Na+ controls hypoxic signalling by the mitochondrial respiratory chain.

All metazoans depend on the consumption of O2 by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O2 to produce reactive oxygen species that can drive cell adaptations1-4, a phenomenon that occurs in hypoxia4-8 and whose precise mechanism remains unknown. Ca2+ is the best known ion that acts as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential10. Here we show that Na+ acts as a second messenger that regulates OXPHOS function and the production of reactive oxygen species by modulating the fluidity of the inner mitochondrial membrane. A conformational shift in mitochondrial complex I during acute hypoxia11 drives acidification of the matrix and the release of free Ca2+ from calcium phosphate (CaP) precipitates. The concomitant activation of the mitochondrial Na+/Ca2+ exchanger promotes the import of Na+ into the matrix. Na+ interacts with phospholipids, reducing inner mitochondrial membrane fluidity and the mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III. The inhibition of Na+ import through the Na+/Ca2+ exchanger is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences for cellular metabolism.

Investigation in the cannabigerol derivative VCE-003.2 as a disease-modifying agent in a mouse model of experimental synucleinopathy.

BACKGROUND: The cannabigerol derivative VCE-003.2, which has activity at the peroxisome proliferator-activated receptor-γ has afforded neuroprotection in experimental models of Parkinson's disease (PD) based on mitochondrial dysfunction (6-hydroxydopamine-lesioned mice) and neuroinflammation (LPS-lesioned mice). Now, we aim to explore VCE-003.2 neuroprotective properties in a PD model that also involves protein dysregulation, other key event in PD pathogenesis. METHODS: To this end, an adeno-associated viral vector serotype 9 coding for a mutated form of the α-synuclein gene (AAV9-SynA53T) was unilaterally delivered in the substantia nigra pars compacta (SNpc) of mice. This model leads to motor impairment and progressive loss of tyrosine hydroxylase-labelled neurons in the SNpc. RESULTS: Oral administration of VCE-003.2 at 20 mg/kg for 14 days improved the performance of mice injected with AAV9-SynA53T in various motor tests, correlating with the preservation of tyrosine hydroxylase-labelled neurons in the SNpc. VCE-003.2 also reduced reactive microgliosis and astrogliosis in the SNpc. Furthermore, we conducted a transcriptomic analysis in the striatum of mice injected with AAV9-SynA53T and treated with either VCE-003.2 or vehicle, as well as control animals. This analysis aimed to identify gene families specifically altered by the pathology and/or VCE-003.2 treatment. Our data revealed pathology-induced changes in genes related to mitochondrial function, lysosomal cell pathways, immune responses, and lipid metabolism. In contrast, VCE-003.2 treatment predominantly affected the immune response through interferon signaling. CONCLUSION: Our study broadens the neuroprotective potential of VCE-003.2, previously described against mitochondrial dysfunction, oxidative stress, glial reactivity and neuroinflammation in PD. We now demonstrate its efficacy against another key pathogenic event in PD as α-synuclein dysregulation. Furthermore, our investigation sheds light on the molecular mechanisms underlying VCE-003.2 revealing its role in regulating interferon signaling. These findings, together with a favorable ADMET profile, enhance the preclinical interest of VCE-003.2 towards its future clinical development in PD.

Tensor decomposition of stimulated monocyte and macrophage gene expression profiles identifies neurodegenerative disease-specific trans-eQTLs.

Recent human genetic studies suggest that cells of the innate immune system have a primary role in the pathogenesis of neurodegenerative diseases. However, the results from these studies often do not elucidate how the genetic variants affect the biology of these cells to modulate disease risk. Here, we applied a tensor decomposition method to uncover disease associated gene networks linked to distal genetic variation in stimulated human monocyte and macrophage gene expression profiles. We report robust evidence that some disease associated genetic variants affect the expression of multiple genes in trans. These include a Parkinson's disease locus influencing the expression of genes mediated by a protease that controls lysosomal function, and Alzheimer's disease loci influencing the expression of genes involved in type 1 interferon signaling, myeloid phagocytosis, and complement cascade pathways. Overall, we uncover gene networks in induced innate immune cells linked to disease associated genetic variants, which may help elucidate the underlying biology of disease.

Multi-omic insights into Parkinson's Disease: From genetic associations to functional mechanisms.

Genome-Wide Association Studies (GWAS) have elucidated the genetic components of Parkinson's Disease (PD). However, because the vast majority of GWAS association signals fall within non-coding regions, translating these results into an interpretable, mechanistic understanding of the disease etiology remains a major challenge in the field. In this review, we provide an overview of the approaches to prioritize putative causal variants and genes as well as summarise the primary findings of previous studies. We then discuss recent efforts to integrate multi-omics data to identify likely pathogenic cell types and biological pathways implicated in PD pathogenesis. We have compiled full summary statistics of cell-type, tissue, and phentoype enrichment analyses from multiple studies of PD GWAS and provided them in a standardized format as a resource for the research community (https://github.com/RajLabMSSM/PD_omics_review). Finally, we discuss the experimental, computational, and conceptual advances that will be necessary to fully elucidate the effects of functional variants and genes on cellular dysregulation and disease risk.

Central Activation of Alpha7 Nicotinic Signaling Attenuates LPS-Induced Neuroinflammation and Sickness Behavior in Adult but Not in Aged Animals.

We previously reported that lipopolysaccharide (LPS) challenge caused microglial-mediated neuroinflammation and sickness behavior that was amplified in aged mice. As α7 nAChRs are implicated in the "Cholinergic anti-inflammatory pathway", we aimed to determine how α7 nAChR stimulation modulates microglial phenotype in an LPS-induced neuroinflammation model in adult and aged mice. For this, BALB/c mice were injected intraperitoneally with LPS (0.33 mg/kg) and treated with the α7 nAChR agonist PNU282987, using different administration protocols. LPS challenge reduced body weight and induced lethargy and social withdrawal in adult mice. Peripheral (intraperitoneal) co-administration of the α7 nAChR agonist PNU282987 with LPS, attenuated body weight loss and sickness behavior associated with LPS challenge in adult mice, and reduced microglial activation with suppression of IL-1ß and TNFα mRNA levels. Furthermore, central (intracerebroventricular) administration of the α7 nAChR agonist, even 2 h after LPS injection, attenuated the decrease in social exploratory behavior and microglial activation induced by peripheral administration of LPS, although this recovery was not achieved if activation of α7 nAChRs was performed peripherally. Finally, we observed that the positive results of central activation of α7 nAChRs were lost in aged mice. In conclusion, we provide evidence that stimulation of α7 nAChR signaling reduces microglial activation in an in vivo LPS-based model, but this cholinergic-dependent regulation seems to be dysfunctional in microglia of aged mice.

The APPswe/PS1A246E mutations in an astrocytic cell line leads to increased vulnerability to oxygen and glucose deprivation, Ca2+ dysregulation, and mitochondrial abnormalities.

Growing evidence suggests a close relationship between Alzheimer's Disease (AD) and cerebral hypoxia. Astrocytes play a key role in brain homeostasis and disease states, while some of the earliest changes in AD occur in astrocytes. We have therefore investigated whether mutations associated with AD increase astrocyte vulnerability to ischemia. Two astroglioma cell lines derived from APPSWE /PS1A246E (APP, amyloid precursor protein; PS1, presenilin 1) transgenic mice and controls from normal mice were subjected to oxygen and glucose deprivation (OGD), an in vitro model of ischemia. Cell death was increased in the APPSWE /PS1A246E line compared to the control. Increasing extracellular calcium concentration ([Ca2+ ]) exacerbated cell death in the mutant but not in the control cells. In order to explore cellular Ca2+ homeostasis, the cells were challenged with ATP or thapsigargin and [Ca2+ ] was measured by fluorescence microscopy. Changes in cytosolic Ca2+ concentration ([Ca2+ ]c ) were potentiated in the APPSWE /PS1A246E transgenic line. Mitochondrial function was also altered in the APPSWE /PS1A246E astroglioma cells; mitochondrial membrane potential and production of reactive oxygen species were increased, while mitochondrial basal respiratory rate and ATP production were decreased compared to control astroglioma cells. These results suggest that AD mutations in astrocytes make them more sensitive to ischemia; Ca2+ dysregulation and mitochondrial dysfunction may contribute to this increased vulnerability. Our results also highlight the role of astrocyte dyshomeostasis in the pathophysiology of neurodegenerative brain disorders.

Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge.

Activation of the peripheral immune system elicits a coordinated response from the central nervous system. Key to this immune to brain communication is that glia, microglia, and astrocytes, interpret and propagate inflammatory signals in the brain that influence physiological and behavioral responses. One issue in glial biology is that morphological analysis alone is used to report on glial activation state. Therefore, our objective was to compare behavioral responses after in vivo immune (lipopolysaccharide, LPS) challenge to glial specific mRNA and morphological profiles. Here, LPS challenge induced an immediate but transient sickness response with decreased locomotion and social interaction. Corresponding with active sickness behavior (2-12 h), inflammatory cytokine mRNA expression was elevated in enriched microglia and astrocytes. Although proinflammatory cytokine expression in microglia peaked 2-4 h after LPS, astrocyte cytokine, and chemokine induction was delayed and peaked at 12 h. Morphological alterations in microglia (Iba-1(+)) and astrocytes (GFAP(+)), however, were undetected during this 2-12 h timeframe. Increased Iba-1 immunoreactivity and de-ramified microglia were evident 24 and 48 h after LPS but corresponded to the resolution phase of activation. Morphological alterations in astrocytes were undetected after LPS. Additionally, glial cytokine expression did not correlate with morphology after four repeated LPS injections. In fact, repeated LPS challenge was associated with immune and behavioral tolerance and a less inflammatory microglial profile compared with acute LPS challenge. Overall, induction of glial cytokine expression was sequential, aligned with active sickness behavior, and preceded increased Iba-1 or GFAP immunoreactivity after LPS challenge.

Positive allosteric modulation of alpha-7 nicotinic receptors promotes cell death by inducing Ca(2+) release from the endoplasmic reticulum.

Positive allosteric modulation of α7 isoform of nicotinic acetylcholine receptors (α7-nAChRs) is emerging as a promising therapeutic approach for central nervous system disorders such as schizophrenia or Alzheimer's disease. However, its effect on Ca(2+) signaling and cell viability remains controversial. This study focuses on how the type II positive allosteric modulator (PAM II) PNU120596 affects intracellular Ca(2+) signaling and cell viability. We used human SH-SY5Y neuroblastoma cells overexpressing α7-nAChRs (α7-SH) and their control (C-SH). We monitored cytoplasmic and endoplasmic reticulum (ER) Ca(2+) with Fura-2 and the genetically encoded cameleon targeting the ER, respectively. Nicotinic inward currents were measured using patch-clamp techniques. Viability was assessed using methylthiazolyl blue tetrazolium bromide or propidium iodide staining. We observed that in the presence of a nicotinic agonist, PNU120596 (i) reduced viability of α7-SH but not of C-SH cells; (ii) significantly increased inward nicotinic currents and cytosolic Ca(2+) concentration; (iii) released Ca(2+) from the ER by a Ca(2+) -induced Ca(2+) release mechanism only in α7-SH cells; (iv) was cytotoxic in rat organotypic hippocampal slice cultures; and, lastly, all these effects were prevented by selective blockade of α7-nAChRs, ryanodine receptors, or IP3 receptors. In conclusion, positive allosteric modulation of α7-nAChRs with the PAM II PNU120596 can lead to dysregulation of ER Ca(2+) , overloading of intracellular Ca(2+) , and neuronal cell death. This study focuses on how the type II positive allosteric modulator PNU120596 (PAM II PNU12) affects intracellular Ca(2+) signaling and cell viability. Using SH-SY5Y neuroblastoma cells overexpressing α7-nAChRs (α7-SH) and their control (C-SH), we find that PAM of α7-nAChRs with PNU120596: (i) increases inward calcium current (ICa ) and cytosolic Ca(2+) concentration ([Ca(2+) ]cyt ); (ii) releases Ca(2+) from the ER ([Ca(2+) ]ER ) by a Ca(2+) -induced Ca(2+) release mechanism; and (iv) reduces cell viability. These findings were corroborated in rat hippocampal organotypic cultures. [Ca(2+) ]cyt , cytosolic Ca(2+) concentration; [Ca(2+) ]ER , endoplasmic reticulum Ca(2+) concentration; α7 nAChR, α7 isoform of nicotinic acetylcholine receptors; α7-SH, SH-SY5Y stably overexpressing α7 nAChRs cells; C-SH, control SH-SY5Y cells; Nic, nicotine; PNU12, PNU120596.

A new mutation in the Parkinson's-related FBXO7 gene impairs mitochondrial and proteasomal function.

Around 10% of Parkinson's disease (PD) cases are associated with mutations in various genes, including FBXO7, which encodes the substrate-recognition component for the Skp1-Cullin-F-box (SCF) class of ubiquitin E3 ligases that target proteins for proteasomal degradation. In their recent study, Al Rawi et al. characterized a new mutation in FBXO7, L250P, in a pediatric patient. Their findings reveal that the L250P mutation abolishes Fbxo7 interaction with the proteasome regulator, proteasome inhibitor 31kD (PI31), affecting proteasomal activity and the ubiquitination of some of the ligase's targets. Furthermore, the authors show that this previously undescribed mutation impairs mitochondrial function and mitophagy, emphasizing the importance of mitochondrial and proteasomal dysfunction in PD pathogenesis.

The mitochondrial Na+/Ca2+ exchanger NCLX is implied in the activation of hypoxia-inducible factors.

Eukaryotic cells and organisms depend on oxygen for basic living functions, and they display a panoply of adaptations to situations in which oxygen availability is diminished (hypoxia). A number of these responses in animals are mediated by changes in gene expression programs directed by hypoxia-inducible factors (HIFs), whose main mechanism of stabilization and functional activation in response to decreased cytosolic oxygen concentration was elucidated two decades ago. Human acute responses to hypoxia have been known for decades, although their precise molecular mechanism for oxygen sensing is not fully understood. It is already known that a redox component, linked with reactive oxygen species (ROS) production of mitochondrial origin, is implied in these responses. We have recently described a mechanism by which the mitochondrial sodium/calcium exchanger, NCLX, participates in mitochondrial electron transport chain regulation and ROS production in response to acute hypoxia. Here we show that NCLX is also implied in the response to hypoxia mediated by the HIFs. By using a NCLX inhibitor and interference RNA we show that NCLX activity is necessary for HIF-α subunits stabilization in hypoxia and for HIF-1-dependent transcriptional activity. We also show that hypoxic mitochondrial ROS production is not required for HIF-1α stabilization under all circumstances, suggesting that the basal cytosolic redox state or other mechanism(s) could be operating in the NCLX-mediated response to hypoxia that operates through HIF-α stabilization. This finding provides a link between acute and medium-term responses to hypoxia, reinforcing a central role of mitochondrial cell signalling in the response to hypoxia.

LRRK2 G2019S variant is associated with transcriptional changes in Parkinson's disease human myeloid cells under proinflammatory environment.

The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is a major risk factor for the development of Parkinson's disease (PD). LRRK2, although ubiquitously expressed, is highly abundant in cells of the innate immune system. Given the importance of central and peripheral immune cells in the development of PD, we sought to investigate the consequences of the G2019S mutation on microglial and monocyte transcriptome and function. We have generated large-scale transcriptomic profiles of isogenic human induced microglial cells (iMGLs) and patient derived monocytes carrying the G2019S mutation under baseline culture conditions and following exposure to the proinflammatory factors IFNγ and LPS. We demonstrate that the G2019S mutation exerts a profound impact on the transcriptomic profile of these myeloid cells, and describe corresponding functional differences in iMGLs. The G2019S mutation led to an upregulation in lipid metabolism and phagolysosomal pathway genes in untreated and LPS/IFNγ stimulated iMGLs, which was accompanied by an increased phagocytic capacity of myelin debris. We also identified dysregulation of cell cycle genes, with a downregulation of the E2F4 regulon. Transcriptomic characterization of human-derived monocytes carrying the G2019S mutation confirmed alteration in lipid metabolism associated genes. Altogether, these findings reveal the influence of G2019S on the dysregulation of the myeloid cell transcriptome under proinflammatory conditions.

The Cannabigerol Derivative VCE-003.2 Exerts Therapeutic Effects in 6-Hydroxydopamine-Lesioned Mice: Comparison with The Classic Dopaminergic Replacement Therapy.

(1) Background: A cannabigerol aminoquinone derivative, so-called VCE-003.2, has been found to behave as a neuroprotective agent (administered both i.p. and orally) in different experimental models of Parkinson's disease (PD) in mice. These effects were exerted through mechanisms that involved the activation of a regulatory site within the peroxisome proliferator-activated receptor-γ (PPAR-γ). (2) Methods: We are now interested in comparing such neuroprotective potential of VCE-003.2, orally administered, with the effect of the classic dopaminergic replacement therapy with L-DOPA/benserazide in similar conditions, using 6-hydroxydopamine-lesioned mice. (3) Results: The oral administration of VCE-003.2 during 14 days at the dose of 20 mg/kg improved, as expected, the neurological status (measured in motor tests) in these mice. This correlated with a preservation of TH-labelled neurons in the substantia nigra. By contrast, the treatment with L-DOPA/benserazide (during 7 days at 2 mg/kg) was significantly less active in these experimental conditions, in concordance with their profile as a mere symptom-alleviating agent. (4) Conclusions: Our results confirmed again the therapeutic profile of VCE-003.2 in experimental PD and revealed a different and more relevant effect, as a disease modifier, compared to the classic symptom-alleviating L-DOPA treatment. This reinforces the interest in VCE-003.2 for a future clinical development in this disease.

Endocannabinoid-Binding Receptors as Drug Targets.

Cannabis plant has been used from ancient times with therapeutic purposes for treating human pathologies, but the identification of the cellular and molecular mechanisms underlying the therapeutic properties of the phytocannabinoids, the active compounds in this plant, occurred in the last years of the past century. In the late 1980s and early 1990s, seminal studies demonstrated the existence of cannabinoid receptors and other elements of the so-called endocannabinoid system. These G protein-coupled receptors (GPCRs) are a key element in the functions assigned to endocannabinoids and appear to serve as promising pharmacological targets. They include CB1, CB2, and GPR55, but also non-GPCRs can be activated by endocannabinoids, like ionotropic receptor TRPV1 and even nuclear receptors of the PPAR family. Their activation, inhibition, or simply modulation have been associated with numerous physiological effects at both central and peripheral levels, which may have therapeutic value in different human pathologies, then providing a solid experimental explanation for both the ancient medicinal uses of Cannabis plant and the recent advances in the development of cannabinoid-based specific therapies. This chapter will review the scientific knowledge generated in the last years around the research on the different endocannabinoid-binding receptors and their signaling mechanisms. Our intention is that this knowledge may help readers to understand the relevance of these receptors in health and disease conditions, as well as it may serve as the theoretical basis for the different experimental protocols to investigate these receptors and their signaling mechanisms that will be described in the following chapters.

Long-read RNA-seq atlas of novel microglia isoforms elucidates disease-associated genetic regulation of splicing.

Microglia, the innate immune cells of the central nervous system, have been genetically implicated in multiple neurodegenerative diseases. We previously mapped the genetic regulation of gene expression and mRNA splicing in human microglia, identifying several loci where common genetic variants in microglia-specific regulatory elements explain disease risk loci identified by GWAS. However, identifying genetic effects on splicing has been challenging due to the use of short sequencing reads to identify causal isoforms. Here we present the isoform-centric microglia genomic atlas (isoMiGA) which leverages the power of long-read RNA-seq to identify 35,879 novel microglia isoforms. We show that the novel microglia isoforms are involved in stimulation response and brain region specificity. We then quantified the expression of both known and novel isoforms in a multi-ethnic meta-analysis of 555 human microglia short-read RNA-seq samples from 391 donors, the largest to date, and found associations with genetic risk loci in Alzheimer's disease and Parkinson's disease. We nominate several loci that may act through complex changes in isoform and splice site usage.

Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies.

Microglia have emerged as important players in brain aging and pathology. To understand how genetic risk for neurological and psychiatric disorders is related to microglial function, large transcriptome studies are essential. Here we describe the transcriptome analysis of 255 primary human microglial samples isolated at autopsy from multiple brain regions of 100 individuals. We performed systematic analyses to investigate various aspects of microglial heterogeneities, including brain region and aging. We mapped expression and splicing quantitative trait loci and showed that many neurological disease susceptibility loci are mediated through gene expression or splicing in microglia. Fine-mapping of these loci nominated candidate causal variants that are within microglia-specific enhancers, finding associations with microglial expression of USP6NL for Alzheimer's disease and P2RY12 for Parkinson's disease. We have built the most comprehensive catalog to date of genetic effects on the microglial transcriptome and propose candidate functional variants in neurological and psychiatric disorders.

Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson's disease.

BACKGROUND: Genetic mutations in beta-glucocerebrosidase (GBA) represent the major genetic risk factor for Parkinson's disease (PD). GBA participates in both the endo-lysosomal pathway and the immune response, two important mechanisms involved in the pathogenesis of PD. However, modifiers of GBA penetrance have not yet been fully elucidated. METHODS: We characterized the transcriptomic profiles of circulating monocytes in a population of patients with PD and healthy controls (CTRL) with and without GBA variants (n = 23 PD/GBA, 13 CTRL/GBA, 56 PD, 66 CTRL) and whole blood (n = 616 PD, 362 CTRL, 127 PD/GBA, 165 CTRL/GBA). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Ultrastructural characterization of isolated CD14+ monocytes in the four groups was also performed through electron microscopy. RESULTS: We observed hundreds of differentially expressed genes and dysregulated pathways when comparing manifesting and non-manifesting GBA mutation carriers. Specifically, when compared to idiopathic PD, PD/GBA showed dysregulation in genes involved in alpha-synuclein degradation, aging and amyloid processing. Gene-based outlier analysis confirmed the involvement of lysosomal, membrane trafficking, and mitochondrial processing in manifesting compared to non-manifesting GBA-carriers, as also observed at the ultrastructural levels. Transcriptomic results were only partially replicated in an independent cohort of whole blood samples, suggesting cell-type specific changes. CONCLUSIONS: Overall, our transcriptomic analysis of primary monocytes identified gene targets and biological processes that can help in understanding the pathogenic mechanisms associated with GBA mutations in the context of PD.

Dysregulation of mitochondrial and proteolysosomal genes in Parkinson's disease myeloid cells.

An increasing number of identified Parkinson's disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their role in pathology is not understood. We hypothesize that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To address this, we have generated transcriptomic profiles of monocytes from 230 individuals with sporadic PD and healthy subjects. We observed a dysregulation of mitochondrial and proteasomal pathways. We also generated transcriptomic profiles of primary microglia from brains of 55 subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified 17 PD susceptibility genes whose expression, relative to each risk allele, is altered in monocytes. These findings reveal widespread transcriptomic alterations in PD monocytes, with some being distinct from microglia, and facilitate efforts to understand the roles of myeloid cells in PD as well as the development of biomarkers.

[Prevalence and profile of the frail population in La Palma, Canary Islands]. / Prevalencia y perfil de la persona frágil en la isla de La Palma.

INTRODUCTION: Population ageing requires that health and social systems focus their attention on identifying frailty in the elderly. In the Canary Islands, there are no studies to determine the prevalence of frailty among its population. The objective of this study is to determine the prevalence and profile of frailty in the island of La Palma, Canary Islands, Spain. MATERIAL AND METHOD: A cross-sectional study was conducted to estimate the prevalence and the profile of frailty. The sample were residents over 70 years old, valued by the Fried criteria, and taking into account other related factors. The prevalence is offered with a confidence interval of 95% and is compared with that of other Spanish populations. To determine the profile, a simple comparison of variables was made, followed by using them in logistic regression models. All the tests were bilateral at a P≤0.05 level. RESULTS: The prevalence of frailty in people over 70 years was estimated at 20% (17-23%). This prevalence shows differences with those of other Spanish populations. The factors that showed a relationship with frailty were, being female, widowed, living alone, low physical activity, cognitive impairment, depression, polymedication, and adverse clinical history. Multivariate analysis identifies factors associated with the frailty variables related to marital status, co-existence, polypharmacy, depressive states, and lack of physical exercise. CONCLUSIONS: The elderly population of La Palma have greater frailty compared to that described in other regions of Spain, with their profile being that of a widowed person, with depression, polymedicated, living alone, and not exercising.

Mitochondrial complex I deactivation is related to superoxide production in acute hypoxia.

Mitochondria use oxygen as the final acceptor of the respiratory chain, but its incomplete reduction can also produce reactive oxygen species (ROS), especially superoxide. Acute hypoxia produces a superoxide burst in different cell types, but the triggering mechanism is still unknown. Herein, we show that complex I is involved in this superoxide burst under acute hypoxia in endothelial cells. We have also studied the possible mechanisms by which complex I could be involved in this burst, discarding reverse electron transport in complex I and the implication of PTEN-induced putative kinase 1 (PINK1). We show that complex I transition from the active to 'deactive' form is enhanced by acute hypoxia in endothelial cells and brain tissue, and we suggest that it can trigger ROS production through its Na+/H+ antiporter activity. These results highlight the role of complex I as a key actor in redox signalling in acute hypoxia.

Heme-Oxygenase I and PCG-1α Regulate Mitochondrial Biogenesis via Microglial Activation of Alpha7 Nicotinic Acetylcholine Receptors Using PNU282987.

AIMS: A loss in brain acetylcholine and cholinergic markers, subchronic inflammation, and impaired mitochondrial function, which lead to low-energy production and high oxidative stress, are common pathological factors in several neurodegenerative diseases (NDDs). Glial cells are important for brain homeostasis, and microglia controls the central immune response, where α7 acetylcholine nicotinic receptors (nAChR) seem to play a pivotal role; however, little is known about the effects of this receptor in metabolism. Therefore, the aim of this study was to evaluate if glial mitochondrial energetics could be regulated through α7 nAChR. RESULTS: Primary glial cultures treated with the α7 nicotinic agonist PNU282987 increased their mitochondrial mass and their mitochondrial oxygen consumption without increasing oxidative stress; these changes were abolished when nuclear erythroid 2-related factor 2 (Nrf2) was absent, heme oxygenase-1 (HO-1) was inhibited, or peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) was silenced. More specifically, microglia of animals treated intraperitoneally with the α7 nAChR agonist PNU282987 (10 mg/kg) showed a significant increase in mitochondrial mass. Interestingly, LysMcre-Hmox1Δ/Δ and PGC-1α-/- animals showed lower microglial mitochondrial levels and treatment with PNU282987 did not produce effects on mitochondrial levels. INNOVATION: Increases in microglial mitochondrial mass and metabolism can be achieved via α7 nAChR by a mechanism that implicates Nrf2, HO-1, and PGC-1α. This signaling pathway could open a new strategy for the treatment of NDDs, such as Alzheimer's, characterized by a reduction of cholinergic markers. CONCLUSION: α7 nAChR signaling increases glial mitochondrial mass, both in vitro and in vivo, via HO-1 and PCG-1α. These effects could be of potential benefit in the context of NDDs. Antioxid. Redox Signal. 27, 93-105.