bims-brabim 2021-12-26 papers

bims-brabim

Biomed News

on Brain bioenergetics and metabolism

Issue of 2021–12–26
twenty papers selected by
João Victor Cabral-Costa, University of São Paulo

Directly Reprogrammed Human Neurons to Understand Age-Related Energy Metabolism Impairment and Mitochondrial Dysfunction in Healthy Aging and Neurodegeneration.
The Impact of Medium Chain and Polyunsaturated ω-3-Fatty Acids on Amyloid-β Deposition, Oxidative Stress and Metabolic Dysfunction Associated with Alzheimer's Disease.
Mitophagy in neurological disorders.
Intermittent Fasting and Cognitive Performance - Targeting BDNF as Potential Strategy to Optimise Brain Health.
Unlocking the Complexity of Mitochondrial DNA: A Key to Understanding Neurodegenerative Disease Caused by Injury.
Administration of miR-195 Inhibitor Enhances Memory Function Through Improving Synaptic Degradation and Mitochondrial Dysfunction of the Hippocampal Neurons in SAMP8 Mice.
Hypothalamic Kisspeptin Neurons and the Control of Homeostasis.
IRS1 expression in hippocampus is age-dependent and is required for mature spine maintenance and neuritogenesis.
ROS-Induced mtDNA Release: The Emerging Messenger for Communication between Neurons and Innate Immune Cells during Neurodegenerative Disorder Progression.
Effect of Exercise on Brain Health: The Potential Role of Lactate as a Myokine.
Insulin-Induced Recurrent Hypoglycemia Up-Regulates Glucose Metabolism in the Brain Cortex of Chemically Induced Diabetic Rats.
Approach of probiotics in mental health as a psychobiotics.
Growth hormone receptor contributes to the activation of STAT5 in the hypothalamus of pregnant mice.
Interaction between glucocorticoid receptors and FKBP5 in regulating neurotransmission of the hippocampus.
Disrupted expression of mitochondrial NCLX sensitizes neuroglial networks to excitotoxic stimuli and renders synaptic activity toxic.
The dorsal hippocampal protein targeting to glycogen maintains ionotropic glutamate receptor subunits expression and contributes to working and short-term memories in mice.
Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons.
Lipid droplet availability affects neural stem/progenitor cell metabolism and proliferation.
iPSC-derived cortical neurons to study sporadic Alzheimer disease: a transcriptome comparison with post-mortem brain samples.
Neuronal ROS-induced glial lipid droplet formation is altered by loss of Alzheimer's disease-associated genes.

Oxid Med Cell Longev. 2021 ;2021 5586052

Directly Reprogrammed Human Neurons to Understand Age-Related Energy Metabolism Impairment and Mitochondrial Dysfunction in Healthy Aging and Neurodegeneration.

Camila Gudenschwager, Isadora Chavez, Cesar Cardenas, Christian Gonzalez-Billault.

Brain aging is characterized by several molecular and cellular changes grouped as the hallmarks or pillars of aging, including organelle dysfunction, metabolic and nutrition-sensor changes, stem cell attrition, and macromolecular damages. Separately and collectively, these features degrade the most critical neuronal function: transmission of information in the brain. It is widely accepted that aging is the leading risk factor contributing to the onset of the most prevalent pathological conditions that affect brain functions, such as Alzheimer's, Parkinson's, and Huntington's disease. One of the limitations in understanding the molecular mechanisms involved in those diseases is the lack of an appropriate cellular model that recapitulates the "aged" context in human neurons. The advent of the cellular reprogramming of somatic cells, i.e., dermal fibroblasts, to obtain directly induced neurons (iNs) and induced pluripotent stem cell- (iPSC-) derived neurons is technical sound advances that could open the avenues to understand better the contribution of aging toward neurodegeneration. In this review, we will summarize the commonalities and singularities of these two approaches for the study of brain aging, with an emphasis on the role of mitochondrial dysfunction and redox biology. We will address the evidence showing that iNs retain age-related features in contrast to iPSC-derived neurons that lose the aging signatures during the reprogramming to pluripotency, rendering iNs a powerful strategy to deepen our knowledge of the processes driving normal cellular function decline and neurodegeneration in a human adult model. We will finally discuss the potential utilization of these novel technologies to understand the differential contribution of genetic and epigenetic factors toward neuronal aging, to identify and develop new drugs and therapeutic strategies.

DOI: https://doi.org/10.1155/2021/5586052
Antioxidants (Basel). 2021 Dec 14. pii: 1991. [Epub ahead of print]10(12):

The Impact of Medium Chain and Polyunsaturated ω-3-Fatty Acids on Amyloid-β Deposition, Oxidative Stress and Metabolic Dysfunction Associated with Alzheimer's Disease.

Janine Mett.

  Alzheimer's disease (AD), the most common cause of dementia in the elderly population, is closely linked to a dysregulated cerebral lipid homeostasis and particular changes in brain fatty acid (FA) composition. The abnormal extracellular accumulation and deposition of the peptide amyloid-β (Aβ) is considered as an early toxic event in AD pathogenesis, which initiates a series of events leading to neuronal dysfunction and death. These include the induction of neuroinflammation and oxidative stress, the disruption of calcium homeostasis and membrane integrity, an impairment of cerebral energy metabolism, as well as synaptic and mitochondrial dysfunction. Dietary medium chain fatty acids (MCFAs) and polyunsaturated ω-3-fatty acids (ω-3-PUFAs) seem to be valuable for disease modification. Both classes of FAs have neuronal health-promoting and cognition-enhancing properties and might be of benefit for patients suffering from mild cognitive impairment (MCI) and AD. This review summarizes the current knowledge about the molecular mechanisms by which MCFAs and ω-3-PUFAs reduce the cerebral Aβ deposition, improve brain energy metabolism, and lessen oxidative stress levels.

Keywords:  Alzheimer’s disease; amyloid-β; antioxidants; decanoic acid; docosahexaenoic acid; eicosapentaenoic acid; energy metabolism; medium chain fatty acids; oxidative stress; polyunsaturated fatty acids

DOI:  https://doi.org/10.3390/antiox10121991
J Neuroinflammation. 2021 Dec 22. 18(1): 297

Mitophagy in neurological disorders.

Lijun Zhang, Lei Dai, Deyuan Li.

  Selective autophagy is an evolutionarily conserved mechanism that removes excess protein aggregates and damaged intracellular components. Most eukaryotic cells, including neurons, rely on proficient mitophagy responses to fine-tune the mitochondrial number and preserve energy metabolism. In some circumstances (such as the presence of pathogenic protein oligopolymers and protein mutations), dysfunctional mitophagy leads to nerve degeneration, with age-dependent intracellular accumulation of protein aggregates and dysfunctional organelles, leading to neurodegenerative disease. However, when pathogenic protein oligopolymers, protein mutations, stress, or injury are present, mitophagy prevents the accumulation of damaged mitochondria. Accordingly, mitophagy mediates neuroprotective effects in some forms of neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis) and acute brain damage (e.g., stroke, hypoxic-ischemic brain injury, epilepsy, and traumatic brain injury). The complex interplay between mitophagy and neurological disorders suggests that targeting mitophagy might be applicable for the treatment of neurodegenerative diseases and acute brain injury. However, due to the complexity of the mitophagy mechanism, mitophagy can be both harmful and beneficial, and future efforts should focus on maximizing its benefits. Here, we discuss the impact of mitophagy on neurological disorders, emphasizing the contrast between the positive and negative effects of mitophagy.

Keywords:  Alzheimer's disease; Autophagy; Huntington's disease; Mitophagy; Neurological diseases; Stroke

DOI:  https://doi.org/10.1186/s12974-021-02334-5
Front Neuroendocrinol. 2021 Dec 17. pii: S0091-3022(21)00073-X. [Epub ahead of print] 100971

Intermittent Fasting and Cognitive Performance - Targeting BDNF as Potential Strategy to Optimise Brain Health.

Karin Seidler, Michelle Barrow.

  Aging is the major risk factor for neurodegenerative diseases, accelerated by excessive calorie consumption and sedentary lifestyles. Bioenergetic challenges such as intermittent fasting (IF) have shown to promote lifespan and healthspan via an adaptive stress response. Activity-dependent brain-derived neurotrophic factor (BDNF) has emerged as key regulator of cognitive performance and brain health. This review aims to investigate the pathophysiological mechanisms linking IF and cognitive function with a focus on the role of BDNF, evaluating evidence from pre-clinical and human studies. A systematic literature search was performed. 82 peer-reviewed papers were accepted, critically appraised and summarised in a narrative analysis. Aging-related loss of BDNF has been associated with reduced synaptic plasticity, memory and learning as well as increased risk of cognitive impairment and Alzheimer's disease. IF was consistently reported to upregulate BDNF and improve cognitive performance in animal models. Further research is required to assess cognitive outcomes of IF in humans.

Keywords:  Aging; Alzheimer’s disease; BDNF; brain; cognitive decline; intermittent fasting; learning and memory; neurogenesis; synaptic plasticity

DOI:  https://doi.org/10.1016/j.yfrne.2021.100971
Cells. 2021 Dec 08. pii: 3460. [Epub ahead of print]10(12):

Unlocking the Complexity of Mitochondrial DNA: A Key to Understanding Neurodegenerative Disease Caused by Injury.

Larry N Singh, Shih-Han Kao, Douglas C Wallace.

  Neurodegenerative disorders that are triggered by injury typically have variable and unpredictable outcomes due to the complex and multifactorial cascade of events following the injury and during recovery. Hence, several factors beyond the initial injury likely contribute to the disease progression and pathology, and among these are genetic factors. Genetics is a recognized factor in determining the outcome of common neurodegenerative diseases. The role of mitochondrial genetics and function in traditional neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, is well-established. Much less is known about mitochondrial genetics, however, regarding neurodegenerative diseases that result from injuries such as traumatic brain injury and ischaemic stroke. We discuss the potential role of mitochondrial DNA genetics in the progression and outcome of injury-related neurodegenerative diseases. We present a guide for understanding mitochondrial genetic variation, along with the nuances of quantifying mitochondrial DNA variation. Evidence supporting a role for mitochondrial DNA as a risk factor for neurodegenerative disease is also reviewed and examined. Further research into the impact of mitochondrial DNA on neurodegenerative disease resulting from injury will likely offer key insights into the genetic factors that determine the outcome of these diseases together with potential targets for treatment.

Keywords:  evolution; genetics; genomics; ischaemic stroke; mitochondria; traumatic brain injury

DOI:  https://doi.org/10.3390/cells10123460
J Alzheimers Dis. 2021 Dec 17.

Administration of miR-195 Inhibitor Enhances Memory Function Through Improving Synaptic Degradation and Mitochondrial Dysfunction of the Hippocampal Neurons in SAMP8 Mice.

Zhaoyu Gao, Rui Zhang, Lei Jiang, Huimin Zhou, Qian Wang, Yingxin Ma, Di Zhang, Yushi Qin, Pei Tian, Nan Zhang, Zhongli Shi, Shunjiang Xu.

   BACKGROUND: Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD) and miR-195 is involved in mitochondrial disorder through targeting MFN-2 protein in hippocampal neurons of AD.
OBJECTIVE: To clarify if administration of miR-195 inhibitor could enhance the memory deficits through improving hippocampal neuron mitochondrial dysfunction in SAMP8 mice.
METHODS: The expression of miR-195 was detected by RT-qPCR in primary hippocampal neurons and HT-22 cells treated with Aβ 1-42. Morris water maze (MWM) was used to assess the learning and memory function in SAMP8 mice administrated with antagomir-195. Transmission electron microscopy was employed to determine the morphological changes of synapses and mitochondria of hippocampus in SAMP8 mice. Mitochondrial respiration was measured using a high-resolution oxygraph.
RESULTS: The expression of miR-195 were upregulated in the primary hippocampal neurons and HT-22 cells induced by Aβ 1-42. Inhibition of miR-195 ameliorated the mitochondrial dysfunction in HT-22 cells induced by Aβ 1-42, including mitochondrial morphologic damages, mitochondrial membrane potential, respiration function, and ATP production. Administration of antagomir-195 by the third ventricle injection markedly ameliorated the cognitive function, postsynaptic density thickness, length of synaptic active area, mitochondrial aspect ratio, and area in hippocampus of SAMP8 mice. Finally, antagomir-195 was able to promote an increase in the activity of respiratory chain complex CI and II in SAMP8 mice.
CONCLUSION: This study demonstrated that miR-195 inhibitor ameliorated the cognitive impairment of AD mice by improving mitochondrial structure damages and dysfunction in the hippocampal neurons, which provide an experimental basis for further exploring the treatment strategy of AD.

Keywords:  Alzheimer’s disease; cognitive dysfunction; microRNA-195; mitochondria; synaptic membranes

DOI:  https://doi.org/10.3233/JAD-215301
Endocrinology. 2021 Dec 25. pii: bqab253. [Epub ahead of print]

Hypothalamic Kisspeptin Neurons and the Control of Homeostasis.

Oline K Rønnekleiv, Jian Qiu, Martin J Kelly.

  Hypothalamic kisspeptin (Kiss1) neurons provide indispensable excitatory transmission to GnRH neurons for the coordinated release of gonadotropins, estrous cyclicity and ovulation. But maintaining reproductive functions is metabolically demanding so there must be a coordination with multiple homeostatic functions, and it is apparent that Kiss1 neurons play that role. There are two distinct populations of hypothalamic Kiss1 neurons, namely arcuate nucleus (Kiss1 ARH) neurons and anteroventral periventricular and periventricular nucleus (Kiss1 AVPV/PeN) neurons in rodents, both of which excite GnRH neurons via kisspeptin release but are differentially regulated by ovarian steroids. Estradiol (E2) increases the expression of kisspeptin in Kiss1 AVPV/PeN neurons but decreases its expression in Kiss1 ARH neurons. Also, Kiss1 ARH neurons co-express glutamate and Kiss1 AVPV/PeN neurons co-express GABA, both of which are upregulated by E2 in females. Also, Kiss1 ARH neurons express critical metabolic hormone receptors, and these neurons are excited by insulin and leptin during the fed state. Moreover, Kiss1 ARH neurons project to and excite the anorexigenic proopiomelanocortin (POMC) neurons but inhibit the orexigenic neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons, highlighting their role in regulating feeding behavior. Kiss1 ARH and Kiss1 AVPV/PeN neurons also project to the pre-autonomic paraventricular nucleus (satiety) neurons and the dorsomedial nucleus (energy expenditure) neurons to differentially regulate their function via glutamate and GABA release, respectively. Therefore, this review will address not only how Kiss1 neurons govern GnRH release, but how they control other homeostatic functions through their peptidergic, glutamatergic and GABAergic synaptic connections, providing further evidence that Kiss1 neurons are the key neurons coordinating energy states with reproduction.

Keywords:  DMH; GABA; NKB; PVH; dynorphin; glutamate

DOI:  https://doi.org/10.1210/endocr/bqab253
Mol Cell Neurosci. 2021 Dec 20. pii: S1044-7431(21)00106-8. [Epub ahead of print] 103693

IRS1 expression in hippocampus is age-dependent and is required for mature spine maintenance and neuritogenesis.

Sandra Sánchez-Sarasúa, María Meseguer-Beltrán, Cristina García-Díaz, Maria Teresa Beltrán-Bretones, Nisrin ElMlili, Ana María Sánchez-Pérez.

  Insulin and insulin-like growth factor type I (IGF-1) play prominent roles in brain activity throughout the lifespan. Insulin/IGF1 signaling starts with the activation of the intracellular insulin receptor substrates (IRS). In this work, we performed a comparative study of IRS1 and IRS2, together with the IGF1 (IGF1R) and insulin (IR) receptor expression in the hippocampus and prefrontal cortex during development. We found that IRS1 and IRS2 expression is prominent during development and declines in the aged hippocampus, contrary to IR, which increases in adulthood and aging. In contrast, IGF1R expression is unaffected by age. Expression patterns are similar in the prefrontal cortex. Neurite development occurs postnatally in the rodent hippocampus and cortex, and it declines in the mature and aged brain and is influenced by trophic factors. In our previous work, we demonstrated that knockdown of IRS1 by shRNA impairs learning and reduces synaptic plasticity in a rat model, as measured by synaptophysin puncta in axons. In this study, we report that shIRS1 alters spine maturation in adult hilar hippocampal neurons. Lastly, to understand the role of IRS1 in neuronal neurite tree, we transfect shIRS1 into primary neuronal cultures and observed that shIRS1 reduced neurite branching and neurite length. Our results demonstrate that IRS1/2 and insulin/IGF1 receptors display different age-dependent expression profiles and that IRS1 is required for spine maturation, demonstrating a novel role for IRS1 in synaptic plasticity.

Keywords:  IGF-1; IRS expression; Insulin; Neurite branching; Prefrontal cortex; Sholl analysis; Spine morphology; hippocampus; shRNA

DOI:  https://doi.org/10.1016/j.mcn.2021.103693
Antioxidants (Basel). 2021 Nov 29. pii: 1917. [Epub ahead of print]10(12):

ROS-Induced mtDNA Release: The Emerging Messenger for Communication between Neurons and Innate Immune Cells during Neurodegenerative Disorder Progression.

Yuanxin Zhao, Buhan Liu, Long Xu, Sihang Yu, Jiaying Fu, Jian Wang, Xiaoyu Yan, Jing Su.

  One of the most striking hallmarks shared by various neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, is microglia-mediated and astrocyte-mediated neuroinflammation. Although inhibitions of both harmful proteins and aggregation are major treatments for neurodegenerative diseases, whether the phenomenon of non-normal protein or peptide aggregation is causally related to neuronal loss and synaptic damage is still controversial. Currently, excessive production of reactive oxygen species (ROS), which induces mitochondrial dysfunction in neurons that may play a key role in the regulation of immune cells, is proposed as a regulator in neurological disorders. In this review, we propose that mitochondrial DNA (mtDNA) release due to ROS may act on microglia and astrocytes adjacent to neurons to induce inflammation through activation of innate immune responses (such as cGAS/STING). Elucidating the relationship between mtDNA and the formation of a pro-inflammatory microenvironment could contribute to a better understanding of the mechanism of crosstalk between neuronal and peripheral immune cells and lead to the development of novel therapeutic approaches to neurodegenerative diseases.

Keywords:  ROS; cGAS/STING; mtDNA; neurodegenerative diseases; neuroinflammation

DOI:  https://doi.org/10.3390/antiox10121917
Metabolites. 2021 Nov 29. pii: 813. [Epub ahead of print]11(12):

Effect of Exercise on Brain Health: The Potential Role of Lactate as a Myokine.

Takeshi Hashimoto, Hayato Tsukamoto, Soichi Ando, Shigehiko Ogoh.

  It has been well established in epidemiological studies and randomized controlled trials that habitual exercise is beneficial for brain health, such as cognition and mental health. Generally, it may be reasonable to say that the physiological benefits of acute exercise can prevent brain disorders in late life if such exercise is habitually/chronically conducted. However, the mechanisms of improvement in brain function via chronic exercise remain incompletely understood because such mechanisms are assumed to be multifactorial, such as the adaptation of repeated acute exercise. This review postulates that cerebral metabolism may be an important physiological factor that determines brain function. Among metabolites, the provision of lactate to meet elevated neural activity and regulate the cerebrovascular system and redox states in response to exercise may be responsible for exercise-enhanced brain health. Here, we summarize the current knowledge regarding the influence of exercise on brain health, particularly cognitive performance, with the underlying mechanisms by means of lactate. Regarding the influence of chronic exercise on brain function, the relevance of exercise intensity and modality, particularly high-intensity interval exercise, is acknowledged to induce "metabolic myokine" (i.e., lactate) for brain health.

Keywords:  angiogenesis; brain-derived neurotrophic factor; cerebral blood flow; executive function; insulin-like growth factor-1; mental health; neurogenesis; nicotinamide adenine dinucleotide hydrate; vascular endothelial growth factor

DOI:  https://doi.org/10.3390/metabo11120813
Int J Mol Sci. 2021 Dec 15. pii: 13470. [Epub ahead of print]22(24):

Insulin-Induced Recurrent Hypoglycemia Up-Regulates Glucose Metabolism in the Brain Cortex of Chemically Induced Diabetic Rats.

Susana Cardoso, Paula I Moreira.

  Diabetes is a chronic metabolic disease that seriously compromises human well-being. Various studies highlight the importance of maintaining a sufficient glucose supply to the brain and subsequently safeguarding cerebral glucose metabolism. The goal of the present work is to clarify and disclose the metabolic alterations induced by recurrent hypoglycemia in the context of long-term hyperglycemia to further comprehend the effects beyond brain harm. To this end, chemically induced diabetic rats underwent a protocol of repeatedly insulin-induced hypoglycemic episodes. The activity of key enzymes of glycolysis, the pentose phosphate pathway and the Krebs cycle was measured by spectrophotometry in extracts or isolated mitochondria from brain cortical tissue. Western blot analysis was used to determine the protein content of glucose and monocarboxylate transporters, players in the insulin signaling pathway and mitochondrial biogenesis and dynamics. We observed that recurrent hypoglycemia up-regulates the activity of mitochondrial hexokinase and Krebs cycle enzymes (namely, pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and succinate dehydrogenase) and the protein levels of mitochondrial transcription factor A (TFAM). Both insults increased the nuclear factor erythroid 2-related factor 2 (NRF2) protein content and induced divergent effects in mitochondrial dynamics. Insulin-signaling downstream pathways were found to be down-regulated, and glycogen synthase kinase 3 beta (GSK3β) was found to be activated through both decreased phosphorylation at Ser9 and increased phosphorylation at Y216. Interestingly, no changes in the levels of cAMP response element-binding protein (CREB), which plays a key role in neuronal plasticity and memory, were caused by hypoglycemia and/or hyperglycemia. These findings provide experimental evidence that recurrent hypoglycemia, in the context of chronic hyperglycemia, has the capacity to evoke coordinated adaptive responses in the brain cortex that will ultimately contribute to sustaining brain cell health.

Keywords:  brain cortex; chemically induced diabetes; glucose metabolism; mitochondria; recurrent hypoglycemia; signaling pathways

DOI:  https://doi.org/10.3390/ijms222413470
Arch Microbiol. 2021 Dec 19. 204(1): 30

Approach of probiotics in mental health as a psychobiotics.

Heenu Sharma, Jasveen Bajwa.

  Probiotics are those beneficial microbes that confer various health benefits to humans when integrated in diet in adequate amount. They possess vital metabolites having nutritional and therapeutic properties which provide countless health benefits. Scientific discoveries demonstrated that these living microbial consortiums may exert impact on anxiety, depression, cognitive functions, stress responses and behaviours. Those probiotics that controls the functioning or actions of central nervous system (CNS) conciliated by the gut brain axis (GBA) through neural, humoral and metabolic pathways to ameliorate the gastrointestinal activity as well as anti-depressant and anxiolytic capacity are known as psychobiotics. Few evidences have confirmed the remedial effects of psychobiotics against neurological conditions or disorders. So, therapeutic approach of psychobiotics leads to the future possibilities in the development field for researchers. This review article describes the potential role and mechanism of action of psychobiotics.

Keywords:  Anti-depressant; Gut brain axis; Neurological; Probiotics; Psychobiotics

DOI:  https://doi.org/10.1007/s00203-021-02622-x
Neurosci Lett. 2021 Dec 17. pii: S0304-3940(21)00781-3. [Epub ahead of print]770 136402

Growth hormone receptor contributes to the activation of STAT5 in the hypothalamus of pregnant mice.

Frederick Wasinski, Pryscila D S Teixeira, Edward O List, John J Kopchick, Jose Donato.

  Growth hormone (GH) receptor (GHR) signaling induces the phosphorylation of the signal transducer and activator of transcription 5 (pSTAT5) in the cells of several tissues including in the hypothalamus. During pregnancy, several STAT5-recruiting hormones (e.g., prolactin, GH and placental lactogens) are highly secreted. However, the precise contribution of GHR signaling to the surge of pSTAT5 immunoreactive neurons that occurs in the hypothalamus of pregnant mice is currently unknown. Thus, the objective of the present study was to determine whether GHR expression in neurons is required for inducing pSTAT5 expression in several hypothalamic nuclei during pregnancy. Initially, we demonstrated that late pregnant C57BL/6 mice (gestational day 14 to 18) exhibited increased pulsatile GH secretion compared to virgin females. Next, we confirmed that neuron-specific GHR ablation robustly reduces hypothalamic Ghr mRNA levels and prevents GH-induced pSTAT5 in the arcuate, paraventricular and ventromedial hypothalamic nuclei. Subsequently, the number of pSTAT5 immunoreactive cells was determined in the hypothalamus of late pregnant mice. Although neuron-specific GHR ablation did not affect the number of pSTAT5 immunoreactive cells in the paraventricular nucleus of the hypothalamus, reduced pSTAT5 expression was observed in the arcuate and ventromedial nuclei of pregnant neuron-specific GHR knockouts, compared to control pregnant mice. In summary, a subset of hypothalamic neurons requires GHR signaling to express pSTAT5 during pregnancy. These findings contribute to the understanding of the endocrine factors that affect the activation of transcription factors in the brain during pregnancy.

Keywords:  Cytokines; Growth hormone; Metabolism; Neuroendocrinology; Pregnancy; Transcription factors

DOI:  https://doi.org/10.1016/j.neulet.2021.136402
Neuroscience. 2021 Dec 16. pii: S0306-4522(21)00644-8. [Epub ahead of print]

Interaction between glucocorticoid receptors and FKBP5 in regulating neurotransmission of the hippocampus.

Seungjae Zhang, Myunghyun Cheon, Hoyong Park, Taejoon Kim, ChiHye Chung.

  FK501 binding protein 51 (FKBP5) is a stress response prolyl isomerase that inhibits the translocation of the glucocorticoid receptor (GR) heterocomplex to the nucleus. Previous studies have shown that the expression levels of FKBP5 are positively correlated with psychiatric disorders, including depression and post-traumatic stress disorder. In rodents, FKBP5 deletion in the brain leads to be resilient to stress-induced depression. The hippocampus is known to be one of the primary locations mediating stress responses in the brain by providing negative feedback signals to the hypothalamus-pituitary-adrenal gland axis. Therefore, we aimed to investigate the role of FKBP5 and its interaction with GRs in the hippocampus. We observed that FKBP5 deletion in the hippocampus resulted in a minimal change in synaptic transmission. In the hippocampus, GR activation alters the release probability in inhibitory synapses as well as the postsynaptic contribution of glutamate receptors in excitatory synapses; however, no such alterations were induced in the absence of FKBP5. FKBP5 deficiency causes insensitivity to activated GRs in the hippocampus suggesting that FKBP5 mediates synaptic changes caused by GR activation. Our study provides electrophysiological evidence of stress resilience observed in FKBP5-deficient mice.

Keywords:  FKBP5; corticosterone; glucocorticoid receptor; hippocampus; synaptic transmission

DOI:  https://doi.org/10.1016/j.neuroscience.2021.12.020
J Biol Chem. 2021 Dec 20. pii: S0021-9258(21)01318-1. [Epub ahead of print] 101508

Disrupted expression of mitochondrial NCLX sensitizes neuroglial networks to excitotoxic stimuli and renders synaptic activity toxic.

Anna M Hagenston, Jing Yan, Carlos Bas-Orth, Yanwei Tan, Israel Sekler, Hilmar Bading.

  The mitochondrial sodium/calcium/lithium exchanger (NCLX) is an important mediator of calcium extrusion from mitochondria. In this study, we tested the hypothesis that physiological expression levels of NCLX are essential for maintaining neuronal resilience in the face of excitotoxic challenge. Using a short hairpin RNA (shRNA)-mediated approach, we showed that reduced NCLX expression exacerbates neuronal mitochondrial calcium dysregulation, mitochondrial membrane potential (ΔΨm) breakdown, and reactive oxygen species (ROS) generation during excitotoxic stimulation of primary hippocampal cultures. Moreover, NCLX knockdown-which affected both neurons and glia-resulted not only in enhanced neurodegeneration following an excitotoxic insult, but also in neuronal and astrocytic cell death under basal conditions. Our data also revealed that synaptic activity, which promotes neuroprotective signaling, can become lethal upon NCLX depletion; expression of NCLX-targeted shRNA impaired the clearance of mitochondrial calcium following action potential bursts and was associated both with ΔΨmbreakdown and substantial neurodegeneration in hippocampal cultures undergoing synaptic activity. Finally, we showed that NCLX knockdown within the hippocampal cornu ammonis 1 (CA1) region in vivo causes substantial neuro- and astrodegeneration. In summary, we demonstrated that dysregulated NCLX expression not only sensitizes neuroglial networks to excitotoxic stimuli but notably also renders otherwise neuroprotective synaptic activity toxic. These findings may explain the emergence of neuro- and astrodegeneration in patients with disorders characterized by disrupted NCLX expression or function, and suggest that treatments aimed at enhancing or restoring NCLX function may prevent central nervous system damage in these disease states.

Keywords:  Calcium signaling; NCLX; gene expression; mitochondria; neurotoxicity; synaptic activity

DOI:  https://doi.org/10.1016/j.jbc.2021.101508
J Pharmacol Sci. 2022 Jan;pii: S1347-8613(21)00103-1. [Epub ahead of print]148(1): 108-115

The dorsal hippocampal protein targeting to glycogen maintains ionotropic glutamate receptor subunits expression and contributes to working and short-term memories in mice.

Yuki Kambe, Thu Nguyen Thi, Kohei Hashiguchi, Yoshimune Sameshima, Akira Yamashita, Takashi Kurihara, Atsuro Miyata.

  Brain glycogen metabolism is known to be involved in the learning and memory processes. Protein targeting to glycogen (PTG) is a crucial molecule for glycogenesis, and its expression level is shown to be increased in the dorsal hippocampus during fear memory acquisition and recall, suggesting that PTG may contribute to the memory process. However, its detailed role in the dorsal hippocampus remains unclear. Therefore, we knocked down the expression of PTG in the dorsal hippocampus and attempted to analyze its function behaviorally. PTG expression was found to be enriched in astrocytes. Furthermore, short hairpin RNA against PTG suppressed the expression of PTG in astrocytes. Mice with knockdown of PTG in the dorsal hippocampus showed suppressed alternation behavior in the Y-maze test and reduced memory recall at the first hour after acquisition in the passive avoidance test. Knockdown of mouse dorsal hippocampal astrocyte-specific PTG also impaired working memory in the Y-maze test. GluR1, GluR2, and NR2a subunits expressions were significantly down-regulated in the dorsal hippocampus of mice in which PTG was knocked down. These results indicate that PTG in the dorsal hippocampal astrocytes may contribute to working and short-term memories by maintaining the expression of glutamate receptor subunits.

Keywords:  Astrocytes; Ionotropic glutamate receptors; Protein targeting to glycogen; Short-term memory; Working memory

DOI:  https://doi.org/10.1016/j.jphs.2021.10.008
Front Aging Neurosci. 2021 ;13 766306

Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons.

Sandra Lizbeth Morales-Rosales, Roberto Santín-Márquez, Pedro Posadas-Rodriguez, Ruth Rincon-Heredia, Teresa Montiel, Raúl Librado-Osorio, Armando Luna-López, Nadia Alejandra Rivero-Segura, Claudio Torres, Agustina Cano-Martínez, Alejandro Silva-Palacios, Paulina Cortés-Hernández, Julio Morán, Lourdes Massieu, Mina Konigsberg.

  The decline in brain function during aging is one of the most critical health problems nowadays. Although senescent astrocytes have been found in old-age brains and neurodegenerative diseases, their impact on the function of other cerebral cell types is unknown. The aim of this study was to evaluate the effect of senescent astrocytes on the mitochondrial function of a neuron. In order to evaluate neuronal susceptibility to a long and constant senescence-associated secretory phenotype (SASP) exposure, we developed a model by using cellular cocultures in transwell plates. Rat primary cortical astrocytes were seeded in transwell inserts and induced to premature senescence with hydrogen peroxide [stress-induced premature senescence (SIPS)]. Independently, primary rat cortical neurons were seeded at the bottom of transwells. After neuronal 6 days in vitro (DIV), the inserts with SIPS-astrocytes were placed in the chamber and cocultured with neurons for 6 more days. The neuronal viability, the redox state [reduced glutathione/oxidized glutathione (GSH/GSSG)], the mitochondrial morphology, and the proteins and membrane potential were determined. Our results showed that the neuronal mitochondria functionality was altered after being cocultured with senescent astrocytes. In vivo, we found that old animals had diminished mitochondrial oxidative phosphorylation (OXPHOS) proteins, redox state, and senescence markers as compared to young rats, suggesting effects of the senescent astrocytes similar to the ones we observed in vitro. Overall, these results indicate that the microenvironment generated by senescent astrocytes can affect neuronal mitochondria and physiology.

Keywords:  aging; astrocyte; cellular senescence; mitochondria; redox state

DOI:  https://doi.org/10.3389/fnagi.2021.766306
Nat Commun. 2021 Dec 21. 12(1): 7362

Lipid droplet availability affects neural stem/progenitor cell metabolism and proliferation.

Mergim Ramosaj, Sofia Madsen, Vanille Maillard, Valentina Scandella, Daniel Sudria-Lopez, Naoya Yuizumi, Ludovic Telley, Marlen Knobloch.

Neural stem/progenitor cells (NSPCs) generate new neurons throughout adulthood. However, the underlying regulatory processes are still not fully understood. Lipid metabolism plays an important role in regulating NSPC activity: build-up of lipids is crucial for NSPC proliferation, whereas break-down of lipids has been shown to regulate NSPC quiescence. Despite their central role for cellular lipid metabolism, the role of lipid droplets (LDs), the lipid storing organelles, in NSPCs remains underexplored. Here we show that LDs are highly abundant in adult mouse NSPCs, and that LD accumulation is significantly altered upon fate changes such as quiescence and differentiation. NSPC proliferation is influenced by the number of LDs, inhibition of LD build-up, breakdown or usage, and the asymmetric inheritance of LDs during mitosis. Furthermore, high LD-containing NSPCs have increased metabolic activity and capacity, but do not suffer from increased oxidative damage. Together, these data indicate an instructive role for LDs in driving NSPC behaviour.

DOI: https://doi.org/10.1038/s41467-021-27365-7
Toxicol Lett. 2021 Dec 15. pii: S0378-4274(21)00915-2. [Epub ahead of print]

iPSC-derived cortical neurons to study sporadic Alzheimer disease: a transcriptome comparison with post-mortem brain samples.

M C T Verheijen, J Krauskopf, F Caiment, M Nazaruk, Q F Wen, M H M van Herwijnen, D A Hauser, M Gajjar, C Verfaillie, Y Vermeiren, P P De Deyn, M M J Wittens, A Sieben, S Engelborghs, W Dejonckheere, K Princen, G Griffioen, E L Roggen, J J Briedé.

  Alzheimer's disease (AD) is the most common cause of dementia, characterized by the progressive impairment of cognition and memory loss. Sporadic AD (sAD) represents approximately 95% of the AD cases and is induced by a complex interplay between genetic and environmental factors called "Alzheimerogens". Heavy metals (e.g. copper) and pesticides (e.g. fipronil) can affect many AD-related processes, including neuroinflammation (considered as AD-inducing factor). Research would benefit from in vitro models to investigate effects of Alzheimerogens. We compared transcriptomics changes in sAD induced pluripotent stem cell (iPSC) derived cortical neurons to differentially expressed genes (DEGs) identified in post-mortem AD brain tissue. These analyses showed that many AD-related processes could be identified in the sAD iPSC-derived neurons, and furthermore, could even identify more DEGs functioning in these processes than post-mortem AD-brain tissue. Thereafter, we exposed the iPSCs to AD-inducing factors (copper(II)chloride, fipronil sulfone and an inflammatory cytokine cocktail). Cytokine exposure induced expression of immune related genes while copper-exposure affected genes involved in lipid and cholesterol metabolism, which are known AD-related processes. Fipronil-exposure did not result in significant transcriptomic changes, although prolonged exposures or higher doses may be necessary. Overall, we show that iPSC-derived cortical neurons can be beneficial in vitro models to identify Alzheimerogens and AD-related molecular mechanisms.

Keywords:  Alzheimerogens; Alzheimers disease; gene expression; iPSCs; sAD; toxicology

DOI:  https://doi.org/10.1016/j.toxlet.2021.12.009
Proc Natl Acad Sci U S A. 2021 Dec 28. pii: e2112095118. [Epub ahead of print]118(52):

Neuronal ROS-induced glial lipid droplet formation is altered by loss of Alzheimer's disease-associated genes.

Matthew J Moulton, Scott Barish, Isha Ralhan, Jinlan Chang, Lindsey D Goodman, Jake G Harland, Paul C Marcogliese, Jan O Johansson, Maria S Ioannou, Hugo J Bellen.

  A growing list of Alzheimer's disease (AD) genetic risk factors is being identified, but the contribution of each variant to disease mechanism remains largely unknown. We have previously shown that elevated levels of reactive oxygen species (ROS) induces lipid synthesis in neurons leading to the sequestration of peroxidated lipids in glial lipid droplets (LD), delaying neurotoxicity. This neuron-to-glia lipid transport is APOD/E-dependent. To identify proteins that modulate these neuroprotective effects, we tested the role of AD risk genes in ROS-induced LD formation and demonstrate that several genes impact neuroprotective LD formation, including homologs of human ABCA1, ABCA7, VLDLR, VPS26, VPS35, AP2A, PICALM, and CD2AP Our data also show that ROS enhances Aβ42 phenotypes in flies and mice. Finally, a peptide agonist of ABCA1 restores glial LD formation in a humanized APOE4 fly model, highlighting a potentially therapeutic avenue to prevent ROS-induced neurotoxicity. This study places many AD genetic risk factors in a ROS-induced neuron-to-glia lipid transfer pathway with a critical role in protecting against neurotoxicity.

Keywords:  Alzheimer’s disease; Drosophila; GWAS; lipid droplet; peroxidated lipid transfer

DOI:  https://doi.org/10.1073/pnas.2112095118