Abnormal tau build-up is a hallmark of Alzheimer’s disease (AD) and more than 20 other serious ne... more Abnormal tau build-up is a hallmark of Alzheimer’s disease (AD) and more than 20 other serious neurodegenerative diseases. Mitochondria are paramount organelles playing a predominant role in cellular bioenergetics, namely by providing the main source of cellular energy via adenosine triphosphate generation. Abnormal tau impairs almost every aspect of mitochondrial function, from mitochondrial respiration to mitophagy. The aim of our study was to investigate the effects of spermidine, a polyamine which exerts neuroprotective effects, on mitochondrial function in a cellular model of tauopathy. Recent evidence identified autophagy as the main mechanism of action of spermidine on life-span prolongation and neuroprotection, but the effects of spermidine on abnormal tau-induced mitochondrial dysfunction have not yet been investigated. We used SH-SY5Y cells stably expressing a mutant form of human tau protein (P301L tau mutation) or cells expressing the empty vector (control cells). We sho...
A potential explanation for the spatiotemporal accumulation of pathological lesions in the brain ... more A potential explanation for the spatiotemporal accumulation of pathological lesions in the brain of patients with neurodegenerative protein misfolding diseases (PMDs) is cell-to-cell transmission of aggregation-prone, misfolded proteins. Little is known about central to peripheral transmission and its contribution to pathology. We show that transmission of Huntington’s disease- (HD-) associated mutant HTT exon 1 (mHTTEx1) occurs across the neuromuscular junctions in human iPSC cultures and in vivo in wild-type mice. We found that transmission is an active and dynamic process, that happens prior to aggregate formation and is regulated by synaptic activity. Furthermore, we find that transmitted mHTTEx1 causes HD-relevant pathology at a molecular and functional level in human muscle cells, even in the presence of ubiquitous expression mHTTEx1. With this work we uncover a casual-link between mHTTEx1 synaptic transmission and pathology, highlighting the therapeutic potential in blocking ...
Mitochondria play a paramount role in cell survival and death because they are orchestrating both... more Mitochondria play a paramount role in cell survival and death because they are orchestrating both energy metabolism and apoptotic pathways, while impaired mitochondrial function leads inevitably to disease, especially neurodegeneration. The purpose of the present thesis was therefore to deepen our understanding of the regulation of mitochondrial function, with a focus on mitochondrial bioenergetics and dynamics. Our key findings were that: i) neurosteroids represent promising molecules which are able to increase mitochondrial bioenergetics via enhancement of mitochondrial respiration in healthy condition; ii) neurosteroids are able to alleviate Alzheimer’s disease-related bioenergetic deficits; iii) the circadian clock is able to regulate mitochondrial bioenergetics and dynamics, and vice versa. Collectively, our results contribute to a better understanding of how mitochondria function, and could have multiple implications with regard to the regulation of metabolic homeostasis in he...
Skeletal muscle dysfunction, wasting and synaptic pathology is a hallmark of Huntington’s disease... more Skeletal muscle dysfunction, wasting and synaptic pathology is a hallmark of Huntington’s disease (HD). Similar as for the nervous system the pathological lesions and clinical symptoms progressively worsen with disease coarse. Cell-to-cell transmission of toxic mutant huntingtin (mHTT) has been shown to occur and could be a potential explanation for the progressive accumulation of pathological lesions and clinical symptoms in time. However, the mechanism and contribution of mHTT cell-to-cell transmission to pathology in an environment of ubiquitous expression of the mutant protein is not well understood. Here, we show that the HD-associated mHTT exon 1 (mHTTEx1) is transmitted from human induced pluripotent stem cell-(hiPSC-) derived motor neurons (MNs) to isogenic hiPSC-derived myotubes across functionally active neuromuscular junctions (NMJ) and in vivo in wild-type mice from the M1 motor cortex to spinal MNs and skeletal muscles. Increased synaptic connectivity and activity enhan...
Translational errors frequently arise during protein synthesis, producing misfolded and dysfuncti... more Translational errors frequently arise during protein synthesis, producing misfolded and dysfunctional proteins. Chronic stress resulting from translation errors may be particularly relevant in tissues that must synthesize and secrete large amounts of secretory proteins. Here, we studied the proteostasis networks in the liver of mice that express the Rps2-A226Y ribosomal ambiguity (ram) mutation to increase the translation error rate across all proteins. We found that Rps2-A226Y mice lack activation of the eIF2 kinase/ATF4 pathway, the main component of the integrated stress response (ISR), as well as the IRE1 and ATF6 pathways of the ER unfolded protein response (ER-UPR). Instead, we found downregulation of chronic ER stress responses, as indicated by reduced gene expression for lipogenic pathways and acute phase proteins, possibly via upregulation of Sirtuin-1. In parallel, we observed activation of alternative proteostasis responses, including the proteasome and the formation of s...
Studies on the sporadic form of Alzheimer's disease (AD) have revealed three classes of risk ... more Studies on the sporadic form of Alzheimer's disease (AD) have revealed three classes of risk factor: age, genetics, and sex. These risk factors point to a metabolic dysregulation as the origin of AD. Adaptive alterations in cerebral metabolism are the rationale for the Metabolic Reprogramming (MR) Theory of the origin of AD. The theory contends that the progression toward AD involves three adaptive events: a hypermetabolic phase, a prolonged prodromal phase, and a metabolic collapse. This article exploits the MR Theory to elucidate the effect of hormonal changes on the origin and progression of AD in women. The theory invokes bioenergetic signatures of the menopausal transition to propose sex-specific diagnostic program and therapeutic strategies.
The brain is the most energy-consuming organ of the body and impairments in brain energy metaboli... more The brain is the most energy-consuming organ of the body and impairments in brain energy metabolism will affect neuronal functionality and viability. Brain aging is marked by defects in energetic metabolism. Abnormal tau protein is a hallmark of tauopathies, including Alzheimer’s disease (AD). Pathological tau was shown to induce bioenergetic impairments by affecting mitochondrial function. Although it is now clear that mutations in the tau-coding gene lead to tau pathology, the causes of abnormal tau phosphorylation and aggregation in non-familial tauopathies, such as sporadic AD, remain elusive. Strikingly, both tau pathology and brain hypometabolism correlate with cognitive impairments in AD. The aim of this review is to discuss the link between age-related decrease in brain metabolism and tau pathology. In particular, the following points will be discussed: (i) the common bioenergetic features observed during brain aging and tauopathies; (ii) how age-related bioenergetic defects...
Abnormal tau protein aggregation in the brain is a hallmark of tauopathies, such as frontotempora... more Abnormal tau protein aggregation in the brain is a hallmark of tauopathies, such as frontotemporal lobar degeneration and Alzheimer’s disease. Substantial evidence has been linking tau to neurodegeneration, but the underlying mechanisms have yet to be clearly identified. Mitochondria are paramount organelles in neurons, as they provide the main source of energy (adenosine triphosphate) to these highly energetic cells. Mitochondrial dysfunction was identified as an early event of neurodegenerative diseases occurring even before the cognitive deficits. Tau protein was shown to interact with mitochondrial proteins and to impair mitochondrial bioenergetics and dynamics, leading to neurotoxicity. In this review, we discuss in detail the different impacts of disease-associated tau protein on mitochondrial functions, including mitochondrial transport, network dynamics, mitophagy and bioenergetics. We also give new insights about the effects of abnormal tau protein on mitochondrial neuroste...
Neurosteroids are steroids synthetized in the nervous system, with the first step of steroidogene... more Neurosteroids are steroids synthetized in the nervous system, with the first step of steroidogenesis taking place within mitochondria with the synthesis of pregnenolone. They exert important brain-specific functions by playing a role in neurotransmission, learning and memory processes, and neuroprotection. Here, we show for the first time that mitochondrial neurosteroidogenesis follows a circadian rhythm and correlates with the rhythmic changes in mitochondrial morphology. We used synchronized human A172 glioma cells, which are steroidogenic cells with a functional core molecular clock, to show that pregnenolone levels and translocator protein (TSPO) are controlled by the clock, probably via circadian regulation of mitochondrial fusion/fission. Key findings were recapitulated in mouse brains. We also showed that genetic or pharmacological abrogation of fusion/fission activity, as well as disturbing the core molecular clock, abolished circadian rhythms of pregnenolone and TSPO. Our f...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting more than 47.5 mil... more Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting more than 47.5 million people worldwide. Metabolic impairments are common hallmarks of AD, and amyloid-β (Aβ) peptide and hyperphosphorylated tau protein-the two foremost histopathological signs of AD-have been implicated in mitochondrial dysfunction. Many neurodegenerative disorders, including AD, show excessive amounts of mis-/unfolded proteins leading to an activation of the unfolded protein response (UPR). In the present study, we aimed to characterize the link between ER stress and bioenergetics defects under normal condition (human SH-SY5Y neuroblastoma cells: control cells) or under pathological AD condition [SH-SY5Y cells overexpressing either the human amyloid precursor protein (APP) or mutant tau (P301L)]. More specifically, we measured UPR gene expression, cell viability, and bioenergetics parameters, such as ATP production and mitochondrial membrane potential (MMP) in basal condition and after an induced ER stress by thapsigargin. We detected highly activated UPR and dysregulated bioenergetics in basal condition in both AD cellular models. Strikingly, acute-induced ER stress increased the activity of the UPR in both AD cellular models, leading to up-regulation of apoptotic pathways, and further dysregulated mitochondrial function.
Mitochondrial fission-fusion dynamics and mitochondrial bioenergetics, including oxidative phosph... more Mitochondrial fission-fusion dynamics and mitochondrial bioenergetics, including oxidative phosphorylation and generation of ATP, are strongly clock controlled. Here we show that these circadian oscillations depend on circadian modification of dynamin-related protein 1 (DRP1), a key mediator of mitochondrial fission. We used a combination of in vitro and in vivo models, including human skin fibroblasts and DRP1-deficient or clock-deficient mice, to show that these dynamics are clock controlled via circadian regulation of DRP1. Genetic or pharmacological abrogation of DRP1 activity abolished circadian network dynamics and mitochondrial respiratory activity and eliminated circadian ATP production. Pharmacological silencing of pathways regulating circadian metabolism and mitochondrial function (e.g., sirtuins, AMPK) also altered DRP1 phosphorylation, and abrogation of DRP1 activity impaired circadian function. Our findings provide new insight into the crosstalk between the mitochondria...
Starting from the central benzodiazepine receptor (CBR) ligand CGS‐13767, we designed a series of... more Starting from the central benzodiazepine receptor (CBR) ligand CGS‐13767, we designed a series of imidazoquinazolinone derivatives acting as 18 kDa translocator protein (TSPO) ligands, and deprived of affinity for CBR. These compounds, as well as ligands of reference (Ro5‐4864, XBD173, SSR180575), were assessed for their ability to restore neurosteroidogenesis and energy production in SH‐SY5Y neuroblastoma cell lines expressing amyloid protein precursor (APP). Our results show the potential neuroprotective effect of TSPO ligands, but highlight a strong discrepancy in the active concentrations, nanomolar for ATP production while pregnenolone production is restored in the micromolar range.
Aging is defined as a progressive time‐related accumulation of changes responsible for or at leas... more Aging is defined as a progressive time‐related accumulation of changes responsible for or at least involved in the increased susceptibility to disease and death. The brain seems to be particularly sensitive to the aging process since the appearance of neurodegenerative diseases, including Alzheimer's disease, is exponential with the increasing age. Mitochondria were placed at the center of the ‘free‐radical theory of aging’, because these paramount organelles are not only the main producers of energy in the cells, but also to main source of reactive oxygen species. Thus, in this review, we aim to look at brain aging processes from a mitochondrial point of view by asking: (i) What happens to brain mitochondrial bioenergetics and dynamics during aging? (ii) Why is the brain so sensitive to the age‐related mitochondrial impairments? (iii) Is there a sex difference in the age‐induced mitochondrial dysfunction? Understanding mitochondrial physiology in the context of brain aging may ...
Abnormal tau build-up is a hallmark of Alzheimer’s disease (AD) and more than 20 other serious ne... more Abnormal tau build-up is a hallmark of Alzheimer’s disease (AD) and more than 20 other serious neurodegenerative diseases. Mitochondria are paramount organelles playing a predominant role in cellular bioenergetics, namely by providing the main source of cellular energy via adenosine triphosphate generation. Abnormal tau impairs almost every aspect of mitochondrial function, from mitochondrial respiration to mitophagy. The aim of our study was to investigate the effects of spermidine, a polyamine which exerts neuroprotective effects, on mitochondrial function in a cellular model of tauopathy. Recent evidence identified autophagy as the main mechanism of action of spermidine on life-span prolongation and neuroprotection, but the effects of spermidine on abnormal tau-induced mitochondrial dysfunction have not yet been investigated. We used SH-SY5Y cells stably expressing a mutant form of human tau protein (P301L tau mutation) or cells expressing the empty vector (control cells). We sho...
A potential explanation for the spatiotemporal accumulation of pathological lesions in the brain ... more A potential explanation for the spatiotemporal accumulation of pathological lesions in the brain of patients with neurodegenerative protein misfolding diseases (PMDs) is cell-to-cell transmission of aggregation-prone, misfolded proteins. Little is known about central to peripheral transmission and its contribution to pathology. We show that transmission of Huntington’s disease- (HD-) associated mutant HTT exon 1 (mHTTEx1) occurs across the neuromuscular junctions in human iPSC cultures and in vivo in wild-type mice. We found that transmission is an active and dynamic process, that happens prior to aggregate formation and is regulated by synaptic activity. Furthermore, we find that transmitted mHTTEx1 causes HD-relevant pathology at a molecular and functional level in human muscle cells, even in the presence of ubiquitous expression mHTTEx1. With this work we uncover a casual-link between mHTTEx1 synaptic transmission and pathology, highlighting the therapeutic potential in blocking ...
Mitochondria play a paramount role in cell survival and death because they are orchestrating both... more Mitochondria play a paramount role in cell survival and death because they are orchestrating both energy metabolism and apoptotic pathways, while impaired mitochondrial function leads inevitably to disease, especially neurodegeneration. The purpose of the present thesis was therefore to deepen our understanding of the regulation of mitochondrial function, with a focus on mitochondrial bioenergetics and dynamics. Our key findings were that: i) neurosteroids represent promising molecules which are able to increase mitochondrial bioenergetics via enhancement of mitochondrial respiration in healthy condition; ii) neurosteroids are able to alleviate Alzheimer’s disease-related bioenergetic deficits; iii) the circadian clock is able to regulate mitochondrial bioenergetics and dynamics, and vice versa. Collectively, our results contribute to a better understanding of how mitochondria function, and could have multiple implications with regard to the regulation of metabolic homeostasis in he...
Skeletal muscle dysfunction, wasting and synaptic pathology is a hallmark of Huntington’s disease... more Skeletal muscle dysfunction, wasting and synaptic pathology is a hallmark of Huntington’s disease (HD). Similar as for the nervous system the pathological lesions and clinical symptoms progressively worsen with disease coarse. Cell-to-cell transmission of toxic mutant huntingtin (mHTT) has been shown to occur and could be a potential explanation for the progressive accumulation of pathological lesions and clinical symptoms in time. However, the mechanism and contribution of mHTT cell-to-cell transmission to pathology in an environment of ubiquitous expression of the mutant protein is not well understood. Here, we show that the HD-associated mHTT exon 1 (mHTTEx1) is transmitted from human induced pluripotent stem cell-(hiPSC-) derived motor neurons (MNs) to isogenic hiPSC-derived myotubes across functionally active neuromuscular junctions (NMJ) and in vivo in wild-type mice from the M1 motor cortex to spinal MNs and skeletal muscles. Increased synaptic connectivity and activity enhan...
Translational errors frequently arise during protein synthesis, producing misfolded and dysfuncti... more Translational errors frequently arise during protein synthesis, producing misfolded and dysfunctional proteins. Chronic stress resulting from translation errors may be particularly relevant in tissues that must synthesize and secrete large amounts of secretory proteins. Here, we studied the proteostasis networks in the liver of mice that express the Rps2-A226Y ribosomal ambiguity (ram) mutation to increase the translation error rate across all proteins. We found that Rps2-A226Y mice lack activation of the eIF2 kinase/ATF4 pathway, the main component of the integrated stress response (ISR), as well as the IRE1 and ATF6 pathways of the ER unfolded protein response (ER-UPR). Instead, we found downregulation of chronic ER stress responses, as indicated by reduced gene expression for lipogenic pathways and acute phase proteins, possibly via upregulation of Sirtuin-1. In parallel, we observed activation of alternative proteostasis responses, including the proteasome and the formation of s...
Studies on the sporadic form of Alzheimer's disease (AD) have revealed three classes of risk ... more Studies on the sporadic form of Alzheimer's disease (AD) have revealed three classes of risk factor: age, genetics, and sex. These risk factors point to a metabolic dysregulation as the origin of AD. Adaptive alterations in cerebral metabolism are the rationale for the Metabolic Reprogramming (MR) Theory of the origin of AD. The theory contends that the progression toward AD involves three adaptive events: a hypermetabolic phase, a prolonged prodromal phase, and a metabolic collapse. This article exploits the MR Theory to elucidate the effect of hormonal changes on the origin and progression of AD in women. The theory invokes bioenergetic signatures of the menopausal transition to propose sex-specific diagnostic program and therapeutic strategies.
The brain is the most energy-consuming organ of the body and impairments in brain energy metaboli... more The brain is the most energy-consuming organ of the body and impairments in brain energy metabolism will affect neuronal functionality and viability. Brain aging is marked by defects in energetic metabolism. Abnormal tau protein is a hallmark of tauopathies, including Alzheimer’s disease (AD). Pathological tau was shown to induce bioenergetic impairments by affecting mitochondrial function. Although it is now clear that mutations in the tau-coding gene lead to tau pathology, the causes of abnormal tau phosphorylation and aggregation in non-familial tauopathies, such as sporadic AD, remain elusive. Strikingly, both tau pathology and brain hypometabolism correlate with cognitive impairments in AD. The aim of this review is to discuss the link between age-related decrease in brain metabolism and tau pathology. In particular, the following points will be discussed: (i) the common bioenergetic features observed during brain aging and tauopathies; (ii) how age-related bioenergetic defects...
Abnormal tau protein aggregation in the brain is a hallmark of tauopathies, such as frontotempora... more Abnormal tau protein aggregation in the brain is a hallmark of tauopathies, such as frontotemporal lobar degeneration and Alzheimer’s disease. Substantial evidence has been linking tau to neurodegeneration, but the underlying mechanisms have yet to be clearly identified. Mitochondria are paramount organelles in neurons, as they provide the main source of energy (adenosine triphosphate) to these highly energetic cells. Mitochondrial dysfunction was identified as an early event of neurodegenerative diseases occurring even before the cognitive deficits. Tau protein was shown to interact with mitochondrial proteins and to impair mitochondrial bioenergetics and dynamics, leading to neurotoxicity. In this review, we discuss in detail the different impacts of disease-associated tau protein on mitochondrial functions, including mitochondrial transport, network dynamics, mitophagy and bioenergetics. We also give new insights about the effects of abnormal tau protein on mitochondrial neuroste...
Neurosteroids are steroids synthetized in the nervous system, with the first step of steroidogene... more Neurosteroids are steroids synthetized in the nervous system, with the first step of steroidogenesis taking place within mitochondria with the synthesis of pregnenolone. They exert important brain-specific functions by playing a role in neurotransmission, learning and memory processes, and neuroprotection. Here, we show for the first time that mitochondrial neurosteroidogenesis follows a circadian rhythm and correlates with the rhythmic changes in mitochondrial morphology. We used synchronized human A172 glioma cells, which are steroidogenic cells with a functional core molecular clock, to show that pregnenolone levels and translocator protein (TSPO) are controlled by the clock, probably via circadian regulation of mitochondrial fusion/fission. Key findings were recapitulated in mouse brains. We also showed that genetic or pharmacological abrogation of fusion/fission activity, as well as disturbing the core molecular clock, abolished circadian rhythms of pregnenolone and TSPO. Our f...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting more than 47.5 mil... more Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting more than 47.5 million people worldwide. Metabolic impairments are common hallmarks of AD, and amyloid-β (Aβ) peptide and hyperphosphorylated tau protein-the two foremost histopathological signs of AD-have been implicated in mitochondrial dysfunction. Many neurodegenerative disorders, including AD, show excessive amounts of mis-/unfolded proteins leading to an activation of the unfolded protein response (UPR). In the present study, we aimed to characterize the link between ER stress and bioenergetics defects under normal condition (human SH-SY5Y neuroblastoma cells: control cells) or under pathological AD condition [SH-SY5Y cells overexpressing either the human amyloid precursor protein (APP) or mutant tau (P301L)]. More specifically, we measured UPR gene expression, cell viability, and bioenergetics parameters, such as ATP production and mitochondrial membrane potential (MMP) in basal condition and after an induced ER stress by thapsigargin. We detected highly activated UPR and dysregulated bioenergetics in basal condition in both AD cellular models. Strikingly, acute-induced ER stress increased the activity of the UPR in both AD cellular models, leading to up-regulation of apoptotic pathways, and further dysregulated mitochondrial function.
Mitochondrial fission-fusion dynamics and mitochondrial bioenergetics, including oxidative phosph... more Mitochondrial fission-fusion dynamics and mitochondrial bioenergetics, including oxidative phosphorylation and generation of ATP, are strongly clock controlled. Here we show that these circadian oscillations depend on circadian modification of dynamin-related protein 1 (DRP1), a key mediator of mitochondrial fission. We used a combination of in vitro and in vivo models, including human skin fibroblasts and DRP1-deficient or clock-deficient mice, to show that these dynamics are clock controlled via circadian regulation of DRP1. Genetic or pharmacological abrogation of DRP1 activity abolished circadian network dynamics and mitochondrial respiratory activity and eliminated circadian ATP production. Pharmacological silencing of pathways regulating circadian metabolism and mitochondrial function (e.g., sirtuins, AMPK) also altered DRP1 phosphorylation, and abrogation of DRP1 activity impaired circadian function. Our findings provide new insight into the crosstalk between the mitochondria...
Starting from the central benzodiazepine receptor (CBR) ligand CGS‐13767, we designed a series of... more Starting from the central benzodiazepine receptor (CBR) ligand CGS‐13767, we designed a series of imidazoquinazolinone derivatives acting as 18 kDa translocator protein (TSPO) ligands, and deprived of affinity for CBR. These compounds, as well as ligands of reference (Ro5‐4864, XBD173, SSR180575), were assessed for their ability to restore neurosteroidogenesis and energy production in SH‐SY5Y neuroblastoma cell lines expressing amyloid protein precursor (APP). Our results show the potential neuroprotective effect of TSPO ligands, but highlight a strong discrepancy in the active concentrations, nanomolar for ATP production while pregnenolone production is restored in the micromolar range.
Aging is defined as a progressive time‐related accumulation of changes responsible for or at leas... more Aging is defined as a progressive time‐related accumulation of changes responsible for or at least involved in the increased susceptibility to disease and death. The brain seems to be particularly sensitive to the aging process since the appearance of neurodegenerative diseases, including Alzheimer's disease, is exponential with the increasing age. Mitochondria were placed at the center of the ‘free‐radical theory of aging’, because these paramount organelles are not only the main producers of energy in the cells, but also to main source of reactive oxygen species. Thus, in this review, we aim to look at brain aging processes from a mitochondrial point of view by asking: (i) What happens to brain mitochondrial bioenergetics and dynamics during aging? (ii) Why is the brain so sensitive to the age‐related mitochondrial impairments? (iii) Is there a sex difference in the age‐induced mitochondrial dysfunction? Understanding mitochondrial physiology in the context of brain aging may ...
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Papers by Amandine Grimm