bims-brabim Biomed News
on Brain bioenergetics and metabolism
Issue of 2021–12–05
fourteen papers selected by
João Victor Cabral-Costa, University of São Paulo
  1. Nutrients, Cognitive Function, and Brain Aging: What We Have Learned from Dogs.
  2. The metabolic signaling of the nucleoredoxin-like 2 gene supports brain function.
  3. Hippocampal Neuropeptide Y2 receptor blockade improves spatial memory retrieval and modulates limbic brain metabolism.
  4. Lactate supply from astrocytes to neurons and its role in ischemic stroke-induced neurodegeneration.
  5. Brain transcriptomes of zebrafish and mouse Alzheimer's disease knock-in models imply early disrupted energy metabolism.
  6. Exercise and Syzygium aromaticum reverse memory deficits, apoptosis and mitochondrial dysfunction of the hippocampus in Alzheimer's disease.
  7. A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer's Disease.
  8. Lipid endocannabinoids in energy metabolism, stress and developmental programming.
  9. Intermittent hypoxia treatment alleviates memory impairment in the 6-month-old APPswe/PS1dE9 mice and reduces amyloid beta accumulation and inflammation in the brain.
  10. Shen-Zhi-Ling oral liquid ameliorates cerebral glucose metabolism disorder in early AD via insulin signal transduction pathway in vivo and in vitro.
  11. The Link between Exercise and Homocysteine in the Alzheimer's Disease: A Bioinformatic Network Model.
  12. Mitochondriomics reveals the underlying neuroprotective mechanism of TrkB receptor agonist R13 in the 5×FAD mice.
  13. Preischemic Treadmill Exercise Ameliorates Memory Impairment and Microvasculature Damage in Rat Model of Chronic Cerebral Hypoperfusion.
  14. Deficient thyroid hormone transport to the brain leads to impairments in axonal caliber and oligodendroglial development.
  1. Med Sci (Basel). 2021 Nov 18. pii: 72. [Epub ahead of print]9(4):
    Nutrients, Cognitive Function, and Brain Aging: What We Have Learned from Dogs.
    Yuanlong Pan.
      Due to a difference in genetics, environmental factors, and nutrition, just like in people, dogs age at different rates. Brain aging in people and dogs share similar morphological changes including irreversible cortical atrophy, cerebral amyloid angiopathy, and ventricular enlargement. Due to severe and irreversible brain atrophy, some aging dogs develop cognitive dysfunction syndrome (CDS), which is equivalent to dementia or Alzheimer's disease (AD) in people. The risk factors and causes of CDS in dogs have not been fully investigated, but age, gender, oxidative stress, and deficiency of sex hormones appears to be associated with increased risk of accelerated brain aging and CDS in dogs. Both AD and CDS are incurable diseases at this moment, therefore more efforts should be focused on preventing or reducing brain atrophy and minimizing the risk of AD in people and CDS in dogs. Since brain atrophy leads to irreversible cognitive decline and dementia, an optimal nutritional solution should be able to not only enhance cognitive function during aging but also reduce irreversible brain atrophy. Up to now, only one nutritional intervention has demonstrated both cognition-enhancing benefits and atrophy-reducing benefits.
    Keywords:  aging; atrophy; brain; cognitive function; cortical; ketone bodies; learning; medium-chain triglycerides; memory; neurogenesis
    DOI:  https://doi.org/10.3390/medsci9040072
  2. Redox Biol. 2021 Nov 25. pii: S2213-2317(21)00358-X. [Epub ahead of print]48 102198
    The metabolic signaling of the nucleoredoxin-like 2 gene supports brain function.
    Céline Jaillard, Farah Ouechtati, Emmanuelle Clérin, Géraldine Millet-Puel, Mariangela Corsi, Najate Aït-Ali, Frédéric Blond, Quentin Chevy, Lara Gales, Mélissa Farinelli, Deniz Dalkara, José-Alain Sahel, Jean-Charles Portais, Jean-Christophe Poncer, Thierry Léveillard.
      The nucleoredoxin gene NXNL2 encodes for two products through alternative splicing, rod-derived cone viability factor-2 (RdCVF2) that mediates neuronal survival and the thioredoxin-related protein (RdCVF2L), an enzyme that regulates the phosphorylation of TAU. To investigate the link between NXNL2 and tauopathies, we studied the Nxnl2 knockout mouse (Nxnl2-/-). We established the expression pattern of the Nxnl2 gene in the brain using a Nxnl2 reporter mouse line, and characterized the behavior of the Nxnl2-/- mouse at 2 months of age. Additionally, long term potential recording and metabolomic from hippocampal specimens were collected at 2 months of age. We studied TAU oligomerization, phosphorylation and aggregation in Nxnl2-/- brain at 18 months of age. Finally, newborn Nxnl2-/- mice were treated with adeno-associated viral vectors encoding for RdCVF2, RdCVF2L or both and measured the effect of this therapy on long-term potential, glucose metabolism and late-onset tauopathy. Nxnl2-/- mice at 2 months of age showed severe behavioral deficiency in fear, pain sensitivity, coordination, learning and memory. The Nxnl2-/- also showed deficits in long-term potentiation, demonstrating that the Nxnl2 gene is involved in regulating brain functions. Dual delivery of RdCVF2 and RdCVF2L in newborn Nxnl2-/- mice fully correct long-term potentiation through their synergistic action. The expression pattern of the Nxnl2 gene in the brain shows a predominant expression in circumventricular organs, such as the area postrema. Glucose metabolism of the hippocampus of Nxnl2-/- mice at 2 months of age was reduced, and was not corrected by gene therapy. At 18-month-old Nxnl2-/- mice showed brain stigmas of tauopathy, such as oligomerization, phosphorylation and aggregation of TAU. This late-onset tauopathy can be prevented, albeit with modest efficacy, by recombinant AAVs administrated to newborn mice. The Nxnl2-/- mice have memory dysfunction at 2-months that resembles mild-cognitive impairment and at 18-months exhibit tauopathy, resembling to the progression of Alzheimer's disease. We propose the Nxnl2-/- mouse is a model to study multistage aged related neurodegenerative diseases. The NXNL2 metabolic and redox signaling is a new area of therapeutic research in neurodegenerative diseases.
    Keywords:  Area postrema; Gene therapy; Glucose metabolism; Hippocampus; Long-term potentiation; Metabolomics; Tauopathy; Thioredoxin
    DOI:  https://doi.org/10.1016/j.redox.2021.102198
  3. Neurobiol Learn Mem. 2021 Nov 25. pii: S1074-7427(21)00183-0. [Epub ahead of print] 107561
    Hippocampal Neuropeptide Y2 receptor blockade improves spatial memory retrieval and modulates limbic brain metabolism.
    Marta Méndez-Couz, Héctor González-Pardo, Jorge L Arias, Nélida M Conejo.
       INTRODUCTION: The neuropeptide Y (NPY) is broadly distributed in the central nervous system (CNS), and it has been related to neuroprotective functions. NPY seems to be an important component to counteract brain damage and cognitive impairment mediated by drugs of abuse and neurodegenerative diseases, and both NPY and its Y2 receptor (Y2R) are highly expressed in the hippocampus, critical for learning and memory. We have recently demonstrated its influence on cognitive functions; however, the specific mechanism and involved brain regions where NPY modulates spatial memory by acting on Y2R remain unclear.
    METHODS: Here, we examined the involvement of the hippocampal NPY Y2R in spatial memory and associated changes in brain metabolism by bilateral administration of the selective antagonist BIIE0246 into the rat dorsal hippocampus. To further evaluate the relationship between memory functions and neuronal activity, we analysed the regional expression of the mitochondrial enzyme cytochrome c oxidase (CCO) as an index of oxidative metabolic capacity in limbic and non-limbic brain regions.
    RESULTS: The acute blockade of NPY Y2R significantly improved spatial memory recall in rats trained in the Morris water maze that matched metabolic activity changes in spatial memory processing regions. Specifically, CCO activity changes were found in the dentate gyrus of the dorsal hippocampus and CA1 subfield of the ventral hippocampus, the infralimbic region of the PFC and the mammillary bodies.
    CONCLUSIONS: These findings suggest that the NPY hippocampal system, through its Y2R receptor, influences spatial memory recall (retrieval) and exerts control over patterns of brain activation that are relevant for associative learning, probably mediated by Y2R modulation of long-term potentiation and long-term depression.
    Keywords:  Dentate Gyrus; cytochrome C oxidase; infralimbic cortex; mammillary bodies; synaptic plasticity; ventral hippocampus
    DOI:  https://doi.org/10.1016/j.nlm.2021.107561
  4. Neuroscience. 2021 Nov 26. pii: S0306-4522(21)00602-3. [Epub ahead of print]
    Lactate supply from astrocytes to neurons and its role in ischemic stroke-induced neurodegeneration.
    Kazuo Yamagata.
      Glucose transported to the brain is metabolized to lactate in astrocytes and supplied to neuronal cells via a monocarboxylic acid transporter (MCT). Lactate is used in neuronal cells for various functions, including learning and memory formation. Furthermore, lactate can block stroke-induced neurodegeneration. We aimed to clarify the effect of astrocyte-produced lactate on stroke-induced neurodegeneration. Previously published in vivo and in vitro animal and cell studies, respectively, were searched in PubMed, ScienceDirect, and Web of Science. Under physiological conditions, lactate production and release by astrocytes are regulated by changes in lactate dehydrogenase (LDH) and MCT expression. Moreover, considering stroke, lactate production and supply are regulated through hypoxia-inducible factor (HIF)-1α expression, especially with hypoxic stimulation, which may promote neuronal apoptosis; contrastingly, neuronal survival may be promoted via HIF-1α. Stroke stimulation could prevent neurodegeneration through the strong enhancement of lactate production, as well as upregulation of MCT4 expression to accelerate lactate supply. However, studies using astrocytes derived from animal stroke models revealed significantly reduced lactate production and MCT expression. These findings suggest that the lack of lactate supply may strongly contribute to hypoxia-induced neurodegeneration. Furthermore, diminished lactate supply from astrocytes could facilitate stroke-induced neurodegeneration. Therefore, astrocyte-derived lactate may contribute to stroke prevention.
    Keywords:  astrocytes; glutamate; ischemic stroke; lactic acid; monocarboxylic acid transporter; neurodegeneration
    DOI:  https://doi.org/10.1016/j.neuroscience.2021.11.035
  5. Dis Model Mech. 2021 Nov 29. pii: dmm.049187. [Epub ahead of print]
    Brain transcriptomes of zebrafish and mouse Alzheimer's disease knock-in models imply early disrupted energy metabolism.
    Karissa Barthelson, Morgan Newman, Michael Lardelli.
      Energy production is the most fundamentally important cellular activity supporting all other functions, particularly in highly active organs such as brains, Here we summarise transcriptome analyses of young adult (pre-disease) brains from a collection of eleven early-onset familial Alzheimer's disease (EOfAD)-like and non-EOfAD-like mutations in three zebrafish genes. The one cellular activity consistently predicted as affected by only the EOfAD-like mutations is oxidative phosphorylation that produces most of the brain's energy. All the mutations were predicted to affect protein synthesis. We extended our analysis to knock-in mouse models of APOE alleles and found the same effect for the late onset Alzheimer's disease risk allele ε4. Our results support a common molecular basis for initiation of the pathological processes leading to both early and late onset forms of Alzheimer's disease and illustrate the utility of zebrafish and of knock-in, single EOfAD mutation models for understanding the causes of this disease.
    Keywords:  Alzheimer's disease; Brain; Mouse; Oxidative phosphorylation; RNA-seq; Zebrafish
    DOI:  https://doi.org/10.1242/dmm.049187
  6. J Ethnopharmacol. 2021 Nov 29. pii: S0378-8741(21)01101-6. [Epub ahead of print] 114871
    Exercise and Syzygium aromaticum reverse memory deficits, apoptosis and mitochondrial dysfunction of the hippocampus in Alzheimer's disease.
    Fatemeh Panahzadeh, Rahim Mirnasouri, Masoud Rahmati.
       ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD), the most common disease in the brain, is associated with cognitive and mitochondrial dysfunction. Emerging evidence suggests that endurance training and Syzygium aromaticum (L.) Merrill and Perry (Myrtaceae) (commonly referred to as clove) are effective interventions to maintain oxidative balance and improve cognitive function.
    AIM OF THE STUDY: The present study aimed to investigate the effect of endurance training and clove oil affect spatial memory, apoptosis, mitochondrial homeostasis, and cognitive function in Alzheimer's rats.
    MATERIALS AND METHODS: 81 rats were randomly assigned to 9 groups: Healthy (H), sham (sh), Healthy-exercise (HE), Healthy-clove (HC), Healthy-exercise-clove (HEC), Alzheimer's (A), Alzheimer's-exercise (AE), Alzheimer's-clove (AC), and Alzheimer's-exercise-clove (AEC). Alzheimer's induction was induced by the injection of 1-42 amyloid into the CA1 region of the hippocampus. The exercise training protocol was performed for 3 weeks, every day for 30 min in swimming training, and clove oil supplementation (0.1 mg/kg) was gavaged daily for 3 weeks in the supplement rat. Shuttle box test was used to measure spatial memory after the last training session, and to determine the mRNAs and protein levels and apoptosis, Real-Time PCR, immunofluorescent, and tunnel methods were used, respectively.
    RESULTS: Alzheimer's caused a significant decrease in the PRDX6 and GCN5L1 mRNAs and protein levels and a significant increase in apoptosis in the hippocampus of the Alzheimer's group compared to the control group (P = 0.001). Alzheimer's also reduced the time delay in entering the dark environment and increased the time spent in the dark environment (P = 0.001). Following endurance training and consumption of clove oil, spatial memory (P = 0.001), apoptosis (P = 0.001) and mRNAs and protein levels of PRDX6 (P = 0.001) and GCN5L1 (P = 0.017), were recovered in AE, AC and AEC groups, as compared with A group.
    CONCLUSION: Swimming training and consumption of clove can possibly be considered as an effective intervention to maintain oxidative balance and improve mitochondrial homeostasis in Alzheimer's disease.
    Keywords:  Alzheimer's disease; Apoptosis; Clove; Endurance training; Hippocampus
    DOI:  https://doi.org/10.1016/j.jep.2021.114871
  7. J Alzheimers Dis. 2021 Nov 21.
    A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer's Disease.
    Jessica Lynn, Mingi Park, Christiana Ogunwale, George K Acquaah-Mensah.
      Dementias, including the type associated with Alzheimer's disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as "type 3 diabetes". In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3β, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists, and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities.
    Keywords:  Alzheimer’s disease; amyloid; blood-brain barrier; glucagon-like peptide 1; insulin resistance; microbiota; mitochondria; oxidative stress; therapeutics; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3233/JAD-210612
  8. Mol Cell Endocrinol. 2021 Nov 26. pii: S0303-7207(21)00366-X. [Epub ahead of print] 111522
    Lipid endocannabinoids in energy metabolism, stress and developmental programming.
    Mariana Macedo Almeida, Camilla Pereira Dias-Rocha, Camila Calviño Moraes, Isis Hara Trevenzoli.
      The endocannabinoid system (ECS) regulates brain development and function, energy metabolism and stress in a sex-, age- and tissue-dependent manner. The ECS comprises mainly the bioactive lipid ligands anandamide (AEA) and 2-aracdonoylglycerol (2-AG), cannabinoid receptors 1 and 2 (CB1 and CB2), and several metabolizing enzymes. The endocannabinoid tonus is increased in obesity, stimulating food intake and a preference for fat, reward, and lipid accumulation in peripheral tissues, as well as favoring a positive energy balance. Energy balance and stress responses share adaptive mechanisms regulated by the ECS that seem to underlie the complex relationship between feeding and emotional behavior. The ECS is also a key regulator of development. Environmental insults (diet, toxicants, and stress) in critical periods of developmental plasticity, such as gestation, lactation and adolescence, alter the ECS and may predispose individuals to the development of chronic diseases and behavioral changes in the long term. This review is focused on the ECS and the developmental origins of health and disease (DOHaD).
    Keywords:  Developmental plasticity; Endocannabinoids; Epigenetics; Obesity; Sex differences; Stress
    DOI:  https://doi.org/10.1016/j.mce.2021.111522
  9. Alzheimers Res Ther. 2021 Nov 29. 13(1): 194
    Intermittent hypoxia treatment alleviates memory impairment in the 6-month-old APPswe/PS1dE9 mice and reduces amyloid beta accumulation and inflammation in the brain.
    Xiangpei Yue, Yanzhao Zhou, Meng Qiao, Xingnan Zhao, Xin Huang, Tong Zhao, Xiang Cheng, Ming Fan, Yongqi Zhao, Ruoli Chen, Lingling Zhu.
       BACKGROUND: Alzheimer's disease (AD) is a progressive, degenerative, and terminal disease without cure. There is an urgent need for a new strategy to treat AD. The aim of this study was to investigate the effects of intermittent hypoxic treatment (IHT) on cognitive functions in a mouse model of AD and unravel the mechanism of action of IHT.
    METHODS: Six-month-old APPswe/PS1dE9 (APP/PS1) male mice were exposed to hypoxic environment (14.3% O2) 4 h/day for 14 days or 28 days. Cognitive functions were measured by Morris water maze test after either 14 days or 42 days of interval. Thereafter the distribution of amyloid plaque and microglial activation were determined by mouse brain immunohistochemistry, while the amyloid beta (Aβ) and inflammatory cytokines were measured by ELISA and Western Blot. Microarray was used for studying gene expressions in the hippocampus.
    RESULTS: IHT for 14 days or 28 days significantly improved the spatial memory ability of the 6-month-old APP/PS1 mice. The memory improvement by 14 days IHT lasted to 14 days, but not to 42 days. The level of Aβ plaques and neurofilament accumulations was reduced markedly after the IHT exposure. IHT reduced the pro-inflammatory cytokines IL-1β, IL-6 levels, and β-secretase cleavage of APP processing which implies reduced Aβ production. Microarray analysis revealed a large number of genes in the hippocampus were significantly altered which are known to be metabolism-regulated genes.
    CONCLUSIONS: This study provides evidence of the beneficial effect of IHT on the progression of AD by alleviating memory impairment, reducing Aβ accumulation and inflammation in the brain. IHT can be developed as a novel measure to relieve the progression of AD by targeting multiple pathways in the AD pathogenesis.
    Keywords:  APPswe/PS1dE9 mice; Alzheimer’s disease; Amyloid beta; BACE1; Gene expression; Intermittent hypoxia treatment; Neuroinflammation
    DOI:  https://doi.org/10.1186/s13195-021-00935-z
  10. Chin Med. 2021 Dec 02. 16(1): 128
    Shen-Zhi-Ling oral liquid ameliorates cerebral glucose metabolism disorder in early AD via insulin signal transduction pathway in vivo and in vitro.
    Gaofeng Qin, Yunfang Dong, Zhenhong Liu, Zhuoyan Gong, Chenyan Gao, Mingcui Zheng, Meijing Tian, Yannan He, Liqun Zhong, Pengwen Wang.
       BACKGROUND: Shen-Zhi-Ling oral liquid (SZL) is an herbal formula known for its efficacy of nourishing "heart and spleen", and is used for the treatment and prevention of middle- and early-stage dementia. This study investigated the effects of SZL on amelioration of AD, and examined whether the underlying mechanisms from the perspective of neuroprotection are related to brain glucose metabolism.
    METHODS: Firstly, LC-MS/MS was used to analysis the SZL mainly enters the blood component. Then, the effects of SZL on cognitive and behavioral ability of APP/PS1 double transgenic mice and amyloid protein characteristic pathological changes were investigated by behavioral study and morphological observation. The effects of SZL on the ultrastructure of mitochondria, astrocytes, and micrangium related to cerebral glucose metabolism were observed using transmission electron microscopy. Then, micro-PET was also used to observe the effects of SZL on glucose uptake. Furthermore, the effects of SZL on insulin signaling pathway InR/PI3K/Akt and glucose transporters (GLUT1 and GLUT3) were observed by immunohistochemistry, Western-blot and RT-qPCR. Finally, the effects of SZL on brain glucose metabolism and key enzyme were observed. In vitro, the use of PI3K and/or GSK3β inhibitor to observe the effects of SZL drug-containing serum on GLUT1 and GLUT3.
    RESULTS: In vivo, SZL could significantly ameliorate cognitive deficits, retarded the pathological damage, including neuronal degeneration, Aβ peptide aggregation, and ultrastructural damage of hippocampal neurons, improve the glucose uptake, transporters and glucolysis. Beyond that, SZL regulates the insulin signal transduction pathway the insulin signal transduction pathway InR/PI3K/Akt. Furthermore, 15% SZL drug-containing serum increased Aβ42-induced insulin signal transduction-pathway related indicators and GLUT1 and GLUT3 expression in SH-SY5Y cells. The improvement of GLUT1 and GLUT3 in the downstream PI3K/Akt/GSK3β signaling pathway was reversed by the use of PI3K and/or GSK3β inhibitor.
    CONCLUSIONS: In summary, our results demonstrated that improving glucose uptake, transport, and glycolysis in the brain may underlie the neuroprotective effects of SZL, and its potential molecular mechanism may be related to regulate the insulin signal transduction pathway.
    Keywords:  Glucolysis; Glucose metabolism; Glucose transporter; Insulin signal transduction; SH-SY5Y cells; Shenzhiling oral liquid
    DOI:  https://doi.org/10.1186/s13020-021-00540-0
  11. CNS Neurol Disord Drug Targets. 2021 ;20(9): 814-821
    The Link between Exercise and Homocysteine in the Alzheimer's Disease: A Bioinformatic Network Model.
    Luana Lemos Leão, Laís Francielle Francisca Felício, Knut Engedal, Gro Gujord Tangen, Kari Midtbø Kristiansen, Sérgio Henrique Sousa Santos, Alfredo Maurício Batista de Paula, Renato Sobral Monteiro-Junior.
      Elevated peripheral expression of homocysteine (Hcy) is associated with an increased risk of coronary heart disease and stroke, diabetes, and cancer. It is also associated with cognitive impairment as it has been reported that high levels of Hcy cause cognitive dysfunction and memory deficit. Among several etiological factors that contribute to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Hcy seems to directly contribute to the generation of neurotoxicity factors. This study aims to hypothesize the molecular mechanism by which exercise can reduce the risk of neurological complications promoted by hyperhomocysteinemia (HHcy), and discuss how exercise could reduce the risk of developing AD by using bioinformatics network models. According to the genes network, there are connections between proteins and amino acids associated with Hcy, exercise, and AD. Studies have evidenced that exercise may be one of several processes by which acid nitric availability can be maximized in the human body, which is particularly important in reducing cell loss and tau pathology and, thereby, leading to a reduced risk of complications associated with HHcy and AD.
    Keywords:  Alzheimer's disease; Gene interaction network; HHcy.; exercise; homocysteine; nitric oxide; oxidative stress
    DOI:  https://doi.org/10.2174/1871527320666210706122618
  12. Neuropharmacology. 2021 Nov 25. pii: S0028-3908(21)00456-1. [Epub ahead of print]204 108899
    Mitochondriomics reveals the underlying neuroprotective mechanism of TrkB receptor agonist R13 in the 5×FAD mice.
    Ting Li, Xiao Li, Xi Huang, Hao Yu, Shupeng Li, Zaijun Zhang, Yongmei Xie, Xiangrong Song, Jianjun Liu, Xifei Yang, Gongping Liu.
      Decreased energy metabolism and mitochondrial biogenesis defects are implicated in the pathogenesis of Alzheimer's disease (AD). In present study, mitochondriomics analysis revealed significant effects of R13, a prodrug of 7,8-dihydroxyflavone, on mitochondrial protein expression profile, including the proteins related to the biological processes: fatty acid beta-oxidation, fatty acid metabolic process, mitochondrial electron transport, and mitochondrial respiratory chain. Cluster analysis demonstrated that R13 promoted mitochondrial oxidative phosphorylation (OXPHOS). The functional analysis showed that R13 increased ATP levels and enhanced OXPHOS including complex Ⅰ, Ⅱ, Ⅲ and Ⅳ. R13 treatment increased mitochondrial biogenesis by regulating the levels of p-AMPKα, p-CREB, PGC-1α, NRF1 and TFAM as a consequence of activation of TrkB receptor in the 5 × FAD mice. Finally, R13 significantly reduced the levels of tau phosphorylation and Aβ plaque. Our data suggest that R13 may be used for treating AD via enhancing mitochondrial biogenesis and metabolism.
    Keywords:  Alzheimer's disease; Mitochondrial biogenesis; OXPHOS; Proteomics; TrkB
    DOI:  https://doi.org/10.1016/j.neuropharm.2021.108899
  13. Int Neurourol J. 2021 Nov;25(Suppl 2): S72-80
    Preischemic Treadmill Exercise Ameliorates Memory Impairment and Microvasculature Damage in Rat Model of Chronic Cerebral Hypoperfusion.
    Jae-Min Lee, Jongmin Park, Joo-Hee Lee, Min Kyung Song, Youn-Jung Kim.
       PURPOSE: Silent information regulator 1 (SIRT1) in the brain is essential for maintaining cellular homeostasis and plays a neuroprotective role in cerebral ischemia and neurodegenerative disorders. The effect of preischemic treadmill exercise on chronic cerebral hypoperfusion (CCH)-induced spatial learning memory impairment, microvascular injury, and blood-brain barrier (BBB) disruption in relation with SIRT1 expression was evaluated.
    METHODS: Prior to bilateral common carotid artery occlusion (BCCAO) surgery, the rats in the exercise groups performed low-intensity treadmill running for 30 minutes once daily during 8 weeks. BCCAO surgery was performed on male Wistar rats at 12 weeks of age. Spatial learning memory was measured using the Morris water maze test. Neuronal nuclear antigen, SIRT1, and rat endothelial cells antigen 1 were determined by immunohistochemistry and platelet-derived growth factor receptor beta was determined by immunofluorescence.
    RESULTS: Preischemic treadmill exercise ameliorated spatial learning memory impairment and enhanced SIRT1 expression in the BCCAO rats. Preischemic treadmill exercise ameliorated BCCAO-induced damage to microvasculature and pericytes that make up the BBB. The effect of preischemic treadmill exercise was lost with sirtinol treatment.
    CONCLUSION: These results can apply treadmill exercise prior to cerebral ischemia as a rational preventive and therapeutic intervention strategy to improve cognitive dysfunction in CCH patients.
    Keywords:  Bilateral common carotid artery occlusion; Chronic cerebral hypoperfusion; Preischemic treadmill exercise; Silent information regulator 1
    DOI:  https://doi.org/10.5213/inj.2142340.170
  14. Neurobiol Dis. 2021 Nov 24. pii: S0969-9961(21)00316-8. [Epub ahead of print]162 105567
    Deficient thyroid hormone transport to the brain leads to impairments in axonal caliber and oligodendroglial development.
    Víctor Valcárcel-Hernández, Daniela López-Espíndola, Marina Guillén-Yunta, Ángel García-Aldea, Inés López de Toledo Soler, Soledad Bárez-López, Ana Guadaño-Ferraz.
      Mutations in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to profound brain alterations, including myelination impairments, in humans. We aimed to further explore the pathophysiological mechanisms underlying the MCT8 deficiency-associated myelination impairments to unravel new biomarkers and therapeutic targets. We have performed brain histological analysis on an MCT8-deficient subject and histological, ultrastructural, and magnetic resonance imaging (MRI) analysis in the brain of a mouse model of the syndrome, lacking MCT8 and enzyme deiodinase type 2 (DIO2, Mct8/Dio2 KO). We have found that the MCT8-deficient subject presents severely reduced myelin lipid and protein staining and increased proportion of small-caliber myelinated axons in detriment of large-caliber ones. Mct8/Dio2 KO mice present myelination impairments and abnormal oligodendroglial development. We conclude that the greater proportion of small-caliber axons and impairments in the oligodendroglia lineage progression arise as potential mechanisms underlying the permanent myelination defects in MCT8-deficiency. Moreover, we present the Mct8/Dio2 KO mouse model, and MRI as a non-invasive biomarker, as highly valuable tools for preclinical studies involving MCT8 deficiency. These findings contribute to the understanding of the pathological mechanisms in MCT8 deficiency and suggest new biomarkers and therapeutic targets to consider therapeutic options for the neurological defects in patients.
    Keywords:  Axonal caliber; Human brain; MCT8 deficiency; MRI; Mouse model; Myelin; Oligodendroglia; Thyroid hormones; Transmission electron microscopy
    DOI:  https://doi.org/10.1016/j.nbd.2021.105567
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