bims-brabim 2021-12-12 papers

bims-brabim

Biomed News

on Brain bioenergetics and metabolism

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

Mitochondrial Dysfunction as a Causative Factor in Alzheimer's Disease-Spectrum Disorders: Lymphocytes as a Window to the Brain.
Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer's Disease and Stroke.
The Combination of β-Asarone and Icariin Inhibits Amyloid-β and Reverses Cognitive Deficits by Promoting Mitophagy in Models of Alzheimer's Disease.
Mitochondrially-Targeted Therapeutic Strategies for Alzheimer's Disease.
Astrocyte Bioenergetics and Major Psychiatric Disorders.
The Gut Microbiota Metabolite Urolithin B Improves Cognitive Deficits by Inhibiting Cyt C-Mediated Apoptosis and Promoting the Survival of Neurons Through the PI3K Pathway in Aging Mice.
Distribution of androgen receptor mRNA in the prepubertal male and female mouse brain.
Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases?
Brain Intrinsic Functional Activity in Relation to Metabolic Changes in Alzheimer's Disease: A Simultaneous PET/fMRI study.
PINK1 overexpression prevents forskolin-induced tau hyperphosphorylation and oxidative stress in a rat model of Alzheimer's disease.
Bioenergetic Impairment in the Neuro-Glia-Vascular Unit: An Emerging Physiopathology during Aging.
Modulatory Effects of Alpha- and Gamma-Tocopherol on the Mitochondrial Respiratory Capacity and Membrane Potential in an In Vitro Model of Alzheimer's Disease.
Oleanolic Acid Provides Neuroprotection against Ischemic Stroke through the Inhibition of Microglial Activation and NLRP3 Inflammasome Activation.
Mitochondria in Early Forebrain Development: From Neurulation to Mid-Corticogenesis.
Mitophagy in aging and longevity.
Ketogenic diet ameliorates cognitive impairment and neuroinflammation in a mouse model of Alzheimer's disease.
Aberrant role of pyruvate kinase M2 in the regulation of gamma-secretase and memory deficits in Alzheimer's disease.
Potential Crosstalk Between Parkinson's Disease and Energy Metabolism.
Astrocytes: The Housekeepers and Guardians of the CNS.
Drosophila as a model to study autophagy in neurodegenerative diseases and digestive tract.
Effects of exercise training on behavior and brain function after high dose isoproterenol-induced cardiac damage.
Altered protein secretion in Batten disease.
β-hydroxybutyrate Alleviates Learning and Memory Impairment Through the SIRT1 Pathway in D-Galactose-Injured Mice.
High Fat Diet Mediates Amyloid-β Cleaving Enzyme 1 Phosphorylation and SUMOylation, Enhancing Cognitive Impairment in APP/PS1 Mice.
Neuroinflammation-mediated mitochondrial dysregulation involved in postoperative cognitive dysfunction.
Brain Volume Loss, Astrocyte Reduction, and Inflammation in Anorexia Nervosa.
Korean Red Ginseng Improves Astrocytic Mitochondrial Function by Upregulating HO-1-Mediated AMPKα-PGC-1α-ERRα Circuit after Traumatic Brain Injury.
Ketamine Action on Astrocytes Provides New Insights into Rapid Antidepressant Mechanisms.
The Role of Mitochondria in the Pathophysiology of Schizophrenia: A Critical Review of the Evidence Focusing on Mitochondrial Complex One.
Impact of Oxidative DNA Damage and the Role of DNA Glycosylases in Neurological Dysfunction.
Ameliorative effect of Acetyl L-carnitine in Alzheimer's Disease via Downregulating of Homocysteine Levels in Hyperhomocysteinemia Induced Cognitive Deficit in mouse model.
Dietary factors and brain health.
Deep brain stimulation improved depressive-like behaviors and hippocampal synapse deficits by activating the BDNF/mTOR signaling pathway.
Activation of Adenosine Monophosphate-Activated Protein Kinase Drives the Aerobic Glycolysis in Hippocampus for Delaying Cognitive Decline Following Electroacupuncture Treatment in APP/PS1 Mice.

Curr Alzheimer Res. 2021 Dec 08.

Mitochondrial Dysfunction as a Causative Factor in Alzheimer's Disease-Spectrum Disorders: Lymphocytes as a Window to the Brain.

Marko Jörg, Johanna E Plehn, Kristina Friedland, Walter E Müller.

  Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will further increase with longer life expectancy. The AD brain is marked by severe neurodegeneration, such as the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems, especially in the hip- pocampus and cerebral cortex. Recent findings highlight the important role of mitochondrial dys- function and increased oxidative stress in the pathophysiology of late-onset Alzheimer's disease (LOAD). These alterations are not only observed in the brain of AD patients but also in the periph- ery. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and mitochondrial dysfunction as peripheral markers for the detection of AD in blood cells e.g. lymphocytes. We evaluate recent findings regarding impaired mitochondrial function comprising mitochondrial respiration, reduced complex activities of the respiratory chain and altered Mitochon- drial Membrane Potential (MMP) in lymphocytes as well as in neurons. Finally, we will question whether these mitochondrial parameters might be suitable as an early peripheral marker for the de- tection of LOAD but also for the transitional stage between normal aging and Dementia, "Mild Cognitive Impairment" (MCI).

Keywords:  Aging; Dementia; Mild Cognitive Impairment (MCI); lymphocytes; neurodegenerative disease; neurotransmitter systems

DOI:  https://doi.org/10.2174/1567205018666211208141512
Front Aging Neurosci. 2021 ;13 772278

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer's Disease and Stroke.

Nicole Lemon, Elisa Canepa, Marc A Ilies, Silvia Fossati.

  The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS), which participates in the regulation of cerebral blood flow (CBF), delivery of oxygen and nutrients, immunological surveillance, clearance, barrier functions, and CNS homeostasis. Stroke and Alzheimer Disease (AD) are two pathologies with extensive NVU dysfunction. The cell types of the NVU change in both structure and function following an ischemic insult and during the development of AD pathology. Stroke and AD share common risk factors such as cardiovascular disease, and also share similarities at a molecular level. In both diseases, disruption of metabolic support, mitochondrial dysfunction, increase in oxidative stress, release of inflammatory signaling molecules, and blood brain barrier disruption result in NVU dysfunction, leading to cell death and neurodegeneration. Improved therapeutic strategies for both AD and stroke are needed. Carbonic anhydrases (CAs) are well-known targets for other diseases and are being recently investigated for their function in the development of cerebrovascular pathology. CAs catalyze the hydration of CO2 to produce bicarbonate and a proton. This reaction is important for pH homeostasis, overturn of cerebrospinal fluid, regulation of CBF, and other physiological functions. Humans express 15 CA isoforms with different distribution patterns. Recent studies provide evidence that CA inhibition is protective to NVU cells in vitro and in vivo, in models of stroke and AD pathology. CA inhibitors are FDA-approved for treatment of glaucoma, high-altitude sickness, and other indications. Most FDA-approved CA inhibitors are pan-CA inhibitors; however, specific CA isoforms are likely to modulate the NVU function. This review will summarize the literature regarding the use of pan-CA and specific CA inhibitors along with genetic manipulation of specific CA isoforms in stroke and AD models, to bring light into the functions of CAs in the NVU. Although pan-CA inhibitors are protective and safe, we hypothesize that targeting specific CA isoforms will increase the efficacy of CA inhibition and reduce side effects. More studies to further determine specific CA isoforms functions and changes in disease states are essential to the development of novel therapies for cerebrovascular pathology, occurring in both stroke and AD.

Keywords:  Alzheimer’s disease; amyloid beta; carbonic anhydrase (CA); cerebrovascular pathology; inflammation; mitochondria; neurovascular unit (NVU); stroke

DOI:  https://doi.org/10.3389/fnagi.2021.772278
Oxid Med Cell Longev. 2021 ;2021 7158444

The Combination of β-Asarone and Icariin Inhibits Amyloid-β and Reverses Cognitive Deficits by Promoting Mitophagy in Models of Alzheimer's Disease.

Nanbu Wang, Haoyu Wang, Qi Pan, Jian Kang, Ziwen Liang, Ronghua Zhang.

β-Asarone is the main constituent of Acorus tatarinowii Schott and exhibits important effects in diseases such as neurodegenerative and neurovascular diseases. Icariin (ICA) is a major active ingredient of Epimedium that has attracted increasing attention because of its unique pharmacological effects in degenerative disease. In this paper, we primarily explored the effects of the combination of β-asarone and ICA in clearing noxious proteins and reversing cognitive deficits. The accumulation of damaged mitochondria and mitophagy are hallmarks of aging and age-related neurodegeneration, including Alzheimer's disease (AD). Here, we provide evidence that autophagy/mitophagy is impaired in the hippocampus of APP/PS1 mice and in Aβ1-42-induced PC12 cell models. Enhanced mitophagic activity has been reported to promote Aβ and tau clearance in in vitro and in vivo models. Meanwhile, there is growing evidence that treatment of AD should be preceded by intervention before the formation of pathological products. The efficacy of the combination therapy was better than that of the individual therapies applied separately. Then, we found that the combination therapy also inhibited cell and mitochondrial damage by inducing autophagy/mitophagy. These findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis, and that combination treatment with mitophagy inducers represents a potential strategy for therapeutic intervention.

DOI: https://doi.org/10.1155/2021/7158444
Curr Alzheimer Res. 2021 Dec 08.

Mitochondrially-Targeted Therapeutic Strategies for Alzheimer's Disease.

Isaac G Onyango, James P Bennett, Gorazd B Stokin.

  Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disease and the most common cause of dementia among older adults. There are no effective treatments avail- able for the disease, and it is associated with great societal concern because of the substantial costs of providing care to its sufferers, whose numbers will increase as populations age. While multiple causes have been proposed to be significant contributors to the onset of sporadic AD, increased age is a unifying risk factor. In addition to amyloid-β (Aβ) and tau protein playing a key role in the initi- ation and progression of AD, impaired mitochondrial bioenergetics and dynamics are likely major etiological factors in AD pathogenesis and have many potential origins, including Aβ and tau. Mito- chondrial dysfunction is evident in the central nervous system (CNS) and systemically early in the disease process. Addressing these multiple mitochondrial deficiencies is a major challenge of mito- chondrial systems biology. We review evidence for mitochondrial impairments ranging from mito- chondrial DNA (mtDNA) mutations to epigenetic modification of mtDNA, altered gene expres- sion, impaired mitobiogenesis, oxidative stress, altered protein turnover and changed organelle dy- namics (fission and fusion). We also discuss therapeutic approaches, including repurposed drugs, epigenetic modifiers, and lifestyle changes that target each level of deficiency which could poten- tially alter the course of this progressive, heterogeneous Disease while being cognizant that success- ful future therapeutics may require a combinatorial approach.

Keywords:  Alzheimer's disease; bioenergetics; epigenetic modifiers; lifestyle changes; mitochondria; mtDNA; repurposed drugs; β-amyloid

DOI:  https://doi.org/10.2174/1567205018666211208125855
Adv Neurobiol. 2021 ;26 173-227

Astrocyte Bioenergetics and Major Psychiatric Disorders.

Ivan V Maly, Michael J Morales, Mikhail V Pletnikov.

  Ongoing research continues to add new elements to the emerging picture of involvement of astrocyte energy metabolism in the pathophysiology of major psychiatric disorders, including schizophrenia, mood disorders, and addictions. This review outlines what is known about the energy metabolism in astrocytes, the most numerous cell type in the brain, and summarizes the recent work on how specific perturbations of astrocyte bioenergetics may contribute to the neuropsychiatric conditions. The role of astrocyte energy metabolism in mental health and disease is reviewed on the organism, organ, and cell level. Data arising from genomic, metabolomic, in vitro, and neurobehavioral studies is critically analyzed to suggest future directions in research and possible metabolism-focused therapeutic interventions.

Keywords:  Astrocyte; Bioenergetics; Glycolysis; Mitochondria; Psychiatric disorders

DOI:  https://doi.org/10.1007/978-3-030-77375-5_9
Front Pharmacol. 2021 ;12 768097

The Gut Microbiota Metabolite Urolithin B Improves Cognitive Deficits by Inhibiting Cyt C-Mediated Apoptosis and Promoting the Survival of Neurons Through the PI3K Pathway in Aging Mice.

Peng Chen, Fuchao Chen, Jiexin Lei, Gaohua Wang, Benhong Zhou.

  Background: Despite considerable advances in pharmacotherapy, more effective therapeutic interventions for aging-related neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), remain limited. Urolithin B (UB), one of the major subcategories of urolithins (microbiota metabolites) found in various tissues after ellagitannin consumption, has been shown to possess antioxidant, anti-inflammatory, and antiapoptotic effects. However, the neuroprotective effect of UB on brain aging in mice and its potential mechanisms were still unknown. Methods: In the current research, we first assessed the ameliorative effects of UB on oxidative injury and apoptosis induced by H2O2 in neuro-2a cells. Then a subcutaneous injection of D-galactose in mice for 8 weeks was used to establish the aging model to evaluate the protective effects of UB. The capacity of memory and learning, alterations of hippocampus histology and corresponding molecular mechanisms were all evaluated. Results: The D-gal-induced accelerated aging model in vivo demonstrated that UB could significantly ameliorate deficits in learning and memory by inhibiting the accumulation of advanced glycation end products (AGEs) and elevating the expression and activity of Cu, Zn-SOD and CAT. Furthermore, UB downregulated the c-Jun N-terminal kinase (JNK) signaling pathway and prevented cytochrome c release from isolated mitochondria, thereby inhibiting neuronal apoptosis during the aging process. More importantly, UB stimulation of aging mice activated ERK and phosphoinositide 3-kinase (PI3K), leading to neuronal survival along with Akt and p44/42 mitogen-activated protein kinase (MAPK) phosphorylation and activation. Conclusion: In summary, UB effectively alleviated cognitive deficits and ameliorated brain aging-related conditions and could be considered a healthcare product to prevent aging-associated NDs such as AD.

Keywords:  PI3K pathway; UB; aging; apoptosis; d-Gal; learning and memory

DOI:  https://doi.org/10.3389/fphar.2021.768097
J Neuroendocrinol. 2021 Nov 14. e13063

Distribution of androgen receptor mRNA in the prepubertal male and female mouse brain.

Alexandra L Cara, Emily L Henson, Bethany G Beekly, Carol F Elias.

  Androgens are steroid hormones that play a critical role in brain development and sexual maturation by acting upon both androgen receptors (AR) and estrogen receptors (ERα/β) after aromatization. The contribution of estrogens from aromatized androgens in brain development and the central regulation of metabolism, reproduction, and behavior is well defined, but the role of androgens acting on AR has been unappreciated. Here, we map the sex specific expression of Ar in the adult and developing mouse brain. Postnatal days (PND) 12 and 21 were used to target a critical window of prepubertal development. Consistent with previous literature in adults, sex-specific differences in Ar expression were most profound in the bed nucleus of the stria terminalis (BST), medial amygdala (MEA) and medial preoptic area (MPO). Ar expression was also high in these areas at PND 12 and 21 in both sexes. In addition, we describe extra-hypothalamic and extra-limbic areas that show moderate, consistent and similar Ar expression in both sexes at both prepubertal time points. Briefly, Ar expression was observed in olfactory areas of the cerebral cortex, the hippocampus, several thalamic nuclei, and cranial nerve nuclei involved in autonomic sensory and motor function. To further characterize forebrain populations of Ar expressing neurons and determine whether they also coexpress estrogen receptors, we examined expression of Ar, Esr1 and Esr2 in prepubertal mice in selected nuclei. We found populations of neurons in the BST, MEA and MPO that coexpress Ar, but not Esr1 or Esr2, whereas others express a combination of the three receptors. Our findings indicate that various brain areas express Ar during prepubertal development and may play an important role in female neuronal development and physiology.

Keywords:  gonadal steroids; postnatal development; puberty; sex differences

DOI:  https://doi.org/10.1111/jne.13063
Front Neurosci. 2021 ;15 746873

Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases?

Di Hu, Zunren Liu, Xin Qi.

  Many lines of evidence have indicated the therapeutic potential of rescuing mitochondrial integrity by targeting specific mitochondrial quality control pathways in neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. In addition to ATP synthesis, mitochondria are critical regulators of ROS production, lipid metabolism, calcium buffering, and cell death. The mitochondrial unfolded protein response, mitochondrial dynamics, and mitophagy are the three main quality control mechanisms responsible for maintaining mitochondrial proteostasis and bioenergetics. The proper functioning of these complex processes is necessary to surveil and restore mitochondrial homeostasis and the healthy pool of mitochondria in cells. Mitochondrial dysfunction occurs early and causally in disease pathogenesis. A significant accumulation of mitochondrial damage resulting from compromised quality control pathways leads to the development of neuropathology. Moreover, genetic or pharmaceutical manipulation targeting the mitochondrial quality control mechanisms can sufficiently rescue mitochondrial integrity and ameliorate disease progression. Thus, therapies that can improve mitochondrial quality control have great promise for the treatment of neurodegenerative diseases. In this review, we summarize recent progress in the field that underscores the essential role of impaired mitochondrial quality control pathways in the pathogenesis of neurodegenerative diseases. We also discuss the translational approaches targeting mitochondrial function, with a focus on the restoration of mitochondrial integrity, including mitochondrial dynamics, mitophagy, and mitochondrial proteostasis.

Keywords:  mitochondrial dynamics; mitochondrial proteostasis; mitochondrial quality control; mitophagy; neurodegenerative diseases

DOI:  https://doi.org/10.3389/fnins.2021.746873
Annu Int Conf IEEE Eng Med Biol Soc. 2021 Nov;2021 3467-3470

Brain Intrinsic Functional Activity in Relation to Metabolic Changes in Alzheimer's Disease: A Simultaneous PET/fMRI study.

Wanqing Sun, Miao Zhang, Yaoyu Zhang, Biao Li, Yao Li.

Previous studies have shown that the intrinsic brain functional activity significantly reduced in a variety of regions of Alzheimer's disease (AD) patients. However, the associated underlying metabolic mechanism remains not clear. Brain activity is primarily driven by the dynamic activity of neurons and their interconnections, which are regulated by synapses and are closely related to glucose uptakes. Simultaneous FDG-PET/fMRI imaging provides a unique opportunity to measure the concurrent brain functional activity and cerebral glucose metabolism information. In this study, using simultaneous resting-state PET/fMRI imaging, we investigated the concurrent global intrinsic activity and metabolic signal changes in AD patients. Twenty-two controls and nineteen AD patients were included. We compared the whole-brain amplitude of low frequency fluctuations (ALFF) measured using fMRI imaging and glucose uptake maps acquired from PET imaging between the two groups. Both maps showed significant reductions in the precuneus and left inferior parietal lobule (IPL) in AD compared to the control groups. Moreover, the ALFF within the precuneus and left IPL were significantly correlated with the colocalized glucose metabolism. The ALFF in the left IPL was significantly correlated with patient cognitive performance evaluated using MMSE or MoCA. Our findings provide useful insights into the understanding of brain intrinsic functional-metabolic activity and its role in AD pathology.

DOI: https://doi.org/10.1109/EMBC46164.2021.9630966
Acta Pharmacol Sin. 2021 Dec 10.

PINK1 overexpression prevents forskolin-induced tau hyperphosphorylation and oxidative stress in a rat model of Alzheimer's disease.

Xiao-Juan Wang, Lin Qi, Ya-Fang Cheng, Xue-Fei Ji, Tian-Yan Chi, Peng Liu, Li-Bo Zou.

  PTEN-induced putative kinase 1 (PINK1)/parkin pathway mediates mitophagy, which is a specialized form of autophagy. Evidence shows that PINK1 can exert protective effects against stress-induced neuronal cell death. In the present study we investigated the effects of PINK1 overexpression on tau hyperphosphorylation, mitochondrial dysfunction and oxidative stress in a specific rat model of tau hyperphosphorylation. We showed that intracerebroventricular (ICV) microinjection of forskolin (FSK, 80 μmol) induced tau hyperphosphorylation in the rat brain and resulted in significant spatial working memory impairments in Y-maze test, accompanied by synaptic dysfunction (reduced expression of synaptic proteins synaptophysin and postsynaptic density protein 95), and neuronal loss in the hippocampus. Adeno-associated virus (AAV)-mediated overexpression of PINK1 prevented ICV-FSK-induced cognition defect and pathological alterations in the hippocampus, whereas PINK1-knockout significantly exacerbated ICV-FSK-induced deteriorated effects. Furthermore, we revealed that AAV-PINK1-mediated overexpression of PINK1 alleviated ICV-FSK-induced tau hyperphosphorylation by restoring the activity of PI3K/Akt/GSK3β signaling. PINK1 overexpression reversed the abnormal changes in mitochondrial dynamics, defective mitophagy, and decreased ATP levels in the hippocampus. Moreover, PINK1 overexpression activated Nrf2 signaling, thereby increasing the expression of antioxidant proteins and reducing oxidative damage. These results suggest that PINK1 deficiency exacerbates FSK-induced tau pathology, synaptic damage, mitochondrial dysfunction, and antioxidant system defects, which were reversed by PINK1 overexpression. Our data support a critical role of PINK1-mediated mitophagy in controlling mitochondrial quality, tau hyperphosphorylation, and oxidative stress in a rat model of Alzheimer's disease.

Keywords:  Alzheimer’s disease; Forskolin; Nrf2 signaling; PI3K/Akt/GSK3β signaling; PINK1; Tau hyperphosphorylation; mitophagy; oxidative stress

DOI:  https://doi.org/10.1038/s41401-021-00810-5
Aging Dis. 2021 Dec;12(8): 2080-2095

Bioenergetic Impairment in the Neuro-Glia-Vascular Unit: An Emerging Physiopathology during Aging.

Minghao Yuan, Yangyang Wang, Shengyuan Wang, Zhenting Huang, Feng Jin, Qian Zou, Jing Li, Yinshuang Pu, Zhiyou Cai.

  An emerging concept termed the "neuro-glia-vascular unit" (NGVU) has been established in recent years to understand the complicated mechanism of multicellular interactions among vascular cells, glial cells, and neurons. It has been proverbially reported that the NGVU is significantly associated with neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Physiological aging is an inevitable progression associated with oxidative damage, bioenergetic alterations, mitochondrial dysfunction, and neuroinflammation, which is partially similar to the pathology of AD. Thus, senescence is regarded as the background for the development of neurodegenerative diseases. With the exacerbation of global aging, senescence is an increasingly serious problem in the medical field. In this review, the coupling of each component, including neurons, glial cells, and vascular cells, in the NGVU is described in detail. Then, various mechanisms of age-dependent impairment in each part of the NGVU are discussed. Moreover, the potential bioenergetic alterations between different cell types in the NGVU are highlighted, which seems to be an emerging physiopathology associated with the aged brain. Bioenergetic intervention in the NGVU may be a new direction for studies on delaying or diminishing aging in the future.

Keywords:  aging; energy metabolism; neuro-glia-vascular unit

DOI:  https://doi.org/10.14336/AD.2021.04017
Front Pharmacol. 2021 ;12 698833

Modulatory Effects of Alpha- and Gamma-Tocopherol on the Mitochondrial Respiratory Capacity and Membrane Potential in an In Vitro Model of Alzheimer's Disease.

Aslina Pahrudin Arrozi, Wan Zurinah Wan Ngah, Hanafi Ahmad Damanhuri, Suzana Makpol.

  Increased amyloid-beta (Aβ) and amyloid precursor protein (APP) in the brains of Alzheimer's disease (AD) patients are common pathological hallmarks mediating the disease progression. Growing evidence also suggests that mitochondrial abnormalities are an early feature in the pathogenesis of AD. Intervention with antioxidants has received great interest as a molecular strategy for the manipulation of mitochondrial function. Our previous preliminary study using in vitro cell models expressing different types of APP demonstrated that treatment with alpha-tocopherol (ATF) or gamma-tocopherol (GTF) modulates mitochondrial function by reducing mitochondrial reactive oxygen species (ROS), increasing the production of ATP and preventing apoptosis events, especially in cells expressing the mutant APP form. Thus, we hypothesized that ATF or GTF treatment might also alter mitochondrial metabolic pathways such as oxidative phosphorylation. The present study aimed to investigate the role of ATF and GTF in modulating mitochondrial oxidative metabolism using high-resolution respirometry. Our results showed that both ATF and GTF increased the respiratory capacity and membrane potential in the ROUTINE and OXPHOSCI-LINKED states as well as complex IV enzyme activity in wild-type and mutant APP-overexpressing SH-SY5Y cells. Although preliminary, these findings indicate that ATF and GTF modulate mitochondrial oxidative metabolism in APP-overexpressing cells and, in part, may contribute to the planning of strategies for utilizing vitamin E isomers against mitochondrial-related diseases such as AD.

Keywords:  Alzheimer’s disease; amyloid precursor proteins; membrane potential; respiratory capacity; tocopherol

DOI:  https://doi.org/10.3389/fphar.2021.698833
Biomol Ther (Seoul). 2021 Dec 07.

Oleanolic Acid Provides Neuroprotection against Ischemic Stroke through the Inhibition of Microglial Activation and NLRP3 Inflammasome Activation.

Arjun Sapkota, Ji Woong Choi.

  Oleanolic acid (OA), a natural pentacyclic triterpenoid, has been reported to exert protective effects against several neurological diseases through its anti-oxidative and anti-inflammatory activities. The goal of the present study was to evaluate the therapeutic potential of OA against acute and chronic brain injuries after ischemic stroke using a mouse model of transient middle cerebral artery occlusion (tMCAO, MCAO/reperfusion). OA administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, functional neurological deficits, and neuronal apoptosis. Moreover, delayed administration of OA (at 3 h after reperfusion) attenuated brain infarction and improved functional neurological deficits during the acute phase. Such neuroprotective effects were associated with attenuation of microglial activation and lipid peroxidation in the injured brain after the tMCAO challenge. OA also attenuated NLRP3 inflammasome activation in activated microglia during the acute phase. In addition, daily administration of OA for 7 days starting from either immediately after reperfusion or 1 day after reperfusion significantly improved functional neurological deficits and attenuated brain tissue loss up to 21 days after the tMCAO challenge; these findings supported therapeutic effects of OA against ischemic stroke-induced chronic brain injury. Together, these findings showed that OA exerted neuroprotective effects against both acute and chronic brain injuries after tMCAO challenge, suggesting that OA is a potential therapeutic agent to treat ischemic stroke.

Keywords:  Ischemic stroke; Lipid peroxidation; Microglia; NLRP3 inflammasome activation; Oleanolic acid

DOI:  https://doi.org/10.4062/biomolther.2021.154
Front Cell Dev Biol. 2021 ;9 780207

Mitochondria in Early Forebrain Development: From Neurulation to Mid-Corticogenesis.

Ryann M Fame, Maria K Lehtinen.

  Function of the mature central nervous system (CNS) requires a substantial proportion of the body's energy consumption. During development, the CNS anlage must maintain its structure and perform stage-specific functions as it proceeds through discrete developmental stages. While key extrinsic signals and internal transcriptional controls over these processes are well appreciated, metabolic and mitochondrial states are also critical to appropriate forebrain development. Specifically, metabolic state, mitochondrial function, and mitochondrial dynamics/localization play critical roles in neurulation and CNS progenitor specification, progenitor proliferation and survival, neurogenesis, neural migration, and neurite outgrowth and synaptogenesis. With the goal of integrating neurodevelopmental biologists and mitochondrial specialists, this review synthesizes data from disparate models and processes to compile and highlight key roles of mitochondria in the early development of the CNS with specific focus on forebrain development and corticogenesis.

Keywords:  corticogenesis; development; forebrain; metabolism; mitochondria; neural tube closure; neurulation

DOI:  https://doi.org/10.3389/fcell.2021.780207
IUBMB Life. 2021 Dec 10.

Mitophagy in aging and longevity.

Jing Guo, Wei-Chung Chiang.

  The clearance of damaged or unwanted mitochondria by autophagy (also known as mitophagy) is a mitochondrial quality control mechanism postulated to play an essential role in cellular homeostasis, metabolism, and development and confers protection against a wide range of diseases. Proper removal of damaged or unwanted mitochondria is essential for organismal health. Defects in mitophagy are associated with Parkinson's, Alzheimer's disease, cancer, and other degenerative disorders. Mitochondria regulate organismal fitness and longevity via multiple pathways, including cellular senescence, stem cell function, inflammation, mitochondrial unfolded protein response (mtUPR), and bioenergetics. Thus, mitophagy is postulated to be pivotal for maintaining organismal healthspan and lifespan and the protection against aged-related degeneration. In this review, we will summarize recent understanding of the mechanism of mitophagy and aspects of mitochondrial functions. We will focus on mitochondria-related cellular processes that are linked to aging and examine current genetic evidence that supports the hypothesis that mitophagy is a pro-longevity mechanism.

Keywords:  aging; longevity; mitophagy

DOI:  https://doi.org/10.1002/iub.2585
CNS Neurosci Ther. 2021 Dec 10.

Ketogenic diet ameliorates cognitive impairment and neuroinflammation in a mouse model of Alzheimer's disease.

Yunlong Xu, Chenyu Jiang, Junyan Wu, Peidong Liu, Xiaofei Deng, Yadong Zhang, Bo Peng, Yingjie Zhu.

   INTRODUCTION: Alzheimer's disease (AD) is the most common neurodegenerative disorder that causes dementia and affects millions of people worldwide. Although it has devastating outcomes for patients and tremendous economic costs to society, there is currently no effective treatment available.
AIMS: The high-fat, low-carbohydrate ketogenic diet (KD) is an established treatment for refractory epilepsy with a proven efficacy. Although the considerable interest has emerged in recent years for applying KD in AD patients, only few interventional studies in animals and humans have addressed the effects of KD on cognitive impairments, and the results were inconclusive. The aim of this study was to explore the impact of KD on cognitive functions and AD pathology in 5XFAD mice-a validated animal model of AD.
RESULTS: Four months of a ketogenic diet improved spatial learning, spatial memory and working memory in 5XFAD mice. The improvement in cognitive functions was associated with a restored number of neurons and synapses in both the hippocampus and the cortex. Ketogenic diet treatment also reduced amyloid plaque deposition and microglial activation, resulting in reduced neuroinflammation. The positive effect of ketogenic diet on cognitive functions depended on the starting time and the duration of the diet. A shorter period (2 months) of ketogenic diet treatment had a weaker effect. Ketogenic diet initiated at late stage of AD (9 months of age) displayed no effect on cognitive improvement.
CONCLUSIONS: These findings indicate positive effects of ketogenic diet on both cognitive function and histopathology in Alzheimer's disease, which could be due to reduced microglial activation and neuroinflammation. Our findings provide new insights and therapeutic interventions for the treatment of Alzheimer's disease.

Keywords:  Alzheimer's disease; cognitive impairment; ketogenic diet; microglial activation; neuroinflammation

DOI:  https://doi.org/10.1111/cns.13779
Cell Rep. 2021 Dec 07. pii: S2211-1247(21)01596-5. [Epub ahead of print]37(10): 110102

Aberrant role of pyruvate kinase M2 in the regulation of gamma-secretase and memory deficits in Alzheimer's disease.

Jonghee Han, Junho Hyun, Jaesang Park, Sunmin Jung, Yoonseo Oh, Youbin Kim, Shin-Hyeon Ryu, Seo-Hyun Kim, Eun Il Jeong, Dong-Gyu Jo, Sung-Hye Park, Yong-Keun Jung.

  Toxic amyloid beta (Aβ) species cause synaptic dysfunction and neurotoxicity in Alzheimer's disease (AD). As of yet, however, there are no reported regulators for gamma-secretase, which links a risky environment to amyloid accumulation in AD. Here, we report that pyruvate kinase M2 (PKM2) is a positive regulator of gamma-secretase under hypoxia. From a genome-wide functional screen, we identify PKM2 as a gamma-secretase activator that is highly expressed in the brains of both patients and murine models with AD. PKM2 regulates Aβ production and the amount of active gamma-secretase complex by changing the gene expression of aph-1 homolog. Hypoxia induces PKM2 expression, thereby promoting gamma-secretase activity. Moreover, transgenic expression of PKM2 in 3xTg AD model mice enhances hippocampal production of Aβ and exacerbates the impairment of spatial and recognition memory. Taken together, these findings indicate that PKM2 is an important gamma-secretase regulator that promotes Aβ production and memory impairment under hypoxia.

Keywords:  Alzheimer’s disease; amyloid beta; gamma-secretase; hypoxia; pyruvate kinase M2

DOI:  https://doi.org/10.1016/j.celrep.2021.110102
Aging Dis. 2021 Dec;12(8): 2003-2015

Potential Crosstalk Between Parkinson's Disease and Energy Metabolism.

Meiqiu Liu, Qian Jiao, Xixun Du, Mingxia Bi, Xi Chen, Hong Jiang.

  Parkinson's disease (PD) is characterized by the accumulation of alpha-synuclein (α-Syn) in the substantia nigra (SN) and the degeneration of nigrostriatal dopaminergic (DAergic) neurons. Some studies have reported that the pathology of PD originates from the gastrointestinal (GI) tract, which also serves as an energy portal, and develops upward along the neural pathway to the central nervous system (CNS), including the dorsal motor nucleus of vagus (DMV), SN, and hypothalamus, which are also involved in energy metabolism control. Therefore, we discuss the alterations of nuclei that regulate energy metabolism in the development of PD. In addition, due to their anti-inflammatory, antiapoptotic and antioxidative roles, metabolism-related peptides are involved in the progression of PD. Furthermore, abnormal glucose and lipid metabolism are common in PD patients and exacerbate the pathological changes in PD. Therefore, in this review, we attempt to explain the correlation between PD and energy metabolism, which may provide possible strategies for PD treatment.

Keywords:  Energy metabolism; Hypercholesterolemia; Metabolism-related peptides; Obesity; Parkinson’s disease; T2DM

DOI:  https://doi.org/10.14336/AD.2021.0422
Adv Neurobiol. 2021 ;26 21-53

Astrocytes: The Housekeepers and Guardians of the CNS.

Alexei Verkhratsky, Vladimir Parpura, Baoman Li, Caterina Scuderi.

  Astroglia are a diverse group of cells in the central nervous system. They are of the ectodermal, neuroepithelial origin and vary in morphology and function, yet, they can be collectively defined as cells having principle function to maintain homeostasis of the central nervous system at all levels of organisation, including homeostasis of ions, pH and neurotransmitters; supplying neurones with metabolic substrates; supporting oligodendrocytes and axons; regulating synaptogenesis, neurogenesis, and formation and maintenance of the blood-brain barrier; contributing to operation of the glymphatic system; and regulation of systemic homeostasis being central chemosensors for oxygen, CO2 and Na+. Their basic physiological features show a lack of electrical excitability (inapt to produce action potentials), but display instead a rather active excitability based on variations in cytosolic concentrations of Ca2+ and Na+. It is expression of neurotransmitter receptors, pumps and transporters at their plasmalemma, along with transports on the endoplasmic reticulum and mitochondria that exquisitely regulate the cytosolic levels of these ions, the fluctuation of which underlies most, if not all, astroglial homeostatic functions.

Keywords:  Astroglia; Brain homoeostasis; Ca2+ signalling; Ion channels; Na+ signalling; Neurotransmitter receptors; SLC transporters

DOI:  https://doi.org/10.1007/978-3-030-77375-5_2
IUBMB Life. 2021 Dec 07.

Drosophila as a model to study autophagy in neurodegenerative diseases and digestive tract.

Fei-Yang Tzou, Jung-Kun Wen, Jui-Yu Yeh, Shu-Yi Huang, Guang-Chao Chen, Chih-Chiang Chan.

  Autophagy regulates cellular homeostasis by degrading and recycling cytosolic components and damaged organelles. Disruption of autophagic flux has been shown to induce or facilitate neurodegeneration and accumulation of autophagic vesicles is overt in neurodegenerative diseases. The fruit fly Drosophila has been used as a model system to identify new factors that regulate physiology and disease. Here we provide a historical perspective of how the fly models have offered mechanistic evidence to understand the role of autophagy in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Charcot-Marie-Tooth neuropathy, and polyglutamine disorders. Autophagy also plays a pivotal role in maintaining tissue homeostasis and protecting organism health. The gastrointestinal tract regulates organism health by modulating food intake, energy balance, and immunity. Growing evidence is strengthening the link between autophagy and digestive tract health in recent years. Here, we also discuss how the fly models have advanced the understanding of digestive physiology regulated by autophagy.

Keywords:  autophagy; digestive tract; drosophila; neurodegenerative diseases

DOI:  https://doi.org/10.1002/iub.2583
Sci Rep. 2021 Dec 08. 11(1): 23576

Effects of exercise training on behavior and brain function after high dose isoproterenol-induced cardiac damage.

Kata Tóth, Tamás Oroszi, Eddy A van der Zee, Csaba Nyakas, Regien G Schoemaker.

Acute sympathetic stress can result in cardiac fibrosis, but may also lead to mental dysfunction. Exercise training after isoproterenol (ISO)-induced acute sympathetic stress was investigated regarding cardiac damage, neuroinflammation, brain function and behavior. Male Wistar rats (12 months) received ISO or saline. One week later, treadmill running or control handling (sedentary) started. After 4 weeks, cognitive- and exploratory behavior were evaluated, and heart and brain tissues were analyzed regarding cardiac damage, hippocampal neuroinflammation and neuronal function. ISO did not affect cognitive performance nor hippocampal function. However, ISO reduced anxiety, coinciding with locally reduced microglia (processes) size in the hippocampus. Exercise in ISO rats reversed anxiety, did not affect microglia morphology, but increased brain function. Thus, exercise after ISO did not affect cardiac damage, cognition or hippocampal neuroinflammation, but normalized anxiety. Increased localized BDNF expression may indicate improved brain function.

DOI: https://doi.org/10.1038/s41598-021-03107-z
Dis Model Mech. 2021 Dec 01. pii: dmm049152. [Epub ahead of print]14(12):

Altered protein secretion in Batten disease.

Robert J Huber.

  The neuronal ceroid lipofuscinoses (NCLs), collectively known as Batten disease, are a group of neurological diseases that affect all ages and ethnicities worldwide. There are 13 different subtypes of NCL, each caused by a mutation in a distinct gene. The NCLs are characterized by the accumulation of undigestible lipids and proteins in various cell types. This leads to progressive neurodegeneration and clinical symptoms including vision loss, progressive motor and cognitive decline, seizures, and premature death. These diseases have commonly been characterized by lysosomal defects leading to the accumulation of undigestible material but further research on the NCLs suggests that altered protein secretion may also play an important role. This has been strengthened by recent work in biomedical model organisms, including Dictyostelium discoideum, mice, and sheep. Research in D. discoideum has reported the extracellular localization of some NCL-related proteins and the effects of NCL-related gene loss on protein secretion during unicellular growth and multicellular development. Aberrant protein secretion has also been observed in mammalian models of NCL, which has allowed examination of patient-derived cerebrospinal fluid and urine for potential diagnostic and prognostic biomarkers. Accumulated evidence links seven of the 13 known NCL-related genes to protein secretion, suggesting that altered secretion is a common hallmark of multiple NCL subtypes. This Review highlights the impact of altered protein secretion in the NCLs, identifies potential biomarkers of interest and suggests that future work in this area can provide new therapeutic insight.

Keywords:   Dictyostelium discoideum ; Batten disease; Cerebrospinal fluid; Model system; Neuronal ceroid lipofuscinosis; Secretion; Urine

DOI:  https://doi.org/10.1242/dmm.049152
Front Pharmacol. 2021 ;12 751028

β-hydroxybutyrate Alleviates Learning and Memory Impairment Through the SIRT1 Pathway in D-Galactose-Injured Mice.

Xiaojing Yang, Ruonan Wang, Hailun Zhou, Li Wang, Rui Wang, Haomin Li, Baodong Tan, Qiong Wu, Xin Xu, Lianxu Cui, Zaiyu Li, Hua Li.

  Learning and memory impairment is a common clinical symptom of aging and nervous system injuries, and seriously affects quality of life. Memory impairment is associated with increased oxidative stress (OS) and inflammatory response. β-hydroxybutyrate (BHBA) is a water-soluble endogenous small-molecule ketone body that easily crosses the blood-brain barrier and has shown neuroprotection activities. In this study, we investigated the effects and mechanisms of BHBA on D-galactose (D-gal)-induced memory impairment in mice by in vitro and in vivo experiments. BHBA was administered intragastrically to D-gal-injured C57BL/6 mice for 42 days. Water maze performance, the morphology of the hippocampus with Nissl staining, the ACh content, OS, and inflammation status were examined. To further investigate the mechanism, hippocampal neuronal cells (HT22) were treated with BHBA with or without the SIRT1 inhibitor or small interfering RNAs against sirt1 (si-SIRT1) before incubation with D-gal. BHBA significantly improved water maze performance; increased the ACh content, SOD activity, and SIRT1 expression; and decreased AChE and LDH activity, ROS, MDA, IL-1β, TNF-α contents, and NLRP3 expression. Further studies with the SIRT inhibitor or siRNAs against sirt1 reversed the above effects of BHBA. Collectively, BHBA inhibited hippocampal OS and the inflammation process to alleviate learning and memory impairment through activating the SIRT1 pathway in D-gal-injured mice, suggesting that BHBA could be a potential option for drug development of learning and memory impairment induced by nervous system injuries.

Keywords:  FoxO3a; NLRP3; SIRT1; learning and memory impairment; oxidative stress; β-hydroxybutyrate

DOI:  https://doi.org/10.3389/fphar.2021.751028
J Alzheimers Dis. 2021 Dec 01.

High Fat Diet Mediates Amyloid-β Cleaving Enzyme 1 Phosphorylation and SUMOylation, Enhancing Cognitive Impairment in APP/PS1 Mice.

Jian Bao, Zheng Liang, Xiaokang Gong, Jing Yu, Yifan Xiao, Wei Liu, Xiaochuan Wang, Jian-Zhi Wang, Xiji Shu.

   BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in older adults and extracellular accumulation of amyloid-β (Aβ) is one of the two characterized pathologies of AD. Obesity is significantly associated with AD developing factors. Several studies have reported that high fat diet (HFD) influenced Aβ accumulation and cognitive performance during AD pathology. However, the underlying neurobiological mechanisms have not yet been elucidated.
OBJECTIVE: The objective of this study was to explore the underlying neurobiological mechanisms of HFD influenced Aβ accumulation and cognitive performance during AD pathology.
METHODS: 2.5-month-old male APP/PS1 mice were randomly separated into two groups: 1) the normal diet (ND) group, fed a standard diet (10 kcal%fat); and 2) the HFD group, fed a high fat diet (40 kcal%fat, D12492; Research Diets). After 4 months of HFD or ND feeding, mice in the two groups were subjected for further ethological, morphological, and biochemical analyses.
RESULTS: A long-term HFD diet significantly increased perirenal fat and impaired dendritic integrity and aggravated neurodegeneration, and augmented learning and memory deficits in APP/PS1 mice. Furthermore, the HFD increased beta amyloid cleaving enzyme 1 (BACE1) dephosphorylation and SUMOylation, resulting in enhanced enzyme activity and stability, which exacerbated the deposition of amyloid plaques.
CONCLUSION: Our study demonstrates that long-term HFD consumption aggravates amyloid-β accumulation and cognitive impairments, and that modifiable lifestyle factors, such as obesity, can induce BACE1 post-modifications which may contribute to AD pathogenesis.

Keywords:  Alzheimer’s disease; BACE1; SUMOylation; high fat; phosphorylation

DOI:  https://doi.org/10.3233/JAD-215299
Free Radic Biol Med. 2021 Dec 04. pii: S0891-5849(21)00855-8. [Epub ahead of print]178 134-146

Neuroinflammation-mediated mitochondrial dysregulation involved in postoperative cognitive dysfunction.

Yan Yang, Yue Liu, Jixiang Zhu, Shiyu Song, Yulin Huang, Wei Zhang, Yu'e Sun, Jing Hao, Xuli Yang, Qian Gao, Zhengliang Ma, Juan Zhang, Xiaoping Gu.

  Neuroinflammation following peripheral surgery is a pivotal pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the key site of inflammation-mediated neural damage remains unclear. Impaired mitochondrial function is a vital feature of degenerated neurons. Dynamin-related protein 1 (DRP1), a crucial regulator of mitochondrial dynamics, has been shown to play an essential role in synapse formation. Here, we designed experiments to assess whether Drp1-regulated mitochondrial dynamics and function are involved in the pathological processes of POCD and elucidate its relationship with neuroinflammation. Aged mice were subjected to experimental laparotomy under isoflurane anesthesia. Primary neurons and SH-SY5Y cells were exposed to tumor necrosis factor (TNF). We found an increase in Drp1 activation as well as mitochondrial fragmentation both in the hippocampus of mice after surgery and primary neurons after TNF exposure. Pretreatment with Mdivi-1, a Drp1 specific inhibitor, reduced this mitochondrial fragmentation. Drp1 knockdown with small interfering RNA blocked TNF-induced mitochondrial fragmentation in SH-SY5Y cells. However, the application of Mdivi-1 exhibited a negative impact on mitochondrial function and neurite growth in primary neurons. Calcineurin activity was increased in primary neurons after TNF exposure and contributed to the Drp1 activation. The calcineurin inhibitor FK506 exhibited a Drp1-independent function that mitigated mitochondrial dysfunction. Finally, we found that FK506 pretreatment ameliorated the neurite growth in neurons treated with TNF and the learning ability of mice after surgery. Overall, our research indicated a crucial role of mitochondrial function in the pathological processes of POCD, and neuronal metabolic modulation may represent a novel and important target for POCD.

Keywords:  Calcineurin; Drp1; Mitochondrial function; Neuroinflammation; POCD

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.12.004
Adv Neurobiol. 2021 ;26 283-313

Brain Volume Loss, Astrocyte Reduction, and Inflammation in Anorexia Nervosa.

Jochen Seitz, Stefanie Trinh, Vanessa Kogel, Cordian Beyer.

  Anorexia nervosa is the third most common chronic disease in adolescence and is characterized by low body weight, body image distortion, weight phobia, and severe somatic consequences. Among the latter, marked brain volume reduction has been linked to astrocyte cell count reduction of about 50% in gray and white matter, while neuronal and other glial cell counts remain normal. Exact underlying mechanisms remain elusive; however, first results point to important roles of the catabolic state and the very low gonadal steroid hormones in these patients. They also appear to involve inflammatory states of "hungry astrocytes" and interactions with the gut microbiota. Functional impairments could affect the role of astrocytes in supporting neurons metabolically, neurotransmitter reuptake, and synapse formation, among others. These could be implicated in reduced learning, mood alterations, and sleep disturbances often seen in patients with AN and help explain their rigidity and difficulties in relearning processes in psychotherapy during starvation.

Keywords:  Activated astrocytes; Activity-based anorexia; Anorexia nervosa; Astrocyte cell count; Brain volume reduction; Gonadal steroid hormone reduction; Gut-brain axis; Inflammation; Microbiota; Neurocognitive deficits

DOI:  https://doi.org/10.1007/978-3-030-77375-5_12
Int J Mol Sci. 2021 Dec 03. pii: 13081. [Epub ahead of print]22(23):

Korean Red Ginseng Improves Astrocytic Mitochondrial Function by Upregulating HO-1-Mediated AMPKα-PGC-1α-ERRα Circuit after Traumatic Brain Injury.

Minsu Kim, Joohwan Kim, Sunhong Moon, Bo Young Choi, Sueun Kim, Hui Su Jeon, Sang Won Suh, Young-Myeong Kim, Yoon Kyung Choi.

  Heme oxygenase-1 (HO-1) exerts beneficial effects, including angiogenesis and energy metabolism via the peroxisome proliferator-activating receptor-γ coactivator-1α (PGC-1α)-estrogen-related receptor α (ERRα) pathway in astrocytes. However, the role of Korean red ginseng extract (KRGE) in HO-1-mediated mitochondrial function in traumatic brain injury (TBI) is not well-elucidated. We found that HO-1 was upregulated in astrocytes located in peri-injured brain regions after a TBI, following exposure to KRGE. Experiments with pharmacological inhibitors and target-specific siRNAs revealed that HO-1 levels highly correlated with increased AMP-activated protein kinase α (AMPKα) activation, which led to the PGC-1α-ERRα axis-induced increases in mitochondrial functions (detected based on expression of cytochrome c oxidase subunit 2 (MTCO2) and cytochrome c as well as O2 consumption and ATP production). Knockdown of ERRα significantly reduced the p-AMPKα/AMPKα ratio and PGC-1α expression, leading to AMPKα-PGC-1α-ERRα circuit formation. Inactivation of HO by injecting the HO inhibitor Sn(IV) protoporphyrin IX dichloride diminished the expression of p-AMPKα, PGC-1α, ERRα, MTCO2, and cytochrome c in the KRGE-administered peri-injured region of a brain subjected to TBI. These data suggest that KRGE enhanced astrocytic mitochondrial function via a HO-1-mediated AMPKα-PGC-1α-ERRα circuit and consequent oxidative phosphorylation, O2 consumption, and ATP production. This circuit may play an important role in repairing neurovascular function after TBI in the peri-injured region by stimulating astrocytic mitochondrial biogenesis.

Keywords:  AMPKα–PGC-1α–ERRα circuit; Korean red ginseng; astrocytic mitochondrial function; heme oxygenase-1; traumatic brain injury

DOI:  https://doi.org/10.3390/ijms222313081
Adv Neurobiol. 2021 ;26 349-365

Ketamine Action on Astrocytes Provides New Insights into Rapid Antidepressant Mechanisms.

Matjaž Stenovec, Baoman Li, Alexei Verkhratsky, Robert Zorec.

  Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, exerts rapid, potent and long-lasting antidepressant effect already after a single administration of a low dose into depressed individuals. Apart from targeting neuronal NMDARs essential for synaptic transmission, ketamine also interacts with astrocytes, the principal homoeostatic cells of the central nervous system. The cellular mechanisms underlying astrocyte-based rapid antidepressant effect are incompletely understood. Here we overview recent data that describe ketamine-dependent changes in astrocyte cytosolic cAMP activity ([cAMP]i) and ketamine-induced modifications of stimulus-evoked Ca2+ signalling. The latter regulates exocytotic release of gliosignalling molecules and stabilizes the vesicle fusion pore in a narrow configuration that obstructs cargo discharge or vesicle membrane recycling. Ketamine also instigates rapid redistribution of cholesterol in the astrocyte plasmalemma that may alter flux of cholesterol to neurones, where it is required for changes in synaptic plasticity. Finally, ketamine attenuates mobility of vesicles carrying the inward rectifying potassium channel (Kir4.1) and reduces the surface density of Kir4.1 channels that control extracellular K+ concentration, which tunes the pattern of action potential firing in neurones of lateral habenula as demonstrated in a rat model of depression. Thus, diverse, but not mutually exclusive, mechanisms act synergistically to evoke changes in synaptic plasticity leading to sustained strengthening of excitatory synapses necessary for rapid antidepressant effect of ketamine.

Keywords:  Astrocytes; Cholesterol; Endocytosis; Excitability; Exocytosis; Ketamine

DOI:  https://doi.org/10.1007/978-3-030-77375-5_14
Neurosci Biobehav Rev. 2021 Dec 02. pii: S0149-7634(21)00548-0. [Epub ahead of print]

The Role of Mitochondria in the Pathophysiology of Schizophrenia: A Critical Review of the Evidence Focusing on Mitochondrial Complex One.

Thomas Whitehurst, Oliver Howes.

  There has been increasing interest in the role of mitochondrial dysfunction in the pathophysiology of schizophrenia. Dysfunction of mitochondrial complex one (MCI), has been viewed as a potential aetiological mechanism by which mitochondrial dysfunction might interact with alterations in dopamine signalling, glutamatergic dysfunction, and oxidative stress. New lines of evidence from novel approaches make it timely to review evidence for mitochondrial involvement in schizophrenia, with a specific focus on MCI. The most consistent findings in schizophrenia relative to controls are reductions in expression of MCI subunits in post-mortem brain tissue (Cohen's d>0.8); reductions in MCI function in post-mortem brains (d>0.7); and reductions in neural glucose utilisation (d = 0.3-0.6). Antipsychotics may affect glucose utilisation, and, at least in vitro, affect MC1. The findings overall are consistent with MCI dysfunction in schizophrenia, but also highlight the need for in vivo studies to determine the link between MCI dysfunction and symptoms in patients. If new imaging tools confirm MCI dysfunction in the disease, this could pave the way for new treatments targeting this enzyme.

Keywords:  NADH:ubiquinone oxidoreductase; Respiratory complex I; metabolism; mitochondria; mitochondrial complex one; mitochondrial dysfunction; neuroimaging; post-mortem; psychosis; schizophrenia

DOI:  https://doi.org/10.1016/j.neubiorev.2021.11.047
Int J Mol Sci. 2021 Nov 29. pii: 12924. [Epub ahead of print]22(23):

Impact of Oxidative DNA Damage and the Role of DNA Glycosylases in Neurological Dysfunction.

Mirta Mittelstedt Leal de Sousa, Jing Ye, Luisa Luna, Gunn Hildrestrand, Karine Bjørås, Katja Scheffler, Magnar Bjørås.

  The human brain requires a high rate of oxygen consumption to perform intense metabolic activities, accounting for 20% of total body oxygen consumption. This high oxygen uptake results in the generation of free radicals, including reactive oxygen species (ROS), which, at physiological levels, are beneficial to the proper functioning of fundamental cellular processes. At supraphysiological levels, however, ROS and associated lesions cause detrimental effects in brain cells, commonly observed in several neurodegenerative disorders. In this review, we focus on the impact of oxidative DNA base lesions and the role of DNA glycosylase enzymes repairing these lesions on brain function and disease. Furthermore, we discuss the role of DNA base oxidation as an epigenetic mechanism involved in brain diseases, as well as potential roles of DNA glycosylases in different epigenetic contexts. We provide a detailed overview of the impact of DNA glycosylases on brain metabolism, cognition, inflammation, tissue loss and regeneration, and age-related neurodegenerative diseases based on evidence collected from animal and human models lacking these enzymes, as well as post-mortem studies on patients with neurological disorders.

Keywords:  DNA glycosylases; DNA repair; epigenetic markers; neurological disorders; oxidative DNA lesions

DOI:  https://doi.org/10.3390/ijms222312924
Drug Metab Lett. 2021 Dec 08.

Ameliorative effect of Acetyl L-carnitine in Alzheimer's Disease via Downregulating of Homocysteine Levels in Hyperhomocysteinemia Induced Cognitive Deficit in mouse model.

Nisha Verma, Jeetendra Kumar Gupta, Krishna Kumar Varshney, Rajnish Srivastava.

   AIM: The study was aimed at exploring the role of Acetyl L-Carnitine supplementation attenuating dementia and degradation of cognitive abilities in Hyperhomocysteinemia induced AD manifestations in the mouse model.
BACKGROUND: Alzheimer's disease (AD) is a neurological disorder that is marked by dementia, and degradation of cognitive abilities. There is great popularity gained by natural supplements as the treatment for AD, due to the higher toxicities of synthetic drugs. Hyperhomocysteinemia causes excitotoxicity to the cortical neurons, which brought us to the point that amino acids possibly have a role in causing cholinergic deformities, which are an important etiological parameter in AD. Acetyl L-Carnitine a methyl donor with the presence of three chemically reactive methyl groups linked to a nitrogen atom was found to possess neuroprotective activity against experimental models of AD.
OBJECTIVE: The objective of the present investigation was to investigate and evaluate the pharmacological effect of Acetyl L-Carnitine against hyperhomocysteinemia induced Alzheimer's disease (AD) in the mouse model.
MATERIAL AND METHOD: The animals were divided into normal control (vehicle-treated), HHcy (dl-Homocysteine thiolactone treated) negative control, test group i.e., low dose (50mg/kg, p.o) of acetyl L-carnitine (L-ALC), high dose (100mg/kg,p.o) of acetyl L-carnitine (H-ALC), L-ALC+SOV (Sodium orthovanadate) and H-ALC+SOV. HHcy was induced by administration of dl-Homocysteine thiolactone (dl-HCT; 1 g/kg, p.o.) on day-1 to day-15 of experimental schedule to all animals except normal control. The changes in the behaviour pattern of the animals due to neuroinflammation, and cholinergic dysfunction were examined in rotarod, novel objective recognition, passive avoidance, elevated plus maze, and morris water maze analysis. Biochemical investigation includes the estimation of total homocysteine (tHcy), Creatinine Kinase (CK), Acetylcholinesterase (AChE), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and IL-6 and TNF-α.
RESULT: Supplementation of ALC in mouse considerably lowered the HHcy-induced AD manifestations in the experimental animals. It was found that ALC and SOV successfully diminished the behaviour abnormalities and lessened the Hcy-induced alteration in systemic Hcy levels, CK activity, and cholinergic dysfunction with improved bioenergetics in the Prefrontal cortex of the mice.
CONCLUSION: ALC was found to improve the HHcy-induced cognitive disabilities which was found to be associated with the decreased systemic levels of Hcy, CK, and cholinergic abnormalities. It also combats the oxidative stress-induced neuroinflammation with diminished pro-inflammatory markers in the pre frontal cortex. The outcomes collectively indicate ALC's potential to be used as a supplementation in the pharmacotherapy of AD.

Keywords:  Acetyl L-Carnitine; Alzheimer's disease; Hyperhomocysteinemia; Methyl donor; Prefrontal cortex; Sodium orthovanadate

DOI:  https://doi.org/10.2174/1872312814666211209102136
Curr Opin Lipidol. 2021 Dec 09.

Dietary factors and brain health.

Sophie Lefèvre-Arbogast, Aline Thomas, Cécilia Samieri.

PURPOSE OF REVIEW: Nutrition is a complex exposure (i.e., the food exposome) that influences brain function and health through multiple pathways. We review recent epidemiological studies that have improved the characterization of the food exposome and brain health in humans and have revealed promising nutrition-based strategies to prevent cognitive aging.
RECENT FINDINGS: A selection of epidemiological research from the past 18 months of both observational and clinical studies is presented, with a focus on novel findings, including novel nutrient and diet patterns, diet-related approaches to rescue brain energetics defects in aging, and biomarker-based studies to decipher specific neurobiological pathways of nutrition and brain health.
SUMMARY: Although healthy diets such as the Mediterranean diet promote brain health throughout life, specific diets, such as the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay diet, or specific nutrients (LC n-3 polyunsaturated fatty acids, carotenoids, vitamin D, B vitamins, polyphenols) alone or in combination, may prevent cognitive aging. Diet management approaches to rescue brain energetics defects such as the Modified Mediterranean-ketogenic diet may be promising to prevent neurodegenerative diseases. Expanding research also suggests that promotion of a healthy gut microbiome through prebiotic foods may preserve the diet-gut-brain axis with aging. Future studies should explore more individualized preventive approaches through a 'precision nutrition' framework.

DOI: https://doi.org/10.1097/MOL.0000000000000803
Behav Brain Res. 2021 Dec 07. pii: S0166-4328(21)00597-0. [Epub ahead of print] 113709

Deep brain stimulation improved depressive-like behaviors and hippocampal synapse deficits by activating the BDNF/mTOR signaling pathway.

Zuoli Sun, Lina Jia, Dandan Shi, Yi He, Yanping Ren, Jian Yang, Xin Ma.

  Our previous study demonstrated that acute deep brain stimulation (DBS) in the ventromedial prefrontal cortex (vmPFC) remarkably improved the depressive-like behaviors in a rat model of chronic unpredictable mild stress (CUS rats). However, the mechanisms by which chronic DBS altered depressive-like behaviors and reversed cognitive impairment have not been clarified. Recent work has shown that deficits in brain-derived neurotrophic factor (BDNF) and its downstream proteins, including mammalian target of rapamycin (mTOR), might be involved in the pathogenesis of depression. Therefore, we hypothesized that the antidepressant-like and cognitive improvement effects of DBS were achieved by activating the BDNF/mTOR pathway. CUS rats received vmPFC DBS at 20Hz for 1h once a day for 28 days. After four weeks of stimulation, the rats were assessed for the presence of depressive-like behaviors and euthanized to detect BDNF/mTOR signaling using immunoblots. DBS at the vmPFC significantly ameliorated depressive-like behaviors and spatial learning and memory deficits in the CUS rats. Furthermore, DBS restored the reduced synaptic density in the hippocampus induced by CUS and increased the expression or activity of BDNF, Akt, and mTOR in the hippocampus. Thus, the antidepressant-like effects and cognitive improvement produced by vmPFC DBS might be mediated through increased activity of the BDNF/mTOR signaling pathway.

Keywords:  brain-derived neurotrophic factor; deep brain stimulation; depression; mammalian target of rapamycin; synapse

DOI:  https://doi.org/10.1016/j.bbr.2021.113709
Front Cell Neurosci. 2021 ;15 774569

Activation of Adenosine Monophosphate-Activated Protein Kinase Drives the Aerobic Glycolysis in Hippocampus for Delaying Cognitive Decline Following Electroacupuncture Treatment in APP/PS1 Mice.

Jianhong Li, Bingxue Zhang, Weiwei Jia, Minguang Yang, Yuhao Zhang, Jiayong Zhang, Le Li, Tingting Jin, Zhifu Wang, Jing Tao, Lidian Chen, Shengxiang Liang, Weilin Liu.

  Aerobic glycolysis (AG), an important pathway of glucose metabolism, is dramatically declined in Alzheimer's disease (AD). AMP-activated protein kinase (AMPK) is a key regulator to maintain the stability of energy metabolism by promoting the process of AG and regulating glucose metabolism. Interestingly, it has been previously reported that electroacupuncture (EA) treatment can improve cognitive function in AD through the enhancement of glucose metabolism. In this study, we generated AMPK-knockdown mice to confirm the EA effect on AMPK activation and further clarify the mechanism of EA in regulating energy metabolism and improving cognitive function in APP/PS1 mice. The behavioral results showed that EA treatment can improve the learning and memory abilities in APP/PS1 mice. At the same time, the glucose metabolism in the hippocampus was increased detected by MRI-chemical exchange saturation transfer (MRI-CEST). The expression of proteins associated with AG in the hippocampus was increased simultaneously, including hexokinase II (HK2), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and pyruvate kinase M2 (PKM2). Moreover, the knockdown of AMPK attenuated AG activated by EA treatment. In conclusion, this study proves that EA can activate AMPK to enhance the process of AG in the early stage of AD.

Keywords:  Alzheimer’s disease; adenosine monophosphate-activated protein kinase (AMPK); aerobic glycolysis; electroacupuncture; learning and memory

DOI:  https://doi.org/10.3389/fncel.2021.774569