneration.
Diabetes mellitus type 2 (T2DM) has been associated with alterations in the male reproductive tra... more Diabetes mellitus type 2 (T2DM) has been associated with alterations in the male reproductive tract, especially in the epididymis. Although it is known that T2DM alters epididymal physiology, disturbing mitochondrial function and favoring oxidative stress, the mechanisms remain unknown. Sirtuin 1 (SIRT1), peroxisome proliferators-activated receptor γ coactivator 1α (PGC-1α), and sirtuin 3 (SIRT3) are key regulators of mitochondrial function and inducers of antioxidant defenses. In this study, we hypothesized that the epididymal SIRT1/PGC-1α/SIRT3 axis mediates T2DM-induced epididymis dysfunction by controlling the oxidative profile. Using 7 Goto-Kakizaki (GK) rats (a non-obese model that spontaneously develops T2DM early in life), and 7 age-matched Wistar control rats, we evaluated the protein levels of SIRT1, PGC-1α, and SIRT3, as well as the expression of mitochondrial respiratory complexes. The activities of epididymal glutathione peroxidase (GPx), glutathione reductase (GR), sup...
In this work, we imaged the retina of wild-type and triple-transgenic mice model of Alzheimer’s d... more In this work, we imaged the retina of wild-type and triple-transgenic mice model of Alzheimer’s disease (AD) (3xTg-AD), at the ages of one and two months, by optical coherence tomography. Texture analysis of calculated fundus images, for the six most anterior layers of the retina, present widespread differences between groups, demonstrating that retinal changes in the animal model of AD are notorious across the neuroretina. These results and the consistency of data pave the way for the identification of texture biomarkers of disease onset and progression with potential application to the human retina.
Background: The concept 'the retina as a window to the brain' in Alzheimer´s disease (AD)... more Background: The concept 'the retina as a window to the brain' in Alzheimer´s disease (AD) has been explored in recent years since patients sometimes present visual alterations before the first symptoms of dementia. The retina is an extension of the brain and can be assessed by non-invasive methods. However, assessing the retina for AD diagnosis is still a matter of debate. Using the triple transgenic mouse model of AD (3xTg-AD), this study was undertaken to investigate whether the retina and brain undergo similar molecular and cellular changes during the early stages of AD pathology, and if the retina could anticipate the pathological alterations occurring in the brain. Methods: We used the 3xTg-AD and wild-type mice (C57BL6/129S), at 4 and 8 months of age, and assessed several parameters in the retina and brain (hippocampus and cortex): amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) levels, barrier permeability, cell death, neurotransmitter levels and glial changes. ...
Endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which are key events in the init... more Endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which are key events in the initiation and/or progression of several diseases, are correlated with alterations at ER-mitochondria contact sites, the so-called "Mitochondria-Associated Membranes" (MAMs). These intracellular structures are also implicated in NLRP3 inflammasome activation which is an important driver of sterile inflammation, however, the underlying molecular basis remains unclear. This work aimed to investigate the role of ER-mitochondria communication during ER stress-induced NLRP3 inflammasome activation in both peripheral and central innate immune systems, by using THP-1 human monocytes and BV2 microglia cells, respectively, as in vitro models. Markers of ER stress, mitochondrial dynamics and mass, as well as NLRP3 inflammasome activation were evaluated by Western Blot, IL-1β secretion was measured by ELISA, and ER-mitochondria contacts were quantified by transmission electron microscopy. Mitochondrial Ca2+ uptake and polarization were analyzed with fluorescent probes, and measurement of aconitase and SOD2 activities monitored mitochondrial ROS accumulation. ER stress was demonstrated to activate the NLRP3 inflammasome in both peripheral and central immune cells. Studies in monocytes indicate that ER stress-induced NLRP3 inflammasome activation occurs by a Ca2+-dependent and ROS-independent mechanism, which is coupled with upregulation of MAMs-resident chaperones, closer ER-mitochondria contacts, as well as mitochondrial depolarization and impaired dynamics. Moreover, enhanced ER stress-induced NLRP3 inflammasome activation in the immune system was found associated with pathological conditions since it was observed in monocytes derived from bipolar disorder (BD) patients, supporting a pro-inflammatory status in BD. In conclusion, by demonstrating that ER-mitochondria communication plays a key role in the response of the innate immune cells to ER stress, this work contributes to elucidate the molecular mechanisms underlying NLRP3 inflammasome activation under stress conditions, and to disclose novel potential therapeutic targets for diseases associated with sterile inflammation.
Medical and scientific communities have been striving to disentangle the complexity of neurodegen... more Medical and scientific communities have been striving to disentangle the complexity of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), in order to develop a cure or effective treatment for these diseases. Along this journey, it has become important to identify the early events occurring in the prodromal phases of these diseases and the disorders that increase the risk of neurodegeneration highlighting common pathological features. This strategy has led to a wealth of evidence identifying diabetes, mainly type 2 diabetes mellitus (T2DM) as a main risk factor for the onset and progression of AD and PD. Impaired glucose metabolism, insulin resistance, and mitochondrial dysfunction are features common to both type 2 diabetes mellitus (T2DM), and AD and PD, and they appear before clinical diagnosis of the two neurodegenerative diseases. These could represent the strategic nodes of therapeutic intervention. Following this line of thought, a conceivable approach is to repurpose antidiabetic drugs as valuable agents that may prevent or reduce the risk of cognitive decline and neurodegeneration. This review summarizes the past and current findings that link AD and PD with T2DM, emphasizing the common pathological mechanisms. The efficacy of antidiabetic drugs, namely intranasal insulin, metformin, and thiazolidinediones, in the prevention and/or treatment of AD and PD is also discussed.
A diverse range of N-terminally truncated and modified forms of amyloid-β (Aβ) oligomers have bee... more A diverse range of N-terminally truncated and modified forms of amyloid-β (Aβ) oligomers have been discovered in Alzheimer’s disease brains, including the pyroglutamate-Aβ (AβpE3). AβpE3 species are shown to be more neurotoxic when compared with the full-length Aβ peptide. Findings visibly suggest that glutaminyl cyclase (QC) catalyzed the generation of cerebral AβpE3, and therapeutic effects are achieved by reducing its activity. In recent years, efforts to effectively develop QC inhibitors have been pursued worldwide. The inhibitory activity of current QC inhibitors is mainly triggered by zinc-binding groups that coordinate Zn2+ ion in the active site and other common features. Herein, we summarized the current state of discovery and evolution of QC inhibitors as a potential Alzheimer’s disease-modifying strategy.
Alzheimer's disease (AD) is the most common form of dementia in the elderly and, despite the ... more Alzheimer's disease (AD) is the most common form of dementia in the elderly and, despite the tremendous efforts researchers have put into AD research, there are no effective options for prevention and treatment of the disease. The best way to reach this goal is to clarify the mechanisms involved in the onset and progression of AD. In the last few years the views about the drivers of AD have been changing and nowadays it is believed that neuroinflammation takes center stage in disease pathogenesis. Herein, we provide an overview about the role of neuroinflammation in AD describing the role of microglia and astroglia is this process. Then, we will debate the NLRP3 inflammasome putting the focus on its activation through the canonical, non-canonical and alternative pathways and the triggers involved herein namely endoplasmic reticulum stress, mitochondrial dysfunction, reactive oxygen species and amyloid β peptide. Data supporting the hypothesis that inflammasome-mediated peripheral inflammation may contribute to AD pathology will be presented. Finally, a brief discussion about the therapeutic potential of NLRP3 inflammasome modulation is also provided.
Since the first clinical case reported more than 100 years ago, it has been a long and winding ro... more Since the first clinical case reported more than 100 years ago, it has been a long and winding road to demystify the initial pathological events underling the onset of Alzheimer's disease (AD). Fortunately, advanced imaging techniques extended the knowledge regarding AD origin, being well accepted that a decline in brain glucose metabolism occurs during the prodromal phases of AD and is aggravated with the progression of the disease. In this sense, in the last decades, the post-translational modification O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) has emerged as a potential causative link between hampered brain glucose metabolism and AD pathology. This is not surprising taking into account that this dynamic post-translational modification acts as a metabolic sensor that links glucose metabolism to normal neuronal functioning. Within this scenario, the present review aims to summarize the current understanding on the role of O-GlcNAcylation in neuronal physiology and A...
The loss of endothelial cells (ECs) homeostasis is a trigger for cerebrovascular dysfunction that... more The loss of endothelial cells (ECs) homeostasis is a trigger for cerebrovascular dysfunction that is a common event in several neurodegenerative disorders such as Alzheimer's disease (AD). The present work addressed the role of phosphatase 2A (PP2A) in cytoskeleton rearrangement, endoplasmic reticulum (ER) homeostasis, ER-mitochondria communication and mitochondrial dynamics in brain ECs. For this purpose, rat brain endothelial (RBE4) cells were exposed to okadaic acid, a well-known inhibitor of PP2A activity. An increase in the levels of tau phosphorylated on Ser396 and Thr181 residues was observed upon PP2A inhibition, concomitantly with the rearrangement of microtubules and actin cytoskeleton. Under these conditions, an increase in the levels of ER stress markers, namely GRP78, XBP1, p-eIF2α(Ser51), and ERO1α, was observed. Moreover, PP2A inhibition upregulated the Sigma-1 receptor, an ER chaperone located at the ER-mitochondria interface, and enhanced inter-organelle Ca(2+) ...
We here investigate the effects of two exercise modalities (endurance treadmill training-TM and v... more We here investigate the effects of two exercise modalities (endurance treadmill training-TM and voluntary free-wheel activity-FW) on the brain cortex and cerebellum mitochondrial bioenergetics, permeability transition pore (mPTP), oxidative stress, as well as on proteins involved in mitochondrial biogenesis, apoptosis, and quality control. Eighteen male rats were assigned to sedentary-SED, TM and FW groups. Behavioral alterations and ex vivo brain mitochondrial function endpoints were assessed. Proteins involved in oxidative phosphorylation (OXPHOS, including the adenine nucleotide translocator), oxidative stress markers and regulatory proteins (SIRT3, p66shc, UCP2, carbonyls, MDA, -SH, aconitase, Mn-SOD), as well as proteins involved in mitochondrial biogenesis (PGC1α, TFAM) were evaluated. Apoptotic signaling was measured through quantifying caspase 3, 8 and 9-like activities, Bax, Bcl2, CypD, and cofilin expression. Mitochondrial dynamics (Mfn1/2, OPA1 and DRP1) and auto(mito)phagy (LC3II, Beclin1, Pink1, Parkin, p62)-related proteins were also measured by Western blotting. Only the TM exercise group showed increased spontaneous alternation and exploratory activity. Both exercise regimens improved mitochondrial respiratory activity, increased OXPHOS complexes I, III and V subunits in both brain subareas and decreased oxidative stress markers. Increased resistance to mPTP and decreased apoptotic signaling were observed in the brain cortex from TM and in the cerebellum from TM and FW groups. Also, exercise increased the expression of proteins involved in mitochondrial biogenesis, autophagy and fusion, simultaneous with decreased expression of mitochondrial fission-related protein DRP1. In conclusion, physical exercise improves brain cortex and cerebellum mitochondrial function, decreasing oxidative stress and apoptotic related markers. It is also possible that favorable alterations in mitochondrial biogenesis, dynamics and autophagy signaling induced by exercise contributed to increased mitochondrial plasticity leading to a more robust phenotype.
Mitochondria are highly dynamic organelles involved in a multitude of cellular events. Disturbanc... more Mitochondria are highly dynamic organelles involved in a multitude of cellular events. Disturbances of mitochondrial function and dynamics are associated with cells degeneration and death. Neurons, perhaps more than any other cell, depend on mitochondria for their survival. In fact, accumulating evidence reveals that mitochondria take center stage in several neurodegenerative diseases. Here we will give an overview of the mechanisms involved in the maintenance of a healthy mitochondrial pool in neuronal cells and how disturbances in these processes underlie the pathophysiology of three common neurodegenerative disorders, Alzheimer, Parkinson and Huntington diseases. Additionally, we will discuss the role of sirtuins in neurodegeneration and how mitohormesis and vitagenes activation may counteract neurodegenerative events.
: Mitochondria are the powerhouse of the cell. Their primary physiological function is to generat... more : Mitochondria are the powerhouse of the cell. Their primary physiological function is to generate ATP through oxidative phosphorylation via the electron transport chain. Reactive oxygen radicals generated from mitochondria have been implicated in acute brain injuries, like stroke and neurodegeneration. Recent studies have shown that mitochondrially formed oxidants are mediators of molecular signaling and have implicated mitochondria‐dependent apoptosis involving pro‐ and antiapoptotic protein binding, the release of cytochrome c and Smac, the activation of downstream caspase‐9 and ‐3, and the fragmentation of DNA. Oxidative stress and the redox state are also implicated in the survival signaling pathway that involves phosphatidylinositol 3‐kinase (PI3‐K)/Akt and downstream signaling molecular bindings like Bad/Bcl‐XL and phosphorylated Bad/14‐3‐3. Genetically modified mice (SOD1, SOD2) or rats that overexpress or are deficient in superoxide dismutase have provided strong evidence in support of the role of mitochondrial dysfunction and oxidative stress as determinants of neuronal death/survival after stroke and neurodegeneration.
Diabetes mellitus type 2 (T2DM) has been associated with alterations in the male reproductive tra... more Diabetes mellitus type 2 (T2DM) has been associated with alterations in the male reproductive tract, especially in the epididymis. Although it is known that T2DM alters epididymal physiology, disturbing mitochondrial function and favoring oxidative stress, the mechanisms remain unknown. Sirtuin 1 (SIRT1), peroxisome proliferators-activated receptor γ coactivator 1α (PGC-1α), and sirtuin 3 (SIRT3) are key regulators of mitochondrial function and inducers of antioxidant defenses. In this study, we hypothesized that the epididymal SIRT1/PGC-1α/SIRT3 axis mediates T2DM-induced epididymis dysfunction by controlling the oxidative profile. Using 7 Goto-Kakizaki (GK) rats (a non-obese model that spontaneously develops T2DM early in life), and 7 age-matched Wistar control rats, we evaluated the protein levels of SIRT1, PGC-1α, and SIRT3, as well as the expression of mitochondrial respiratory complexes. The activities of epididymal glutathione peroxidase (GPx), glutathione reductase (GR), sup...
In this work, we imaged the retina of wild-type and triple-transgenic mice model of Alzheimer’s d... more In this work, we imaged the retina of wild-type and triple-transgenic mice model of Alzheimer’s disease (AD) (3xTg-AD), at the ages of one and two months, by optical coherence tomography. Texture analysis of calculated fundus images, for the six most anterior layers of the retina, present widespread differences between groups, demonstrating that retinal changes in the animal model of AD are notorious across the neuroretina. These results and the consistency of data pave the way for the identification of texture biomarkers of disease onset and progression with potential application to the human retina.
Background: The concept 'the retina as a window to the brain' in Alzheimer´s disease (AD)... more Background: The concept 'the retina as a window to the brain' in Alzheimer´s disease (AD) has been explored in recent years since patients sometimes present visual alterations before the first symptoms of dementia. The retina is an extension of the brain and can be assessed by non-invasive methods. However, assessing the retina for AD diagnosis is still a matter of debate. Using the triple transgenic mouse model of AD (3xTg-AD), this study was undertaken to investigate whether the retina and brain undergo similar molecular and cellular changes during the early stages of AD pathology, and if the retina could anticipate the pathological alterations occurring in the brain. Methods: We used the 3xTg-AD and wild-type mice (C57BL6/129S), at 4 and 8 months of age, and assessed several parameters in the retina and brain (hippocampus and cortex): amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) levels, barrier permeability, cell death, neurotransmitter levels and glial changes. ...
Uploads
Papers by Paula Moreira