bims-brabim 2021-11-21 papers

bims-brabim

Biomed News

on Brain bioenergetics and metabolism

Issue of 2021‒11‒21
thirty-two papers selected by
João Victor Cabral-Costa
University of São Paulo

MicroRNA-455-3p improves synaptic, cognitive functions and extends lifespan: Relevance to Alzheimer's disease.
Energy matters: presynaptic metabolism and the maintenance of synaptic transmission.
Astrocytic ApoE underlies maturation of hippocampal neurons and cognitive recovery after traumatic brain injury in mice.
Diversity and Regulation of Astrocyte Neurotoxicity in Alzheimer's Disease.
OGDHL Ameliorates Cognitive Impairment and Alzheimer's Disease-Like Pathology via Activating Wnt/β-catenin signaling in Alzheimer's Disease Mice.
Infection and Immunometabolism in the Central Nervous System: A Possible Mechanistic Link Between Metabolic Imbalance and Dementia.
New perspectives on cytoskeletal dysregulation and mitochondrial mislocalization in amyotrophic lateral sclerosis.
Irisin Acts via the PGC-1α and BDNF Pathway to Improve Depression-like Behavior.
Fecal microbiota transplantation protects rotenone-induced Parkinson's disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis.
The neuroprotective effect of increased PINK1 expression following glutamate excitotoxicity in neuronal cells.
Cerebral pressure autoregulation in brain injury and disorders - a scoping review on monitoring, management, and future directions.
Understanding how kinesin motor proteins regulate postsynaptic function in neuron.
Docosahexaenoic acid reduces hypoglycemia-induced neuronal necroptosis via the peroxisome proliferator-activated receptor γ/nuclear factor-κB pathway.
Human brain organogenesis: Toward a cellular understanding of development and disease.
PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis.
A Novel Role for BRIP1/FANCJ in Neuronal Cells Health and in Resolving Oxidative Stress-Induced DNA Lesions.
Mitochondrial aconitase 1 regulates age-related memory impairment via autophagy/mitophagy-mediated neural plasticity in middle-aged flies.
Mouse midbrain dopaminergic neurons survive loss of the PD-associated mitochondrial protein CHCHD2.
Early Post-ischemic Brain Glucose Metabolism Is Dependent on Function of TLR2: a Study Using [18F]F-FDG PET-CT in a Mouse Model of Cardiac Arrest and Cardiopulmonary Resuscitation.
Effect of extracellular volume on the energy stored in transmembrane concentration gradients.
Association of Oxidative Stress with Neurological Disorders.
ADHD symptoms in neurometabolic diseases: Underlying mechanisms and clinical implications.
Lactate transporters in the rat barrel cortex sustain whisker-dependent BOLD fMRI signal and behavioral performance.
Neuronal Mitochondrial Dysfunction and Bioenergetic Failure in Inflammation-Associated Depression.
Discovery of a novel pseudo β-hairpin structure of N-truncated amyloid-β for use as a vaccine against Alzheimer's disease.
Targeting CDK5 in Astrocytes Promotes Calcium Homeostasis Under Excitotoxic Conditions.
Electroacupuncture Pretreatment Alleviates Cerebral Ischemia-Reperfusion Injury by Regulating Mitophagy via mTOR-ULK1/FUNDC1 Axis in Rats.
The Therapeutic Potential and Limitations of Ketones in Traumatic Brain Injury.
Alterations in Glycerolipid and Fatty Acid Metabolic Pathways in Alzheimer's Disease Identified by Urinary Metabolic Profiling: A Pilot Study.
Effects of Sex, Age, and Apolipoprotein E Genotype on Brain Ceramides and Sphingosine-1-Phosphate in Alzheimer's Disease and Control Mice.
Mechanisms of ATP release in pain: role of pannexin and connexin channels.
Plasmalogens improve swimming performance by modulating the expression of genes involved in amino acid and lipid metabolism, oxidative stress, and ferroptosis in an Alzheimer's disease zebrafish model.

Redox Biol. 2021 Nov 09. pii: S2213-2317(21)00342-6. [Epub ahead of print]48 102182

MicroRNA-455-3p improves synaptic, cognitive functions and extends lifespan: Relevance to Alzheimer's disease.

Subodh Kumar, Hallie Morton, Neha Sawant, Erika Orlov, Lloyd E Bunquin, Jangampalli Adi Pradeepkiran, Razelle Alvir, P Hemachandra Reddy.

  BACKGROUND: MicroRNA-455-3p is one of the highly conserved miRNAs involved in multiple cellular functions in humans and we explored its relevance to learning and memory functions in Alzheimer's disease (AD). Our recent in vitro studies exhibited the protective role of miR-455-3p against AD toxicities in reducing full-length APP and amyloid-β (Aβ) levels, and also in reducing defective mitochondrial biogenesis, impaired mitochondrial dynamics and synaptic deficiencies. In the current study, we sought to determine the function of miR-455-3p in mouse models.METHODS: For the first time we generated both transgenic (TG) and knockout (KO) mouse models of miR-455-3p. We determined the lifespan extension, cognitive function, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial morphology, dendritic spine density, synapse numbers and synaptic activity in miR-455-3p TG and KO mice.
RESULTS: MiR-455-3p TG mice lived 5 months longer than wild-type (WT) counterparts, whereas KO mice lived 4 months shorter than WT mice. Morris water maze test showed improved cognitive behavior, spatial learning and memory in miR-455-3p TG mice relative to age-matched WT mice and miR-455-3p KO mice. Further, mitochondrial biogenesis, dynamics and synaptic activities were enhanced in miR-455-3p TG mice, while these were reduced in KO mice. Overall, overexpressed miR-455-3p in mice displayed protective effects, whereas depleted miR-455-3p in mice exhibited deleterious effects in relation to lifespan, cognitive behavior, and mitochondrial and synaptic activities.
CONCLUSION: Both mouse models could be ideal research tools to understand the molecular basis of aging and its relevance to AD and other age-related diseases.

Keywords:  Alzheimer's disease; MicroRNA-455-3p; Mitochondrial biogenesis; Mouse models; Synaptic activity

DOI:  https://doi.org/10.1016/j.redox.2021.102182
Nat Rev Neurosci. 2021 Nov 15.

Energy matters: presynaptic metabolism and the maintenance of synaptic transmission.

Sunan Li, Zu-Hang Sheng.

Synaptic activity imposes large energy demands that are met by local adenosine triphosphate (ATP) synthesis through glycolysis and mitochondrial oxidative phosphorylation. ATP drives action potentials, supports synapse assembly and remodelling, and fuels synaptic vesicle filling and recycling, thus sustaining synaptic transmission. Given their polarized morphological features - including long axons and extensive branching in their terminal regions - neurons face exceptional challenges in maintaining presynaptic energy homeostasis, particularly during intensive synaptic activity. Recent studies have started to uncover the mechanisms and signalling pathways involved in activity-dependent and energy-sensitive regulation of presynaptic energetics, or 'synaptoenergetics'. These conceptual advances have established the energetic regulation of synaptic efficacy and plasticity as an exciting research field that is relevant to a range of neurological disorders associated with bioenergetic failure and synaptic dysfunction.

DOI: https://doi.org/10.1038/s41583-021-00535-8
Commun Biol. 2021 Nov 18. 4(1): 1303

Astrocytic ApoE underlies maturation of hippocampal neurons and cognitive recovery after traumatic brain injury in mice.

Tzong-Shiue Yu, Yacine Tensaouti, Elizabeth P Stephanz, Sana Chintamen, Elizabeth E Rafikian, Mu Yang, Steven G Kernie.

Polymorphisms in the apolipoprotein E (ApoE) gene confer a major genetic risk for the development of late-onset Alzheimer's disease (AD) and are predictive of outcome following traumatic brain injury (TBI). Alterations in adult hippocampal neurogenesis have long been associated with both the development of AD and recovery following TBI and ApoE is known to play a role in this process. In order to determine how ApoE might influence hippocampal injury-induced neurogenesis, we generated a conditional knockout system whereby functional ApoE from astrocytes was ablated prior to injury. While successfully ablating ApoE just prior to TBI in mice, we observed an attenuation in the development of the spines in the newborn neurons. Intriguingly, animals with a double-hit, i.e. injury and ApoE conditionally inactivated in astrocytes, demonstrated the most pronounced impairments in the hippocampal-dependent Morris water maze test, failing to exhibit spatial memory after both acquisition and reversal training trials. In comparison, conditional knockout mice without injury displayed impairments but only in the reversal phase of the test, suggesting accumulative effects of astrocytic ApoE deficiency and traumatic brain injury on AD-like phenotypes. Together, these findings demonstrate that astrocytic ApoE is required for functional injury-induced neurogenesis following traumatic brain injury.

DOI: https://doi.org/10.1038/s42003-021-02841-4
Curr Alzheimer Res. 2021 Nov 16.

Diversity and Regulation of Astrocyte Neurotoxicity in Alzheimer's Disease.

Sadayuki Hashioka, James G McLarnon, Andis Klegeris.

  Astrocytes contribute to brain development and homeostasis and support diverse functions of neurons. These cells also respond to the pathological processes in Alzheimer's disease (AD). There is still considerable debate concerning the overall contribution of astrocytes to AD pathogenesis since both the protective and harmful effects of these cells on neuronal survival have been documented. This review focuses exclusively on the neurotoxic potential of astrocytes while acknowledging that these cells can contribute to neurodegeneration through other mechanisms, for example, by lowered neurotrophic support. We identify reactive oxygen and nitrogen species, tumor necrosis factor α (TNF-α), glutamate, and matrix metalloproteinase (MMP)-9 as molecules that can be directly toxic to neurons and are released by reactive astrocytes. There is also considerable evidence suggesting their involvement in AD pathogenesis. We further discuss the signaling molecules that trigger the neurotoxic response of astrocytes with a focus on human cells. We also highlight microglia, the immune cells of the brain, as critical regulators of astrocyte neurotoxicity. Nuclear imaging and magnetic resonance spectroscopy (MRS) could be used to confirm the contribution of astrocyte neurotoxicity to AD progression. The molecular mechanisms discussed in this review could be targeted in the development of novel therapies for AD.

Keywords:  Reactive astrocytes; glutamate; matrix metalloproteinases; microglia; neurodegeneration; reactive nitrogen species; reactive oxygen species; tumor necrosis factor α

DOI:  https://doi.org/10.2174/1567205018666211117100342
Behav Brain Res. 2021 Nov 16. pii: S0166-4328(21)00561-1. [Epub ahead of print] 113673

OGDHL Ameliorates Cognitive Impairment and Alzheimer's Disease-Like Pathology via Activating Wnt/β-catenin signaling in Alzheimer's Disease Mice.

Li Yao, Xuemin Xu, Yukun Xu, Chunyan Li, Fang Xie, Minghao Guo, Chaoyang Liu, Xiaoming Liu.

  Alzheimer's disease (AD) is one of the most common neurodegenerative diseases related to several types of pathophysiological signs, including β-amyloid (Aβ) plaque accumulation, neuroinflammation, and neurofibrillary tangles. Similar to one of the three subunits of α-ketoglutarate dehydrogenase complex (KGDHC), oxoglutarate dehydrogenase-like (OGDHL) appears to be downregulated in triple-transgenic Alzheimer's (3×Tg-AD) mice. KGDHC activity is specifically reduced in the brains of people with AD. However, the underlying mechanism of OGDHL in the cause of AD is still unknown. Herein, we confirmed the low expression of OGDHL in the brain of 3×Tg-AD based on real-time quantitative PCR, Western blot, and immunohistochemistry. We also found that the upregulation of OGDHL can reduce the memory deficits of 3×Tg-AD mice, thereby reminding its nervous system neuroprotective effect in AD. Next, we confirmed that the increase in OGDHL could reduce neuroinflammation, amyloid plaque load, and tau phosphorylation in 3×Tg-AD mice. Additionally, we showed that the overexpression of OGDHL could activate Wnt/β-catenin signaling based on the expression of Wnt7B in vitro. Taken together, the results show that the rise of OGDHL reasonably improves the cognitive functions according to the activation of the Wnt/β-catenin signaling pathway. Therefore, this enzyme may be a potential strategy for AD treatment.

Keywords:  Alzheimer’s disease; KGDHC; OGDHL; Wnt/β-catenin signaling; cognitive deficits

DOI:  https://doi.org/10.1016/j.bbr.2021.113673
Front Cell Neurosci. 2021 ;15 765217

Infection and Immunometabolism in the Central Nervous System: A Possible Mechanistic Link Between Metabolic Imbalance and Dementia.

Noriko Shinjyo, Kiyoshi Kita.

  Metabolic syndromes are frequently associated with dementia, suggesting that the dysregulation of energy metabolism can increase the risk of neurodegeneration and cognitive impairment. In addition, growing evidence suggests the link between infections and brain disorders, including Alzheimer's disease. The immune system and energy metabolism are in an intricate relationship. Infection triggers immune responses, which are accompanied by imbalance in cellular and organismal energy metabolism, while metabolic disorders can lead to immune dysregulation and higher infection susceptibility. In the brain, the activities of brain-resident immune cells, including microglia, are associated with their metabolic signatures, which may be affected by central nervous system (CNS) infection. Conversely, metabolic dysregulation can compromise innate immunity in the brain, leading to enhanced CNS infection susceptibility. Thus, infection and metabolic imbalance can be intertwined to each other in the etiology of brain disorders, including dementia. Insulin and leptin play pivotal roles in the regulation of immunometabolism in the CNS and periphery, and dysfunction of these signaling pathways are associated with cognitive impairment. Meanwhile, infectious complications are often comorbid with diabetes and obesity, which are characterized by insulin resistance and leptin signaling deficiency. Examples include human immunodeficiency virus (HIV) infection and periodontal disease caused by an oral pathogen Porphyromonas gingivalis. This review explores potential interactions between infectious agents and insulin and leptin signaling pathways, and discuss possible mechanisms underlying the relationship between infection, metabolic dysregulation, and brain disorders, particularly focusing on the roles of insulin and leptin.

Keywords:  dementia; glia; immunometabolism; infection; insulin; leptin; neuroinflammation

DOI:  https://doi.org/10.3389/fncel.2021.765217
Transl Neurodegener. 2021 Nov 15. 10(1): 46

New perspectives on cytoskeletal dysregulation and mitochondrial mislocalization in amyotrophic lateral sclerosis.

Frances Theunissen, Phillip K West, Samuel Brennan, Bojan Petrović, Kosar Hooshmand, P Anthony Akkari, Matt Keon, Boris Guennewig.

  Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective, early degeneration of motor neurons in the brain and spinal cord. Motor neurons have long axonal projections, which rely on the integrity of neuronal cytoskeleton and mitochondria to regulate energy requirements for maintaining axonal stability, anterograde and retrograde transport, and signaling between neurons. The formation of protein aggregates which contain cytoskeletal proteins, and mitochondrial dysfunction both have devastating effects on the function of neurons and are shared pathological features across several neurodegenerative conditions, including ALS, Alzheimer's disease, Parkinson's disease, Huntington's disease and Charcot-Marie-Tooth disease. Furthermore, it is becoming increasingly clear that cytoskeletal integrity and mitochondrial function are intricately linked. Therefore, dysregulations of the cytoskeletal network and mitochondrial homeostasis and localization, may be common pathways in the initial steps of neurodegeneration. Here we review and discuss known contributors, including variants in genetic loci and aberrant protein activities, which modify cytoskeletal integrity, axonal transport and mitochondrial localization in ALS and have overlapping features with other neurodegenerative diseases. Additionally, we explore some emerging pathways that may contribute to this disruption in ALS.

Keywords:  Amyotrophic lateral sclerosis; Axonal transport; Cytoskeleton; Gut microbiome; Mitochondria; Neurodegeneration; Neurofilament

DOI:  https://doi.org/10.1186/s40035-021-00272-z
Clin Nutr Res. 2021 Oct;10(4): 292-302

Irisin Acts via the PGC-1α and BDNF Pathway to Improve Depression-like Behavior.

Danbi Jo, Juhyun Song.

  Depression is the most prevalent psychiatric disorder experienced by the world's population. Mechanisms associated with depression-like behavior have not been fully investigated. Among the therapeutic solution for depression, exercise is considered an important regulator attenuating depressive neuropathology. Exercise has been reported to boost the secretion of myokines such as irisin and myostatin in skeletal muscles. Myokines secreted during exercise are involved in various cellular responses including the endocrine and autocrine systems. Especially, irisin as a cleaved version of fibronectin domain-containing protein 5 has multiple functions such as white fat-browning, energy expenditure increase, anti-inflammatory effects, and mitochondrial function improvement in both systemic circulation and central nervous system. Furthermore, irisin activates energy metabolism-related signaling peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and memory formation-related signaling brain-derived neurotrophic factor involved in depression. However, the role and mechanism of irisin in depression disorder is not obvious until now. Here, we review recent evidences regarding the therapeutic effect of irisin in depression disorder. We suggest that irisin is a key molecule that suppresses several neuropathological mechanisms involved in depression.

Keywords:  Brain-derived neurotrophic factor (BDNF); Depression; Energy metabolism; Irisin; Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α)

DOI:  https://doi.org/10.7762/cnr.2021.10.4.292
Microbiome. 2021 Nov 17. 9(1): 226

Fecal microbiota transplantation protects rotenone-induced Parkinson's disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis.

Zhe Zhao, Jingwen Ning, Xiu-Qi Bao, Meiyu Shang, Jingwei Ma, Gen Li, Dan Zhang.

  BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative disorder, displaying not only well-known motor deficits but also gastrointestinal dysfunctions. Consistently, it has been increasingly evident that gut microbiota affects the communication between the gut and the brain in PD pathogenesis, known as the microbiota-gut-brain axis. As an approach to re-establishing a normal microbiota community, fecal microbiota transplantation (FMT) has exerted beneficial effects on PD in recent studies. Here, in this study, we established a chronic rotenone-induced PD mouse model to evaluate the protective effects of FMT treatment on PD and to explore the underlying mechanisms, which also proves the involvement of gut microbiota dysbiosis in PD pathogenesis via the microbiota-gut-brain axis.RESULTS: We demonstrated that gut microbiota dysbiosis induced by rotenone administration caused gastrointestinal function impairment and poor behavioral performances in the PD mice. Moreover, 16S RNA sequencing identified the increase of bacterial genera Akkermansia and Desulfovibrio in fecal samples of rotenone-induced mice. By contrast, FMT treatment remarkably restored the gut microbial community, thus ameliorating the gastrointestinal dysfunctions and the motor deficits of the PD mice. Further experiments revealed that FMT administration alleviated intestinal inflammation and barrier destruction, thus reducing the levels of systemic inflammation. Subsequently, FMT treatment attenuated blood-brain barrier (BBB) impairment and suppressed neuroinflammation in the substantia nigra (SN), which further decreased the damage of dopaminergic neurons. Additional mechanistic investigation discovered that FMT treatment reduced lipopolysaccharide (LPS) levels in the colon, the serum, and the SN, thereafter suppressing the TLR4/MyD88/NF-κB signaling pathway and its downstream pro-inflammatory products both in the SN and the colon.
CONCLUSIONS: Our current study demonstrates that FMT treatment can correct the gut microbiota dysbiosis and ameliorate the rotenone-induced PD mouse model, in which suppression of the inflammation mediated by the LPS-TLR4 signaling pathway both in the gut and the brain possibly plays a significant role. Further, we prove that rotenone-induced microbiota dysbiosis is involved in the genesis of PD via the microbiota-gut-brain axis. Video abstract.

Keywords:  16S RNA sequencing; Fecal microbiota transplantation; Microbiota-gut-brain axis; Parkinson’s disease; Rotenone-induced mouse model

DOI:  https://doi.org/10.1186/s40168-021-01107-9
Neuroscience. 2021 Nov 16. pii: S0306-4522(21)00579-0. [Epub ahead of print]

The neuroprotective effect of increased PINK1 expression following glutamate excitotoxicity in neuronal cells.

Ya-Nan Dou, Xiuquan Wu, Xiaowei Fei, Zhou Fei.

  Ischemic injury in patients with stroke often leads to neuronal damage and mitochondrial dysfunction. Neuronal injury caused by ischemia can be partly attributed to glutamate (L-Glu) excitotoxicity. Previous studies have shown that PTEN-induced kinase 1 (PINK1) plays a neuroprotective role in ischemic brain injury by regulating mitochondrial integrity and function. However, there are few reports on the expression of PINK1 in L-Glu excitotoxicity models, its effect on neuronal survival, and whether PINK1 plays a protective role in stroke by regulating mitophagy. In the present study, different concentrations of L-Glu inhibited the viability of neurons. After L-Glu treatment at different times, the mRNA level, protein level, and cellular fluorescence intensity of PINK1 first increased and then decreased. Compared with normal cells, cells with low PINK1 expression enhanced the inhibitory effect of L-Glu on neuronal activity, while those with high PINK1 expression showed a protective effect on neurons by alleviating mitochondrial membrane potential loss. In addition, RAP (an autophagy activator) could increase the co-localization of the mitophagy-related proteins light chain 3 (LC3) and Tom20, whereas 3-MA (an autophagy inhibitor) exerted the opposite effect. Finally, we found that L-Glu could induce the expression of PINK1/Parkin/ LC3 in neurons at both mRNA and protein levels, while RAP could further increase their expression, and 3-MA decreased their expression. Taken together, PINK1 protects against L-Glu-induced neuronal injury by protecting mitochondrial function, and the potential protective mechanism may be closely related to the enhancement of mitophagy mediated by the PINK1/Parkin signaling pathway.

Keywords:  Glutamate excitotoxicity; Ischemic stroke; LC3; Mitophagy; PINK1; Parkin

DOI:  https://doi.org/10.1016/j.neuroscience.2021.11.020
World Neurosurg. 2021 Nov 11. pii: S1878-8750(21)01728-9. [Epub ahead of print]

Cerebral pressure autoregulation in brain injury and disorders - a scoping review on monitoring, management, and future directions.

Teodor Svedung Wettervik, Markus Fahlström, Per Enblad, Anders Lewén.

  The role of cerebral pressure autoregulation (CPA) in brain injury and disorders has gained increased interest. The CPA is often disturbed as a consequence of acute brain injury, which contributes to further brain damage and worse outcome. Specifically, in severe traumatic brain injury, CPA disturbances predict worse clinical outcome and targeting an autoregulatory-oriented cerebral perfusion pressure (CPPopt) threshold may improve brain energy metabolism and clinical outcome. In aneurysmal subarachnoid hemorrhage (aSAH), cerebral vasospasm in combination with distal autoregulatory disturbances precipitate delayed cerebral ischemia. The role of CPPopt targets are less clear in aSAH, but high cerebral perfusion pressure targets are generally favorable in the vasospasm phase. In acute ischemia, autoregulatory disturbances may occur and autoregulatory oriented blood pressure (MAPopt) management reduces the risk of hemorrhagic transformation, brain edema, and unfavorable outcome. In chronic occlusive disease such as Moyamoya, the gradual reduction of the cerebral circulation leads to compensatory distal vasodilation and the residual CPA capacity predicts the risk for cerebral ischemia. In spontaneous intracerebral hemorrhage, the role of autoregulatory disturbances is less clear, but CPA disturbances correlate with worse clinical outcome. Also, in community-acquired bacterial meningitis, CPA dysfunction is frequent and correlates with worse clinical outcome, but autoregulatory management is yet to be evaluated. In this review, we discuss the role of CPA in different types of brain injury and disease, the strengths and limitations of the monitoring methods, the potentials of autoregulatory management, and future directions in the field.

Keywords:  Cerebral pressure autoregulation; intracerebral hemorrhage; meningitis; stroke; subarachnoid hemorrhage; traumatic brain injury

DOI:  https://doi.org/10.1016/j.wneu.2021.11.027
FEBS J. 2021 Nov 18.

Understanding how kinesin motor proteins regulate postsynaptic function in neuron.

Ruolin Fan, Kwok-On Lai.

  The Kinesin superfamily proteins (KIFs) are major molecular motors that transport diverse set of cargoes along microtubules to both the axon and dendrite of a neuron. Much of our knowledge about kinesin function is obtained from studies on axonal transport. Emerging evidence reveals how specific kinesin motor proteins carry cargoes to dendrites, including proteins, mRNAs and organelles that are crucial for synapse development and plasticity. In this review, we will summarize the major kinesin motors and their associated cargoes that have been characterized to regulate postsynaptic function in neuron. We will also discuss how specific kinesins are selectively involved in the development of excitatory and inhibitory postsynaptic compartments, their regulation by post-translational modifications, as well as their roles beyond conventional transport carrier.

Keywords:  KIF5; Kinesin; RNA transport; learning and memory; neurotransmitter receptor; organelle transport; post-translational modification; postsynaptic function

DOI:  https://doi.org/10.1111/febs.16285
Brain Res. 2021 Nov 14. pii: S0006-8993(21)00565-5. [Epub ahead of print]1774 147708

Docosahexaenoic acid reduces hypoglycemia-induced neuronal necroptosis via the peroxisome proliferator-activated receptor γ/nuclear factor-κB pathway.

Lin Huang, Yue Zhou, Zhi-Xian Gou, Feng Zhang, Li-Qun Lu.

  DHA has been shown to be neuroprotective and important to neurogenesis, but its role in HG-induced brain injury and the underlying mechanisms remain unknown. To elucidate the therapeutic effect of DHA, we established a mouse model with insulin-induced hypoglycemic brain injury and an in vitro model of HT-22 cells using a sugar-free medium. DHA treatment significantly reduced neuronal death and improved HG-induced learning and memory deficits. Moreover, DHA inhibited neuronal necroptosis and decreased the concentrations of TNF-α, IL-1β and TNFR1. DHA also activated PPAR-γ and suppressed the NF-κB pathway in mouse brain tissues. In vitro, DHA treatment restored the viability and decreased necroptosis of HT-22 cells treated with glucose deprivation. However, the inhibition of PPAR-γ with T0070907 reversed neuroprotective and anti-necroptosis effects of DHA in HG-induced brain injury, which is associated with the activation of the downstream NF-κB pathway. We conclude that DHA displays a protective effect against HG-induced brain injury through the PPAR-γ/NF-κB pathway and represents a promising method to prevent HG-induced brain injury.

Keywords:  Docosahexaenoic acid; Hypoglycemia; Necroptosis; Neuron death; PPAR-γ,neonate

DOI:  https://doi.org/10.1016/j.brainres.2021.147708
Cell. 2021 Nov 12. pii: S0092-8674(21)01177-6. [Epub ahead of print]

Human brain organogenesis: Toward a cellular understanding of development and disease.

Kevin W Kelley, Sergiu P Pașca.

The construction of the human nervous system is a distinctly complex although highly regulated process. Human tissue inaccessibility has impeded a molecular understanding of the developmental specializations from which our unique cognitive capacities arise. A confluence of recent technological advances in genomics and stem cell-based tissue modeling is laying the foundation for a new understanding of human neural development and dysfunction in neuropsychiatric disease. Here, we review recent progress on uncovering the cellular and molecular principles of human brain organogenesis in vivo as well as using organoids and assembloids in vitro to model features of human evolution and disease.

DOI: https://doi.org/10.1016/j.cell.2021.10.003
Protein Cell. 2021 Nov 20.

PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis.

Weili Yang, Xiangyu Guo, Zhuchi Tu, Xiusheng Chen, Rui Han, Yanting Liu, Sen Yan, Qi Wang, Zhifu Wang, Xianxian Zhao, Yunpeng Zhang, Xin Xiong, Huiming Yang, Peng Yin, Huida Wan, Xingxing Chen, Jifeng Guo, Xiao-Xin Yan, Lujian Liao, Shihua Li, Xiao-Jiang Li.

  In vitro studies have established the prevalent theory that the mitochondrial kinase PINK1 protects neurodegeneration by removing damaged mitochondria in Parkinson's disease (PD). However, difficulty in detecting endogenous PINK1 protein in rodent brains and cell lines has prevented the rigorous investigation of the in vivo role of PINK1. Here we report that PINK1 kinase form is selectively expressed in the human and monkey brains. CRISPR/Cas9-mediated deficiency of PINK1 causes similar neurodegeneration in the brains of fetal and adult monkeys as well as cultured monkey neurons without affecting mitochondrial protein expression and morphology. Importantly, PINK1 mutations in the primate brain and human cells reduce protein phosphorylation that is important for neuronal function and survival. Our findings suggest that PINK1 kinase activity rather than its mitochondrial function is essential for the neuronal survival in the primate brains and that its kinase dysfunction could be involved in the pathogenesis of PD.

Keywords:  Parkinson’s disease; mitochondria; neurodegeneration; neurogenesis; non-human primates

DOI:  https://doi.org/10.1007/s13238-021-00888-x
J Alzheimers Dis. 2021 Nov 11.

A Novel Role for BRIP1/FANCJ in Neuronal Cells Health and in Resolving Oxidative Stress-Induced DNA Lesions.

Chinnadurai Mani, Ganesh Acharya, Sudhir Kshirsagar, Murali Vijayan, Hafiz Khan, P Hemachandra Reddy, Komaraiah Palle.

  BACKGROUND: DNA damage accumulation and mitochondrial abnormalities are elevated in neurons during aging and may contribute to neurodegenerative pathologic conditions such as Alzheimer's disease. BRCA1 interacting protein 1 or BRIP1 is a 5' to 3' DNA helicase that catalyzes many abnormal DNA structures during DNA replication, gene transcription, and recombination, and contribute to genomic integrity.OBJECTIVE: BRIP1 functions were reasonably well studied in DNA repair; however, there is limited data on its role and regulation during aging and neurodegenerative diseases.
METHODS: We used immunohistochemistry, western blot, and qRT-PCR assays to analyze the expression of BRIP1. Immunofluorescence studies were performed to study the formation of R-loops, reactive oxygen species (ROS) generation, and mitochondrial morphology. Flow cytometry and transmission electron microscopy were used to evaluate mitochondrial ROS and mitochondrial structures, respectively. Oxygen consumption rate was measured using Seahorse, and the Presto Blue™ assays were used to evaluate cell viability.
RESULTS: Our results demonstrate the expression of BRIP1 in mouse and human brain tissues and in neuronal cell lines. BRIP1 levels were elevated in the hippocampal regions of the brains, specifically in the dentate gyrus. BRIP1 downregulation in neuronal cells caused increased R-loop formation basally and in response to H2O2 treatment. Furthermore, BRIP1 deficient cells exhibited elevated levels of excitotoxicity induced by L-Glutamic acid exposure as evidenced by (mitochondrial) ROS levels, deteriorated mitochondrial health, and cell death compared to BRIP1 proficient neuronal cells.
CONCLUSION: Overall, our results indicate an important role for BRIP1 in maintaining neuronal cell health and homeostasis by suppressing cellular oxidative stress.

Keywords:  BRIP1; DNA damage; L-Glutamic acid; R-loop; mitochondrial stress

DOI:  https://doi.org/10.3233/JAD-215305
Aging Cell. 2021 Nov 19. e13520

Mitochondrial aconitase 1 regulates age-related memory impairment via autophagy/mitophagy-mediated neural plasticity in middle-aged flies.

Yun-Ho Cho, Gye-Hyeong Kim, Joong-Jean Park.

  Age-related memory impairment (AMI) occurs in many species, including humans. The underlying mechanisms are not fully understood. In wild-type Drosophila (w1118 ), AMI appears in the form of a decrease in learning (3-min memory) from middle age (30 days after eclosion [DAE]). We performed in vivo, DNA microarray, and behavioral screen studies to identify genes controlling both lifespan and AMI and selected mitochondrial Acon1 (mAcon1). mAcon1 expression in the head of w1118 decreased with age. Neuronal overexpression of mAcon1 extended its lifespan and improved AMI. Neuronal or mushroom body expression of mAcon1 regulated the learning of young (10 DAE) and middle-aged flies. Interestingly, acetyl-CoA and citrate levels increased in the heads of middle-aged and neuronal mAcon1 knockdown flies. Acetyl-CoA, as a cellular energy sensor, is related to autophagy. Autophagy activity and efficacy determined by the positive and negative changes in the expression levels of Atg8a-II and p62 were proportional to the expression level of mAcon1. Levels of the presynaptic active zone scaffold protein Bruchpilot were inversely proportional to neuronal mAcon1 levels in the whole brain. Furthermore, mAcon1 overexpression in Kenyon cells induced mitophagy labeled with mt-Keima and improved learning ability. Both processes were blocked by pink1 knockdown. Taken together, our results imply that the regulation of learning and AMI by mAcon1 occurs via autophagy/mitophagy-mediated neural plasticity.

Keywords:  aconitase; age-related memory disorders; autophagy; mitochondria; mitophagy; neural plasticity

DOI:  https://doi.org/10.1111/acel.13520
Hum Mol Genet. 2021 Nov 15. pii: ddab329. [Epub ahead of print]

Mouse midbrain dopaminergic neurons survive loss of the PD-associated mitochondrial protein CHCHD2.

Mai K Nguyen, Kevin McAvoy, Szu-Chi Liao, Zak Doric, Iris Lo, Huihui Li, Giovanni Manfredi, Ken Nakamura.

Mutations in the mitochondrial protein CHCHD2 cause autosomal-dominant PD characterized by the preferential loss of substantia nigra dopamine (DA) neurons. Therefore, understanding the function of CHCHD2 in neurons may provide vital insights into how mitochondrial dysfunction contributes to neurodegeneration in PD. To investigate the normal requirement and function of CHCHD2 in neurons, we first examined CHCHD2 levels, and showed that DA neurons have higher CHCHD2 levels than other neuron types, both in vivo and in co-culture. We then generated mice with either a targeted deletion of CHCHD2 in DA neurons, or a deletion in the brain or total body. All three models were viable, and loss of CHCHD2 in the brain did not cause degeneration of DA neurons. Mice lacking CHCHD2 in DA neurons did display sex-specific changes to locomotor activity, but we did not observe differences in assays of muscle strength, exercise endurance, or motor coordination. Furthermore, mitochondria derived from mice lacking CHCHD2 did not display abnormalities in OXPHOS function. Lastly, resilience to CHCHD2 deletion could not be explained by functional complementation by its paralog CHCHD10, as deletion of both CHCHD10 and CHCHD2 did not cause degeneration of DA neurons in the midbrain. These findings support the hypothesis that pathogenic CHCHD2 mutations cause PD through a toxic gain-of-function, rather than loss-of-function mechanism.

DOI: https://doi.org/10.1093/hmg/ddab329
Mol Imaging Biol. 2021 Nov 15.

Early Post-ischemic Brain Glucose Metabolism Is Dependent on Function of TLR2: a Study Using [18F]F-FDG PET-CT in a Mouse Model of Cardiac Arrest and Cardiopulmonary Resuscitation.

Rika Bajorat, Jens Kurth, Jan Stenzel, Brigitte Vollmar, Bernd J Krause, Daniel A Reuter, Tobias Schuerholz, Stefan Bergt.

  PURPOSE: The mammalian brain glucose metabolism is tightly and sensitively regulated. An ischemic brain injury caused by cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) affects cerebral function and presumably also glucose metabolism. The majority of patients who survive CA suffer from cognitive deficits and physical disabilities. Toll-like receptor 2 (TLR2) plays a crucial role in inflammatory response in ischemia and reperfusion (I/R). Since deficiency of TLR2 was associated with increased survival after CA-CPR, in this study, glucose metabolism was measured using non-invasive [18F]F-FDG PET-CT imaging before and early after CA-CPR in a mouse model comparing wild-type (WT) and TLR2-deficient (TLR2-/-) mice. The investigation will evaluate whether FDG-PET could be useful as an additional methodology in assessing prognosis.PROCEDURES: Two PET-CT scans using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]F-FDG) tracer were carried out to measure dynamic glucose metabolism before and early after CPR. To achieve this, anesthetized and ventilated adult female WT and TLR2-/- mice were scanned in PET-CT. After recovery from the baseline scan, the same animals underwent 10-min KCL-induced CA followed by CPR. Approximately 90 min after CA, measurements of [18F]F-FDG uptake for 60 min were started. The [18F]F-FDG standardized uptake values (SUVs) were calculated using PMOD-Software on fused FDG-PET-CT images with the included 3D Mirrione-Mouse-Brain-Atlas.
RESULTS: The absolute SUVmean of glucose in the whole brain of WT mice was increased about 25.6% after CA-CPR. In contrast, the absolute glucose SUV in the whole brain of TLR2-/- mice was not significantly different between baseline and measurements post CA-CPR. In comparison, baseline measurements of both mouse strains show a highly significant difference with regard to the absolute glucose SUV in the whole brain. Values of TLR2-/- mice revealed a 34.6% higher glucose uptake.
CONCLUSIONS: The altered mouse strains presented a different pattern in glucose uptake under normal and ischemic conditions, whereby the post-ischemic differences in glucose metabolism were associated with the function of key immune factor TLR2. There is evidence for using early FDG-PET-CT as an additional diagnostic tool after resuscitation. Further studies are needed to use PET-CT in predicting neurological outcomes.

Keywords:  Brain glucose metabolism; Brain imaging; Cardiac arrest; Cerebral injury; PET-CT; Resuscitation; TLR2; [18F]F-FDG

DOI:  https://doi.org/10.1007/s11307-021-01677-y
Phys Rev E. 2021 Oct;104(4-1): 044409

Effect of extracellular volume on the energy stored in transmembrane concentration gradients.

Reinoud Maex.

The amount of energy that can be retrieved from a concentration gradient across a membrane separating two compartments depends on the relative size of the compartments. Having a larger low-concentration compartment is in general beneficial. It is shown here analytically that the retrieved energy further increases when the high-concentration compartment shrinks during the mixing process, and a general formula is derived for the energy when the ratio of transported solvent to solute varies. These calculations are then applied to the interstitial compartment of the brain, which is rich in Na^{+} and Cl^{-} ions and poor in K^{+}. The reported shrinkage of this compartment, and swelling of the neurons, during oxygen deprivation is shown to enhance the energy recovered from NaCl entering the neurons. The slight loss of energy on the part of K^{+} can be compensated for by the uptake of K^{+} ions by glial cells. In conclusion, the present study proposes that the reported fluctuations in the size of the interstitial compartment of the brain (expansion during sleep and contraction during oxygen deprivation) optimize the amount of energy that neurons can store in, and retrieve from, their ionic concentration gradients.

DOI: https://doi.org/10.1103/PhysRevE.104.044409
Curr Neuropharmacol. 2021 Nov 11.

Association of Oxidative Stress with Neurological Disorders.

Waseem Hassan, Hamsa Noreen, Shakila Rehman, Mohammad Amjad Kamal, Joao Batista Teixeira da Rocha.

  BACKGROUND: Oxidative stress is one of the main contributing factors involved in cerebral biochemical impairment. The higher susceptibility of the central nervous system to reactive oxygen species mediated damage could be attributed to several factors. For example, neurons use a greater quantity of oxygen, many parts of the brain have higher concentraton of iron, and neuronal mitochondria produce huge content of hydrogen peroxide. In addition, neuronal membranes have polyunsaturated fatty acids, which are predominantly vulnerable to oxidative stress (OS). OS is the imbalance between reactive oxygen species generation and cellular antioxidant potential. This may lead to various pathological conditions and diseases, especially neurodegenerative diseases such as, Parkinson's, Alzheimer's, and Huntington's diseases.OBJECTIVES: In this study, we explored the involvement of OS in neurodegenerative diseases.
METHODS: We used different search terms like "oxidative stress and neurological disorders" "free radicals and neurodegenerative disorders" "oxidative stress, free radicals, and neurological disorders" and "association of oxidative stress with the name of disorders taken from the list of neurological disorders. We tried to summarize the source, biological effects, and physiologic functions of ROS.
RESULTS: Finally, it was noted that more than 190 neurological disorders are associated with oxidative stress.

Keywords:  Brain; Neurological disorders; Oxidative stress (OS); Reactive oxygen species (ROS)

DOI:  https://doi.org/10.2174/1570159X19666211111141246
Neurosci Biobehav Rev. 2021 Nov 11. pii: S0149-7634(21)00505-4. [Epub ahead of print]

ADHD symptoms in neurometabolic diseases: Underlying mechanisms and clinical implications.

Selina Cannon Homaei, Helene Barone, Rune Kleppe, Nibal Betari, Andreas Reif, Jan Haavik.

  Neurometabolic diseases (NMDs) are typically caused by genetic abnormalities affecting enzyme functions, which in turn interfere with normal development and activity of the nervous system. Although the individual disorders are rare, NMDs are collectively relatively common and often lead to lifelong difficulties and high societal costs. Neuropsychiatric manifestations, including ADHD symptoms, are prominent in many NMDs, also when the primary biochemical defect originates in cells and tissues outside the nervous system. ADHD symptoms have been described in phenylketonuria, tyrosinemias, alkaptonuria, succinic semialdehyde dehydrogenase deficiency, X-linked ichthyosis, maple syrup urine disease, and several mitochondrial disorders, but are probably present in many other NMDs and may pose diagnostic and therapeutic challenges. Here we review current literature linking NMDs with ADHD symptoms. We cite emerging evidence that many NMDs converge on common neurochemical mechanisms that interfere with monoamine neurotransmitter synthesis, transport, metabolism, or receptor functions, mechanisms that are also considered central in ADHD pathophysiology and treatment. Finally, we discuss the therapeutic implications of these findings and propose a path forward to increase our understanding of these relationships.

Keywords:  Amino acids; Attention Deficit Hyperactivity Disorder (ADHD); Brain; Dopamine; Energy; Metabolic diseases; Mitochondrial dysfunction; Norepinephrine; Phenylketonuria (PKU); Tyrosinemia

DOI:  https://doi.org/10.1016/j.neubiorev.2021.11.012
Proc Natl Acad Sci U S A. 2021 Nov 23. pii: e2112466118. [Epub ahead of print]118(47):

Lactate transporters in the rat barrel cortex sustain whisker-dependent BOLD fMRI signal and behavioral performance.

Hélène Roumes, Charlotte Jollé, Jordy Blanc, Imad Benkhaled, Carolina Piletti Chatain, Philippe Massot, Gérard Raffard, Véronique Bouchaud, Marc Biran, Catherine Pythoud, Nicole Déglon, Eduardo R Zimmer, Luc Pellerin, Anne-Karine Bouzier-Sore.

  Lactate is an efficient neuronal energy source, even in presence of glucose. However, the importance of lactate shuttling between astrocytes and neurons for brain activation and function remains to be established. For this purpose, metabolic and hemodynamic responses to sensory stimulation have been measured by functional magnetic resonance spectroscopy and blood oxygen level-dependent (BOLD) fMRI after down-regulation of either neuronal MCT2 or astroglial MCT4 in the rat barrel cortex. Results show that the lactate rise in the barrel cortex upon whisker stimulation is abolished when either transporter is down-regulated. Under the same paradigm, the BOLD response is prevented in all MCT2 down-regulated rats, while about half of the MCT4 down-regulated rats exhibited a loss of the BOLD response. Interestingly, MCT4 down-regulated animals showing no BOLD response were rescued by peripheral lactate infusion, while this treatment had no effect on MCT2 down-regulated rats. When animals were tested in a novel object recognition task, MCT2 down-regulated animals were impaired in the textured but not in the visual version of the task. For MCT4 down-regulated animals, while all animal succeeded in the visual task, half of them exhibited a deficit in the textured task, a similar segregation into two groups as observed for BOLD experiments. Our data demonstrate that lactate shuttling between astrocytes and neurons is essential to give rise to both neurometabolic and neurovascular couplings, which form the basis for the detection of brain activation by functional brain imaging techniques. Moreover, our results establish that this metabolic cooperation is required to sustain behavioral performance based on cortical activation.

Keywords:  MRS; brain metabolism; fMRI; learning and memory; monocarboxylate transporter

DOI:  https://doi.org/10.1073/pnas.2112466118
Front Neurosci. 2021 ;15 725547

Neuronal Mitochondrial Dysfunction and Bioenergetic Failure in Inflammation-Associated Depression.

Angela Maria Casaril, Robert Dantzer, Carlos Bas-Orth.

  Depression is a leading cause of disability and affects more than 4% of the population worldwide. Even though its pathophysiology remains elusive, it is now well accepted that peripheral inflammation might increase the risk of depressive episodes in a subgroup of patients. However, there is still insufficient knowledge about the mechanisms by which inflammation induces alterations in brain function. In neurodegenerative and neuroinflammatory diseases, extensive studies have reported that inflammation negatively impacts mitochondrial health, contributing to excitotoxicity, oxidative stress, energy deficits, and eventually neuronal death. In addition, damaged mitochondria can release a wide range of damage-associated molecular patterns that are potent activators of the inflammatory response, creating a feed-forward cycle between oxidative stress, mitochondrial impairment, inflammation, and neuronal dysfunction. Surprisingly, the possible involvement of this vicious cycle in the pathophysiology of inflammation-associated depression remains understudied. In this mini-review we summarize the research supporting the association between neuroinflammation, mitochondrial dysfunction, and bioenergetic failure in inflammation-associated depression to highlight the relevance of further studies addressing this crosstalk.

Keywords:  bioenergetics; depression; inflammation; mitochondria; neurons

DOI:  https://doi.org/10.3389/fnins.2021.725547
Mol Psychiatry. 2021 Nov 15.

Discovery of a novel pseudo β-hairpin structure of N-truncated amyloid-β for use as a vaccine against Alzheimer's disease.

Preeti Bakrania, Gareth Hall, Yvonne Bouter, Caroline Bouter, Nicola Beindorff, Richard Cowan, Sarah Davies, Jemma Price, Chido Mpamhanga, Elizabeth Love, David Matthews, Mark D Carr, Thomas A Bayer.

One of the hallmarks of Alzheimer's disease (AD) are deposits of amyloid-beta (Aβ) protein in amyloid plaques in the brain. The Aβ peptide exists in several forms, including full-length Aβ1-42 and Aβ1-40 - and the N-truncated species, pyroglutamate Aβ3-42 and Aβ4-42, which appear to play a major role in neurodegeneration. We previously identified a murine antibody (TAP01), which binds specifically to soluble, non-plaque N-truncated Aβ species. By solving crystal structures for TAP01 family antibodies bound to pyroglutamate Aβ3-14, we identified a novel pseudo β-hairpin structure in the N-terminal region of Aβ and show that this underpins its unique binding properties. We engineered a stabilised cyclic form of Aβ1-14 (N-Truncated Amyloid Peptide AntibodieS; the 'TAPAS' vaccine) and showed that this adopts the same 3-dimensional conformation as the native sequence when bound to TAP01. Active immunisation of two mouse models of AD with the TAPAS vaccine led to a striking reduction in amyloid-plaque formation, a rescue of brain glucose metabolism, a stabilisation in neuron loss, and a rescue of memory deficiencies. Treating both models with the humanised version of the TAP01 antibody had similar positive effects. Here we report the discovery of a unique conformational epitope in the N-terminal region of Aβ, which offers new routes for active and passive immunisation against AD.

DOI: https://doi.org/10.1038/s41380-021-01385-7
Front Cell Neurosci. 2021 ;15 643717

Targeting CDK5 in Astrocytes Promotes Calcium Homeostasis Under Excitotoxic Conditions.

Luisa Fernanda Toro-Fernández, Juan Camilo Zuluaga-Monares, Ana María Saldarriaga-Cartagena, Gloria Patricia Cardona-Gómez, Rafael Posada-Duque.

  Glutamate excitotoxicity triggers overactivation of CDK5 and increases calcium influx in neural cells, which promotes dendritic retraction, spine loss, increased mitochondrial calcium from the endoplasmic reticulum, and neuronal death. Our previous studies showed that CDK5 knockdown (KD) in astrocytes improves neurovascular integrity and cognitive functions and exerts neuroprotective effects. However, how CDK5-targeted astrocytes affect calcium regulation and whether this phenomenon is associated with changes in neuronal plasticity have not yet been analyzed. In this study, CDK5 KD astrocytes transplanted in CA3 remained at the injection site without proliferation, regulated calcium in the CA1 hippocampal region after excitotoxicity by glutamate in ex vivo hippocampal slices, improving synapsin and PSD95 clustering. These CDK5 KD astrocytes induced astrocyte stellation and neuroprotection after excitotoxicity induced by glutamate in vitro. Also, these effects were supported by CDK5 inhibition (CDK5i) in vitro through intracellular stabilization of calcium levels in astrocytes. Additionally, these cells in cocultures restored calcium homeostasis in neurons, redistributing calcium from somas to dendrites, accompanied by dendrite branching, higher dendritic spines and synapsin-PSD95 clustering. In summary, induction of calcium homeostasis at the CA1 hippocampal area by CDK5 KD astrocytes transplanted in the CA3 area highlights the role of astrocytes as a cell therapy target due to CDK5-KD astrocyte-mediated synaptic clustering, calcium spreading regulation between both areas, and recovery of the intracellular astrocyte-neuron calcium imbalance and plasticity impairment generated by glutamate excitotoxicity.

Keywords:  CDK5; astrocyte; calcium homeostasis; excitotoxicity; hippocampus; synaptic protein

DOI:  https://doi.org/10.3389/fncel.2021.643717
J Stroke Cerebrovasc Dis. 2021 Nov 11. pii: S1052-3057(21)00607-8. [Epub ahead of print]31(1): 106202

Electroacupuncture Pretreatment Alleviates Cerebral Ischemia-Reperfusion Injury by Regulating Mitophagy via mTOR-ULK1/FUNDC1 Axis in Rats.

Weiqian Tian, Minmin Zhu, Yudi Zhou, Chenlu Mao, Rong Zou, Yaomei Cui, Sha Li, Juan Zhu, Cheng Hu.

  OBJECTIVE: Electroacupuncture (EA) pretreatment has been shown to alleviate cerebral ischemia-reperfusion (I/R) injury; however, the underlying mechanism remains unclear. To investigate the involvement of mTOR signaling in the protective role of EA in I/R-induced brain damage and mitochondrial injury.METHODS: Sprague-Dawley male rats were pretreated with vehicle, EA (at Baihui and Shuigou acupoints), or rapamycin + EA for 30 min daily for 5 consecutive days, followed by the middle cerebral artery occlusion to induce I/R injury. The neurological functions of the rats were assessed using the Longa neurological deficit scores. The rats were sacrificed immediately after neurological function assessment. The brains were obtained for the measurements of cerebral infarct area. The mitochondrial structural alterations were observed under transmission electron microscopy. The mitochondrial membrane potential changes were detected by JC-1 staining. The alterations in autophagy-related protein expression were examined using Western blot analysis.
RESULTS: Compared with untreated I/R rats, EA-pretreated rats exhibited significantly decreased neurological deficit scores and cerebral infarct volumes. EA pretreatment also reversed I/R-induced mitochondrial structural abnormalities and loss of mitochondrial membrane potential. Furthermore, EA pretreatment downregulated the protein expression of LC3-II, p-ULK1, and FUNDC1 while upregulating the protein expression of p-mTORC1 and LC3-I. Rapamycin effectively blocked the above-mentioned effects of EA.
CONCLUSION: EA pretreatment at Baihui and Shuigou alleviates cerebral I/R injury and mitochondrial impairment in rats through activating the mTORC1 signaling. The suppression of autophagy-related p-ULK1/FUNDC1 pathway is involved in the neuroprotective effects of EA.

Keywords:  Cerebral ischemia-reperfusion injury; Electroacupuncture; FUNDC1; Mitophagy; ULK1

DOI:  https://doi.org/10.1016/j.jstrokecerebrovasdis.2021.106202
Front Neurol. 2021 ;12 723148

The Therapeutic Potential and Limitations of Ketones in Traumatic Brain Injury.

Savannah Anne Daines.

  Traumatic brain injury (TBI) represents a significant health crisis. To date, no FDA approved pharmacotherapies are available to prevent the neurological deficits caused by TBI. As an alternative to pharmacotherapy treatment of TBI, ketones could be used as a metabolically based therapeutic strategy. Ketones can help combat post-traumatic cerebral energy deficits while also reducing inflammation, oxidative stress, and neurodegeneration. Experimental models of TBI suggest that administering ketones to TBI patients may provide significant benefits to improve recovery. However, studies evaluating the effectiveness of ketones in human TBI are limited. Unanswered questions remain about age- and sex-dependent factors, the optimal timing and duration of ketone supplementation, and the optimal levels of circulating and cerebral ketones. Further research and improvements in metabolic monitoring technology are also needed to determine if ketone supplementation can improve TBI recovery outcomes in humans.

Keywords:  cerebral metabolism; glucose; ketogenic; ketone; ketosis; traumatic brain injury

DOI:  https://doi.org/10.3389/fneur.2021.723148
Front Neurol. 2021 ;12 719159

Alterations in Glycerolipid and Fatty Acid Metabolic Pathways in Alzheimer's Disease Identified by Urinary Metabolic Profiling: A Pilot Study.

Yumi Watanabe, Kensaku Kasuga, Takayoshi Tokutake, Kaori Kitamura, Takeshi Ikeuchi, Kazutoshi Nakamura.

  An easily accessible and non-invasive biomarker for the early detection of Alzheimer's disease (AD) is needed. Evidence suggests that metabolic dysfunction underlies the pathophysiology of AD. While urine is a non-invasively collectable biofluid and a good source for metabolomics analysis, it is not yet widely used for this purpose. This small-scale pilot study aimed to examine whether the metabolic profile of urine from AD patients reflects the metabolic dysfunction reported to underlie AD pathology, and to identify metabolites that could distinguish AD patients from cognitively healthy controls. Spot urine of 18 AD patients (AD group) and 18 age- and sex-matched, cognitively normal controls (control group) were analyzed by mass spectrometry (MS). Capillary electrophoresis time-of-flight MS and liquid chromatography-Fourier transform MS were used to cover a larger range of molecules with ionic as well as lipid characteristics. A total of 304 ionic molecules and 81 lipid compounds of 12 lipid classes were identified. Of these, 26 molecules showed significantly different relative concentrations between the AD and control groups (Wilcoxon's rank-sum test). Moreover, orthogonal partial least-squares discriminant analysis revealed significant discrimination between the two groups. Pathway searches using the KEGG database, and pathway enrichment and topology analysis using Metaboanalyst software, suggested alterations in molecules relevant to pathways of glycerolipid and glycerophospholipid metabolism, thermogenesis, and caffeine metabolism in AD patients. Further studies of urinary metabolites will contribute to the early detection of AD and understanding of its pathogenesis.

Keywords:  Alzheimer's disease; CE-TOFMS; LC-FTMS; biomarker; targeted lipidomics; targeted metabolomics; urine

DOI:  https://doi.org/10.3389/fneur.2021.719159
Front Aging Neurosci. 2021 ;13 765252

Effects of Sex, Age, and Apolipoprotein E Genotype on Brain Ceramides and Sphingosine-1-Phosphate in Alzheimer's Disease and Control Mice.

Sandra den Hoedt, Simone M Crivelli, Frank P J Leijten, Mario Losen, Jo A A Stevens, Marina Mané-Damas, Helga E de Vries, Jochen Walter, Mina Mirzaian, Eric J G Sijbrands, Johannes M F G Aerts, Adrie J M Verhoeven, Pilar Martinez-Martinez, Monique T Mulder.

  Apolipoprotein ε4 (APOE)4 is a strong risk factor for the development of Alzheimer's disease (AD) and aberrant sphingolipid levels have been implicated in AD. We tested the hypothesis that the APOE4 genotype affects brain sphingolipid levels in AD. Seven ceramides and sphingosine-1-phosphate (S1P) were quantified by LC-MSMS in hippocampus, cortex, cerebellum, and plasma of <3 months and >5 months old human APOE3 and APOE4-targeted replacement mice with or without the familial AD (FAD) background of both sexes (145 animals). APOE4 mice had higher Cer(d18:1/24:0) levels in the cortex (1.7-fold, p = 0.002) than APOE3 mice. Mice with AD background showed higher levels of Cer(d18:1/24:1) in the cortex than mice without (1.4-fold, p = 0.003). S1P levels were higher in all three brain regions of older mice than of young mice (1.7-1.8-fold, all p ≤ 0.001). In female mice, S1P levels in hippocampus (r = -0.54 [-0.70, -0.35], p < 0.001) and in cortex correlated with those in plasma (r = -0.53 [-0.71, -0.32], p < 0.001). Ceramide levels were lower in the hippocampus (3.7-10.7-fold, all p < 0.001), but higher in the cortex (2.3-12.8-fold, p < 0.001) of female than male mice. In cerebellum and plasma, sex effects on individual ceramides depended on acyl chain length (9.5-fold lower to 11.5-fold higher, p ≤ 0.001). In conclusion, sex is a stronger determinant of brain ceramide levels in mice than APOE genotype, AD background, or age. Whether these differences impact AD neuropathology in men and women remains to be investigated.

Keywords:  Alzheimer’s disease; S1P; aging; apolipoprotein E4; ceramide; sex differences

DOI:  https://doi.org/10.3389/fnagi.2021.765252
Purinergic Signal. 2021 Nov 18.

Mechanisms of ATP release in pain: role of pannexin and connexin channels.

Manuel F Muñoz, Theanne N Griffith, Jorge E Contreras.

  Pain is a physiological response to bodily damage and serves as a warning of potential threat. Pain can also transform from an acute response to noxious stimuli to a chronic condition with notable emotional and psychological components that requires treatment. Indeed, the management of chronic pain is currently an important unmet societal need. Several reports have implicated the release of the neurotransmitter adenosine triphosphate (ATP) and subsequent activation of purinergic receptors in distinct pain etiologies. Purinergic receptors are broadly expressed in peripheral neurons and the spinal cord; thus, purinergic signaling in sensory neurons or in spinal circuits may be critical for pain processing. Nevertheless, an outstanding question remains: what are the mechanisms of ATP release that initiate nociceptive signaling? Connexin and pannexin channels are established conduits of ATP release and have been suggested to play important roles in a variety of pathologies, including several models of pain. As such, these large-pore channels represent a new and exciting putative pharmacological target for pain treatment. Herein, we will review the current evidence for a role of connexin and pannexin channels in ATP release during nociceptive signaling, such as neuropathic and inflammatory pain. Collectively, these studies provide compelling evidence for an important role of connexins and pannexins in pain processing.

Keywords:  ATP release; Acute pain; Chronic pain; Connexins; Pannexins

DOI:  https://doi.org/10.1007/s11302-021-09822-6
Food Funct. 2021 Nov 16.

Plasmalogens improve swimming performance by modulating the expression of genes involved in amino acid and lipid metabolism, oxidative stress, and ferroptosis in an Alzheimer's disease zebrafish model.

Junli Feng, Gongshuai Song, Yuanyuan Wu, Xi Chen, Jie Pang, Yaxi Xu, Qing Shen, Shunyuan Guo, Manman Zhang.

Plasmalogens (PLs) are critical to human health. Studies have reported a link between the downregulation of PLs levels and cognitive impairments in patients with Alzheimer's disease (AD). However, the underlying mechanisms remain to be clarified. In the present study, an AlCl3-induced AD zebrafish model was established, and the model was used to elucidate the neuroprotective effects of PLs on AD by analysing the transcriptional profiles of zebrafish in the control, AD model, AD_PL, and PL groups. Chronic AlCl3 exposure caused swimming performance impairments in the zebrafish, yet PLs supplementation could improve the dyskinesia recovery rate in the AD zebrafish model. Through transcriptional profiling, a total of 5413 statistically significant differentially expressed genes (DEGs) were identified among the groups. In addition to the DEGs involved in amino acid metabolism, we found that the genes related to iron homeostasis, lipid peroxidation, and oxidative stress, all of which contribute to ferroptosis, were dramatically altered among different groups. These results suggest that seafood-derived PLs, in addition to their role in eliminating oxidative stress, can improve the swimming performance in AlCl3-exposed zebrafish partly by suppressing neuronal ferroptosis and accelerating synaptic transmission at the transcriptional level. This study provides evidence for PLs to be developed as a functional food supplement to relieve AD symptoms.

DOI: https://doi.org/10.1039/d1fo01471d