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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.

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 findings provide new insights into the crosstalk between mitochondrial function (here, neurosteroidogenesis) and circadian cycles.

Summary: Neurons are highly dependent on mitochondria, but little is known about how they react to a local mitochondrial oxidative insult. We therefore developed a protocol in primary hippocampal cultures that combines the photosensitizer mito-KillerRed with fluorescent biosensors and photoactivatable GFP. We found in both the soma and dendrites that neurons restrict the local increase in mitochondria-derived reactive oxygen species and the decrease in ATP production to the damaged compartment, by quarantining mitochondria. Although the cytosol of both the soma and dendrites became oxidized after mito-KillerRed activation, dendrites were more sensitive to the oxidative insult. Importantly, the impaired mitochondria exhibited decreased motility and fusion, thereby avoiding the spread of oxidation throughout the neuron. These results establish how neurons manage oxidative damage and increase our understanding about the somatodendritic regulation of mitochondrial functions after a local oxidative insult. : Physiology; Neuroscience; Cell Biology Subject Areas: Physiology, Neuroscience, Cell Biology

Background: Gelsemium sempervirens (GS) is a traditional medicinal plant, described at ultra-low doses as a remedy for a variety of psychological and behavioral symptoms of anxiety and depression. Changes in neural plasticity have been shown to play a significant role in the onset and development of those mental illnesses. Mitochondria play an extremely important role in the central nervous system by being the main energy producer through the oxidative phosphorylation and being involved particularly in the regulation of cell survival or death, as well as synaptic plasticity. Neurite outgrowth is the differentiation process by which neurons establish synapses through the protrusion of neurons and their extension. Methods: Because the effects of GS dilutions on mitochondrial function and neuroplasticity remain elusive, we aimed to investigate whether a treatment with GS at low doses (centesimal dilutions, C) improved bioenergetics parameters such as ATP production, mitochondrial respiration as well as cellular glycolysis before to characterize its effects on neurite outgrowth. Nerve growth factor (NGF), which is known as a promotor of cell growth and survival, was used as a positive control. Results: Our results demonstrate that GS dilutions (3C and 5C) efficiently ameliorated the bioenergetics of SH-SY5Y neuroblastoma cells by increasing cellular ATP level and mitochondrial respiration as well as promoting the cell survival. In addition, GS dilutions significantly improved neurite extension in the 2D as well as 3D culture model after 3 days of treatment. 3C and 5C dilutions showed similar functional effects than those obtained with the positive control nerve growth factor (NGF). Conclusions: These findings indicate that GS dilutions modulate the mitochondrial bioenergetic phenotype and improve the neurite formation. The mitochondrial function improving properties of GS dilutions might represent one possible important pathway contributing to its neuroprotective effectiveness. Key words: Gelsemium dilutions, mitochondria, bioenergetics, neurite outgrowth.

BackgroundStandardized Ginkgo biloba extract (GBE) has demonstrated efficacy in the cognitive functional neuropsychiatric symptoms of patients with Alzheimer's disease (AD). With regard to its underlying molecular mode of action, first evidence was provided that GBE was able to modulate neuronal outgrowth in vitro, but the mechanisms underlying GBE effects on neuroplasticity remain unclear.Methodology/principal findingsIn this study, we investigated the effect of GBE on neurite outgrowth using SH-SY5Y neuroblastoma cells in a 2D and 3D surface culture. The effects of the GBE LI1370 on neuroplasticity and neurite outgrowth were compared to those of nerve growth factor (NGF, 50 ng/ml) which was used as a positive control. We evaluated several parameters of neurite outgrowth such as the neurite number, total neurite length and extend of branching. Our findings showed that GBE (10 and 100 μg/ml) significantly increased neurite outgrowth in the 2D as well as 3D culture model after 3 days of treatment with a comparable effect than that NGF. The use of the 3D cell culture allowed us to better reproduce the in vivo neuronal microenvironment for the evaluation the neurite formation after GBE treatment. In addition, we assessed the effects of GBE on the Akt/mTOR pathway, which is known to promote neuroplasticity induced by nerve growth factors. We showed that GBE treatment induced an increase of phosphorylated IGF1R (Tyr1135/Tyr1136), Akt (Ser473), TSC2 (Ser939), mTOR (Ser2448), PTEN (Ser380) and GSK3β (Ser9).ConclusionTogether, these findings indicate that GBE promotes neurite growth and activates the PI3K/Akt/mTOR pathway suggesting that this plant extract supports neuronal plasticity.

International audience; Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expression is upregulated in neuropathologies such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands based on an imidazoquinazolinone termed 2a and 2b, stimulated pregnenolone synthesis and ATP production in vitro. In the present study, we compared their effects to those of TSPO ligands described in the literature (XBD173, SSR-180,575, and Ro5-4864) by profiling the mitochondrial bioenergetic phenotype before and after treatment and investigating the protective effects of these ligands after oxidative injury in a cellular model of AD overexpressing amyloid-β (Aβ). Of note, ATP levels increased with rising pregnenolone levels suggesting that the energetic performance of mitochondria is linked to an increased production of this neurosteroid via TSPO modulation. Our results further demonstrate that the TSPO ligands 2a and 2b exerted neuroprotective effects by improving mitochondrial respiration, reducing reactive oxygen species and thereby decreasing oxidative stress-induced cell death as well as lowering Aβ levels. The compounds 2a and 2b show similar or even better functional effects than those obtained with the reference TSPO ligands XBD173 and SSR-180.575. These findings indicate that the new TSPO ligands modulate mitochondrial bioenergetic phenotype and protect against oxidative injury probably through the de novo synthesis of neurosteroids, suggesting that these compounds could be potential new therapeutic tools for the treatment of neurodegenerative disease.

Alzheimer’s disease (AD) is the most common form of dementia affecting people mainly in their sixth decade of life and at a higher age. It is an extensively studied neurodegenerative disorder yet incurable to date. While its main postmortem brain hallmarks are the presence of amyloid-βplaques and hyperphosphorylated tau tangles, the onset of the disease seems to be largely correlated to mitochondrial dysfunction, an early event in the disease pathogenesis. AD is characterized by flawed energy metabolism in the brain and excessive oxidative stress, processes that involve less adenosine triphosphate (ATP) and more reactive oxygen species (ROS) production respectively. Mitochondria are at the center of both these processes as they are responsible for energy and ROS generation through mainly oxidative phosphorylation. StandardizedGinkgo bilobaextract (GBE), resveratrol, and phytoestrogens as well as the neurosteroid allopregnanolone have shown not only some mitochondria-modulating properties but also significant antioxidant potential inin vitroandin vivostudies. According to our review of the literature, GBE, resveratrol, allopregnanolone, and phytoestrogens showed promising effects on mitochondria in a descending evidence order and, notably, this order pattern is in line with the existing clinical evidence level for each entity. In this review, the effects of these four entities are discussed with special focus on their mitochondria-modulating effects and their mitochondria-improving and antioxidant properties across the spectrum of cognitive decline-related disorders. Evidence from preclinical and clinical studies on their mechanisms of action are summarized and highlighted.

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 neurosteroidogenesis, as well as on the endoplasmic reticulum-mitochondria coupling. A better understanding of the pathomechanisms of abnormal tau-induced mitochondrial failure may help to identify new targets for therapeutic interventions.

Translocator protein 18 kDa (TSPO) is a mitochondrial protein located in the outer membrane and involved in cholesterol translocation, a prerequisite for steroid biosynthesis. TSPO modulation also appears to play a role in other mitochondrial functions, including mitochondrial respiration and cell survival. In the central nervous system, its expression is up‐regulated in neuropathology such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands, named 2a and 2b, stimulated pregnenolone synthesis and ATP production in a cellular model of AD overproducing β‐amyloid peptide. The present study aimed to evaluate the impact of the new TSPO ligands on mitochondrial dysfunction in a cellular model of AD‐related tauopathy (human neuroblastoma cells SH‐SY5Y stably overexpressing the P301L‐mutant Tau) presenting mitochondrial impairments, including a decreased ATP synthesis and mitochondrial membrane potential, as well as a decrease in pregnenolone synthesis compared to control cells. The effects of our new ligands were compared with those of TSPO ligands described in the literature (XBD173, SSR‐180,575 and Ro5‐4864). The TSPO ligands 2a and 2b exerted beneficial mitochondrial modulatory effects by increasing ATP levels and mitochondrial membrane potential, paralleled by an increase of pregnenolone levels in mutant Tau cells, as well as in control cells. The compounds 2a and 2b showed effects on mitochondrial activity similar to those obtained with the TSPO ligands of reference. These findings indicate that the new TSPO ligands modulate the mitochondrial bioenergetic phenotype as well as the de novo synthesis of neurosteroids in a cellular model of AD‐related tauopathy, suggesting that these compounds could be potential new therapeutic tools for the treatment of AD.

Alzheimer’s disease (AD) is the most common form of dementia affecting people mainly in their sixth decade of life and at a higher age. It is an extensively studied neurodegenerative disorder yet incurable to date. While its main postmortem brain hallmarks are the presence of amyloid-β plaques and hyperphosphorylated tau tangles, the onset of the disease seems to be largely correlated to mitochondrial dysfunction, an early event in the disease pathogenesis. AD is characterized by flawed energy metabolism in the brain and excessive oxidative stress, processes that involve less adenosine triphosphate (ATP) and more reactive oxygen species (ROS) production respectively. Mitochondria are at the center of both these processes as they are responsible for energy and ROS generation through mainly oxidative phosphorylation. Standardized Ginkgo biloba extract (GBE), resveratrol, and phytoestrogens as well as the neurosteroid allopregnanolone have shown not only some mitochondria-modulating properties but also significant antioxidant potential in in vitro and in vivo studies. According to our review of the literature, GBE, resveratrol, allopregnanolone, and phytoestrogens showed promising effects on mitochondria in a descending evidence order and, notably, this order pattern is in line with the existing clinical evidence level for each entity. In this review, the effects of these four entities are discussed with special focus on their mitochondria-modulating effects and their mitochondria-improving and antioxidant properties across the spectrum of cognitive decline-related disorders. Evidence from preclinical and clinical studies on their mechanisms of action are summarized and highlighted.

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. Electronic supplementary material The online version of this article (10.1007/s00018-019-03009-4) contains supplementary material, which is available to authorized users.

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 mitochondrial network and circadian cycles.

Mitochondria play an essential role in the generation of steroid hormones including the female sex hormones. These hormones are, in turn, able to modulate mitochondrial activities. Mitochondria possess crucial roles in cell maintenance, survival and well-being, because they are the main source of energy as well as of reactive oxygen species (ROS) within the cell. The impairment of these important organelles is one of the central features of aging. In women's health, estrogen plays an important role during adulthood not only in the estrous cycle, but also in the brain via neuroprotective, neurotrophic and antioxidant modes of action. The hypestrogenic state in the peri- as well as in the prolonged postmenopause might increase the vulnerability of elderly women to brain degeneration and age-related pathologies. However, the underlying mechanisms that affect these processes are not well elucidated. Understanding the relationship between estrogen and mitochondria might therefore provide better insights into the female aging process. Thus, in this review, we first describe mitochondrial dysfunction in the aging brain. Second, we discuss the estrogen-dependent actions on the mitochondrial activity, including recent evidence of the estrogen-brain-derived neurotrophic factor and estrogen-sirtuin 3 (SIRT3) pathways, as well as their potential implications during female aging.

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.

Ageing is an inevitable biological process that results in a progressive structural and functional decline, as well as biochemical alterations that altogether lead to reduced ability to adapt to environmental changes. As clock oscillations and clock-controlled rhythms are not resilient to the ageing process, ageing of the circadian system may also increase susceptibility to age-related pathologies such as Alzheimer's disease (AD). Besides the amyloid-beta protein (Aβ)-induced metabolic decline and neuronal toxicity in AD, numerous studies have demonstrated that the disruption of sleep and circadian rhythms is one of the common and earliest signs of the disease. In this study, we addressed the questions of whether Aβ contributes to an abnormal molecular circadian clock leading to a bioenergetic imbalance. For this purpose, we used different oscillator cellular models: human skin fibroblasts, human glioma cells, as well as mouse primary cortical and hippocampal neurons. We first evaluated the circadian period length, a molecular clock property, in the presence of different Aβ species. We report here that physiologically relevant Aβ1-42 concentrations ranging from 10nM to 500nM induced an increase of the period length in human skin fibroblasts, human A172 glioma cells as well as in mouse primary neurons whereas the reverse control peptide Aβ42-1, which is devoid of toxic action, did not influence the circadian period length within the same concentration range. To better understand the underlying mechanisms that are involved in the Aβ-related alterations of the circadian clock, we examined the cellular metabolic state in the human primary skin fibroblast model. Notably, under normal conditions, ATP levels displayed circadian oscillations, which correspond to the respective circadian pattern of mitochondrial respiration. In contrast, Aβ1-42 treatment provoked a strong dampening in the metabolic oscillations of ATP levels as well as mitochondrial respiration and, in addition, induced an increased oxidized state. Overall, we gain here new insights into the deleterious cycle involved in Aβ -induced decay of the circadian rhythms leading to metabolic deficits, which may contribute to the failure in mitochondrial energy metabolism associated with the pathogenesis of AD.

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 help identify therapeutic targets against neurodegeneration. This article is part of a series “Beyond Amyloid”.

Recent data indicate that Alzheimer's disease (AD) is associated with disturbances of the circadian rhythm in patients. We examined the effect of amyloid-β (Aβ) peptide, the main component of the senile plaques playing a critical role in the deregulation of calcium (Casup2+/sup) homeostasis in AD, on the circadian oscillation of cytosolic calcium (Casup2+/sup) levelsiiin vitro/i/i. The experiments we carried out in human primary skin fibroblasts. This cell line was previously shown to exhibit circadian rhythms of clock genes. Moreover, the basic clock properties of these peripheral cells closely mimic those measured physiologically and behaviorally in human and do not change during aging. In this study we showed that i) cytosolic Casup2+/suposcillations depend on the activation of purinergic P2X7 receptors; and ii) these oscillations are abolished in the presence of Aβ. In total, our new findings may help to deepen our understanding of the molecular mechanisms involved in AD-related circadian alterations.

The mammalian ShcA adaptor protein p66Shc is a key regulator of mitochondrial reactive oxygen species (ROS) production and has previously been shown to mediate amyloid β (Aβ)-peptide-induced cytotoxicity in vitro. Moreover, p66Shc is involved in mammalian longevity and lifespan determination as revealed in the p66Shc knockout mice, which are characterized by a 30% prolonged lifespan, lower ROS levels and protection from age-related impairment of physical and cognitive performance. In this study, we hypothesized a role for p66Shc in Aβ-induced toxicity in vivo and investigated the effects of genetic p66Shc deletion in the PSAPP transgenic mice, an established Alzheimer's disease mouse model of β-amyloidosis. p66Shc-ablated PSAPP mice were characterized by an improved survival and a complete rescue of Aβ-induced cognitive deficits at the age of 15 months. Importantly, these beneficial effects on survival and cognitive performance were independent of Aβ levels and amyloid plaque deposition, but were associated with improved brain mitochondrial respiration, a reversal of mitochondrial complex I dysfunction, restored adenosine triphosphate production and reduced ROS levels. The results of this study support a role for p66Shc in Aβ-related mitochondrial dysfunction and oxidative damage in vivo, and suggest that p66Shc ablation may be a promising novel therapeutic strategy against Aβ-induced toxicity and cognitive impairment.

Allopregnanolone (AP) is supposed to exert beneficial actions including anxiolysis, analgesia, neurogenesis and neuroprotection. However, although mitochondrial dysfunctions are evidenced in neurodegenerative diseases, AP actions against neurodegeneration-induced mitochondrial deficits have never been investigated. Also, the therapeutic exploitation of AP is limited by its difficulty to pass the liver and its rapid clearance after sulfation or glucuronidation of its 3-hydroxyl group. Therefore, the characterization of novel potent neuroprotective analogs of AP may be of great interest. Thus, we synthesized a set of AP analogs (ANS) and investigated their ability to counteract APP-overexpression-evoked bioenergetic deficits and to protect against oxidative stress-induced death of control and APP-transfected SH-SY5Y cells known as a reliable cellular model of Alzheimer's disease (AD). Especially, we examined whether ANS were more efficient than AP to reduce mitochondrial dysfunctions or bioenergetic decrease leading to neuronal cell death. Our results showed that the ANS BR 297 exhibits notable advantages over AP with regards to both protection of mitochondrial functions and reduction of oxidative stress. Indeed, under physiological conditions, BR 297 does not promote cell proliferation but efficiently ameliorates the bioenergetics by increasing cellular ATP level and mitochondrial respiration. Under oxidative stress situations, BR 297 treatment, which decreases ROS levels, improves mitochondrial respiration and cell survival, appears more potent than AP to protect control and APP-transfected cells against H2O2-induced death. Our findings lend further support to the neuroprotective effects of BR 297 emphasizing this analog as a promising therapeutic tool to counteract age- and AD-related bioenergetic deficits. journal article 2017 Mar 2016 12 13 imported

Significance: Alzheimer's disease (AD) is an age related progressive neurodegenerative disorder mainly affecting elderly individuals. The pathology of AD is characterized by amyloid plaques (aggregates of amyloid ß [Aß]) and neurofibrillary tangles (aggregates of tau) but the mechanisms underlying this dysfunction are still partially unclear. Recent Advances: A growing body of evidence supports mitochondrial dysfunction as a prominent and early chronic oxidative stress associated event that contributes to synaptic abnormalities and ultimately selective neuronal degeneration in AD. Critical Issues: In this review we discuss on the one hand whether mitochondrial decline observed in brain aging is a determinant event in the onset of AD and on the other hand the close interrelationship of this organelle with Aß and tau in the pathogenic process underlying AD. Moreover we summarize evidence from aging and Alzheimer models showing that the harmful trio "aging Aß and tau protein" triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation (OXPHOS) elevation of reactive oxygen species production and interaction with mitochondrial proteins contributing to the development and progression of the disease. Future Directions: The aging process may weaken the mitochondrial OXPHOS system in a more general way over many years providing a basis for the specific and destructive effects of Aß and tau. Establishing strategies involving efforts to protect cells at the mitochondrial level by stabilizing or restoring mitochondrial function and energy homeostasis appears to be challenging but very promising route on the horizon. Antioxid. Redox Signal. 16 1456 1466.

Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration.

Alzheimer's disease (AD) is characterized by the presence of amyloid plaques (aggregates of amyloid-β [Aβ]) and neurofibrillary tangles (aggregates of tau) in the brain, but the underlying mechanisms of the disease are still partially unclear. A growing body of evidence supports mitochondrial dysfunction as a prominent and early, chronic oxidative stress-associated event that contributes to synaptic abnormalities, and, ultimately, selective neuronal degeneration in AD. Using a high-resolution respirometry system, we shed new light on the close interrelationship of this organelle with Aβ and tau in the pathogenic process underlying AD by showing a synergistic effect of these two hallmark proteins on the oxidative phosphorylation capacity of mitochondria isolated from the brain of transgenic AD mice. In the present chapter, we first introduce the principle of the Aβ and tau interaction on mitochondrial respiration, and secondly, we describe in detail the used respiratory protocol.

Epidemiological studies revealed that two-thirds of Alzheimer's disease (AD) patients are women and the drop of sex steroid hormones after the menopause has been proposed to be one risk factor in AD. Similarly, the decrease of circulating testosterone levels with aging may also increase the risk of AD in men. Studies attest the neuroprotective effects of sex hormones in animal models of AD, but clinical trial data remain controversial. Here, we discuss the implication of mitochondria in gender differences observed in AD patients and animal models of AD. We summarize the role of mitochondria in aging and AD, pointing to the potential correlation between the loss of sex hormones and changes in the brain redox status. We discuss the protective effects of the sex hormones, estradiol, progesterone and testosterone with a specific focus on mitochondrial dysfunction in AD. The understanding of pathological processes linking the loss of sex hormones with mitochondrial dysfunction and mechanisms that initiate the disease onset may open new avenues for the development of gender-specific therapeutic approaches.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that represents the most common form of dementia among the elderly. Despite the fact that AD was studied for decades, the underlying mechanisms that trigger this neuropathology remain unresolved. Since the onset of cognitive deficits occurs generally within the 6th decade of life, except in rare familial case, advancing age is the greatest known risk factor for AD. To unravel the pathogenesis of the disease, numerous studies use cellular and animal models based on genetic mutations found in rare early onset familial AD (FAD) cases that represent less than 1 % of AD patients. However, the underlying process that leads to FAD appears to be distinct from that which results in late-onset AD. As a genetic disorder, FAD clearly is a consequence of malfunctioning/mutated genes, while late-onset AD is more likely due to a gradual accumulation of age-related malfunction. Normal aging and AD are both marked by defects in brain metabolism and increased oxidative stress, albeit to varying degrees. Mitochondria are involved in these two phenomena by controlling cellular bioenergetics and redox homeostasis. In the present review, we compare the common features observed in both brain aging and AD, placing mitochondrial in the center of pathological events that separate normal and pathological aging. We emphasize a bioenergetic model for AD including the inverse Warburg hypothesis which postulates that AD is a consequence of mitochondrial deregulation leading to metabolic reprogramming as an initial attempt to maintain neuronal integrity. After the failure of this compensatory mechanism, bioenergetic deficits may lead to neuronal death and dementia. Thus, mitochondrial dysfunction may represent the missing link between aging and sporadic AD, and represent attractive targets against neurodegeneration.

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 health and disease states associated with mitochondrial impairments and/or circadian disruption., Les mitochondries jouent un rôle primordial dans la survie et la mort cellulaire car elles gouvernent à la fois le métabolisme énergétique et les voies apoptotiques. Un dysfonctionnement mitochondrial dans les neurones peut donc conduire à la neurodégénérescence ou à une neuropathologie. Notre objectif a été d'étudier la régulation de la fonction mitochondriale, en particulier la bioénergétique, pour contribuer à l'amélioration des connaissances actuelles sur les mitochondries. Nos résultats montrent que: i) les neurostéroïdes améliorent la bioénergétique mitochondriale en stimulant la respiration cellulaire en condition normale; ii) les neurostéroïdes réduisent les déficits bioénergétiques observés dans la maladie d'Alzheimer; iii) l'horloge circadienne développe une régulation réciproque avec la bioénergétique et la dynamique mitochondriales. Les résultats de cette thèse ouvrent des perspectives intéressantes pour l'élaboration de stratégies régulatrices de l'homéostasie métabolique chez le sujet sain et chez le patient atteint d'une pathologie due à un dysfonctionnement mitochondrial et/ou une altération des rythmes biologiques.

Alzheimer's disease (AD) is a conformational disease that is characterized by amyloid-β (Aβ) deposition in the brain. Aβ exerts its toxicity in part by receptor-mediated interactions that cause down-stream protein misfolding and aggregation, as well as mitochondrial dysfunction. Recent reports indicate that Aβ may also interact directly with intracellular proteins such as the mitochondrial enzyme ABAD (Aβ binding alcohol dehydrogenase) in executing its toxic effects. Mitochondrial dysfunction occurs early in AD, and Aβ's toxicity is in part mediated by inhibition of ABAD as shown previously with an ABAD decoy peptide. Here, we employed AG18051, a novel small ABAD-specific compound inhibitor, to investigate the role of ABAD in Aβ toxicity. Using SH-SY5Y neuroblastoma cells, we found that AG18051 partially blocked the Aβ-ABAD interaction in a pull-down assay while it also prevented the Aβ42-induced down-regulation of ABAD activity, as measured by levels of estradiol, a known hormone and product of ABAD activity. Furthermore, AG18051 is protective against Aβ42 toxicity, as measured by LDH release and MTT absorbance. Specifically, AG18051 reduced Aβ42-induced impairment of mitochondrial respiration and oxidative stress as shown by reduced ROS (reactive oxygen species) levels. Guided by our previous finding of shared aspects of the toxicity of Aβ and human amylin (HA), with the latter forming aggregates in Type 2 diabetes mellitus (T2DM) pancreas, we determined whether AG18051 would also confer protection from HA toxicity. We found that the inhibitor conferred only partial protection from HA toxicity indicating distinct pathomechanisms of the two amyloidogenic agents. Taken together, our results present the inhibition of ABAD by compounds such as AG18051 as a promising therapeutic strategy for the prevention and treatment of AD, and suggest levels of estradiol as a suitable read-out. journal article research support, non-u.s. gov't 2011 2011 12 12 imported