Palmitiinihaposta harkittavaksi asiaa

The mitochondrial damage-cGAS-STING-IRF3 pathway is critically involved in metabolic stress-induced endothelial inflammation.

MBP, tau ja mikrotubulit

Glia. 2015 Sep;63(9):1621-35. doi: 10.1002/glia.22832. Epub 2015 Apr 4.

Downregulation of the microtubule associated protein tau impairs process outgrowth and myelin basic protein mRNA transport in oligodendrocytes.

Seiberlich V¹, Bauer NG^1,2, Schwarz L¹, Ffrench-Constant C², Goldbaum O¹, Richter-Landsberg C¹.

Abstract

Oligodendrocytes, the myelin forming cells of the CNS, are characterized by their numerous membranous extensions, which enwrap neuronal axons and form myelin sheaths. During differentiation oligodendrocytes pass different morphological stages, downregulate the expression of the proteoglycan NG2, and acquire major myelin specific proteins, such as myelin basic proteins (MBP) and proteolipid protein (PLP).

MBP mRNA is transported in RNA granules along the microtubules (MTs) to the periphery and translated locally. MTs participate in the elaboration and stabilization of the myelin forming extensions and are essential for cellular sorting processes. Their dynamic properties are regulated by microtubule associated proteins (MAPs).

 The MAP tau is present in oligodendrocytes and involved in the regulation and stabilization of the MT network. To further elucidate the functional significance of tau in oligodendrocytes, we have downregulated tau by siRNA technology and studied the effects on cell differentiation and neuron-glia contact formation. The data show that tau knockdown impairs process outgrowth and leads to a decrease in MBP expression.
 Furthermore, MBP mRNA transport to distant cellular extensions is impaired and cells remain in the NG2 stage. In myelinating cocultures with dorsal root ganglion neurons, oligodendrocyte precursor cells after tau miR RNA lentiviral knockdown develop into NG2 positive cells with very long and thin processes, contacting axons loosely, but fail to form internodes. This demonstrates that tau is important for MBP mRNA transport and involved in process formation. The disturbance of the balance of tau leads to abnormalities in oligodendrocyte differentiation, neuron-glia contact formation and the early myelination process. KEYWORDS:

Fyn kinase; NG2 cells; microtubule bundling; myelination; neuron-glia interaction; rat brain



(2)

Biol Chem. 2016 Mar;397(3):185-94. doi: 10.1515/hsz-2015-0157.

Protein aggregate formation in oligodendrocytes: tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration.

Richter-Landsberg C.

Oligodendrocytes are dependent on an intact, dynamic microtubule (MT) network, which participates in the elaboration and stabilization of myelin forming extensions, and is essential for cellular sorting processes. The microtubule-associated protein tau is constituent of oligodendrocytes. During culture maturation it is developmentally regulated and important for MT stability, MT formation and intracellular trafficking. Downregulation of tau impairs process outgrowth and the transport of myelin basic protein (MBP) mRNA to the cell periphery. Cells fail to differentiate into MBP-expressing, sheet-forming oligodendrocytes. Tau-positive inclusions originating in oligodendrocytes and white matter pathology are prominent in frontotemporal dementias, such as Pick's disease, progressive supranuclear palsy and corticobasal degeneration.

An impairment or overload of the proteolytic degradation systems, i.e. the ubiquitin proteasomal system and the lysosomal degradation pathway, has been connected to the formation of protein aggregates. Large protein aggregates are excluded from the proteasome and degraded by autophagy, which is a highly selective process and requires receptor proteins for ubiquitinated proteins, including histone deacetylase 6 (HDAC6). HDAC6 is present in oligodendrocytes, and α-tubulin and tau are substrates of HDAC6.

  In this review our current knowledge of the role of tau and protein aggregate formation in oligodendrocyte cell culture systems is summarized.

Myelin basic protein

Alzheimers Res Ther. 2018 Jan 9;10(1):1. doi: 10.1186/s13195-017-0329-8.

Diffusion kurtosis imaging allows the early detection and longitudinal follow-up of amyloid-β-induced pathology.

Praet J¹, Manyakov NV², Muchene L³, Mai Z^1,4, Terzopoulos V^4,5, de Backer S⁶, Torremans A⁷, Guns PJ^1,8, Van De Casteele T², Bottelbergs A², Van Broeck B², Sijbers J⁹, Smeets D^1,4, Shkedy Z³, Bijnens L², Pemberton DJ², Schmidt ME², Van der Linden A¹, Verhoye M¹⁰.

Abstract

BACKGROUND:

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly population. In this study, we used the APP/PS1 transgenic mouse model to explore the feasibility of using diffusion kurtosis imaging (DKI) as a tool for the early detection of microstructural changes in the brain due to amyloid-β (Aβ) plaque deposition.

METHODS:

We longitudinally acquired DKI data of wild-type (WT) and APP/PS1 mice at 2, 4, 6 and 8 months of age, after which these mice were sacrificed for histological examination. Three additional cohorts of mice were also included at 2, 4 and 6 months of age to allow voxel-based co-registration between diffusion tensor and diffusion kurtosis  metrics and immunohistochemistry.

RESULTS:

Changes were observed in diffusion tensor (DT) and diffusion kurtosis (DK) metrics in many of the 23 regions of interest that were analysed. Mean and axial kurtosis were greatly increased owing to Aβ-induced pathological changes in the motor cortex of APP/PS1 mice at 4, 6 and 8 months of age. Additionally, fractional anisotropy (FA) was decreased in APP/PS1 mice at these respective ages. Linear discriminant analysis of the motor cortex data indicated that combining diffusion tensor and diffusion kurtosis metrics permits improved separation of WT from APP/PS1 mice compared with either diffusion tensor or diffusion kurtosis metrics alone. We observed that mean kurtosis and FA are the critical metrics for a correct genotype classification.
 Furthermore, using a newly developed platform to co-register the in vivo diffusion-weighted magnetic resonance imaging with multiple 3D histological stacks, we found high correlations between DK metrics and anti-Aβ (clone 4G8) antibody,
 glial fibrillary acidic protein (GFAP),
 ionised calcium-binding adapter molecule 1
 and myelin basic protein (MBP)  immunohistochemistry.
 Finally, we observed reduced FA in the septal nuclei of APP/PS1 mice at all ages investigated.
 The latter was at least partially also observed by voxel-based statistical parametric mapping, which showed significantly reduced FA in the septal nuclei, as well as in the corpus callosum, of 8-month-old APP/PS1 mice compared with WT mice.

CONCLUSIONS:

Our results indicate that DKI metrics hold tremendous potential for the early detection and longitudinal follow-up of Aβ-induced pathology.

KEYWORDS:

APP/PS1; Alzheimer’s disease; Diffusion kurtosis imaging; Diffusion tensor imaging; Magnetic resonance imaging

PMID:

29370870

DOI:

10.1186/s13195-017-0329-8

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Selkäytimen demyelinoitumisen vaara huumeen käyttäjillä

Front Neurol. 2018 Feb 6;9:49. doi: 10.3389/fneur.2018.00049. eCollection 2018.

Thioredoxin-1 Protects Spinal Cord from Demyelination Induced by Methamphetamine through Suppressing Endoplasmic Reticulum Stress and Inflammation. Yang L^1,2,3, Guo Y², Huang M², Wu X², Li X², Chen G², Li Y², Bai J².

Tiivistelmä: Abstract

Kautta maailman  huumeena käytetty  psykostomulantti  on metyyli-amfetamiini (meth) . Siitä on alkanut kertyä vakavaa tietoa:  se aiheuttaa aivovauriota. Muutama harva tutkija  on raportoinut myös demyelinisoitumisesta ( siis  hermoston eristävän kaapeliaineksen heikentymisestä. 

Tässä artikkelissa  tiedotetaan että  tioredoxiini-1/Trx-1 ( kehon redox-järjestelmään kuuluva proteiini)  pystyy suojelemaan hermosoluja eri stressitiloissa. Mutta siitä ei ole aiemmin   selvitetty, voisiko, se ehkä  vastavaikuttaa  myös metamfetamiinin aiheuttamaan demyelinoitumiseen.

• Methamphetamine (METH) is a psychostimulant abused around the world. Emerging evidence indicates that METH causes brain damage. However, there are very few reports on METH-induced demyelination. Thioredoxin-1 (Trx-1) is a redox regulating protein and plays the roles in protecting neurons from various stresses. However, whether Trx-1 resists demyelination induced by METH has not been reported. 

Tässä tutkimuksessa  havaittiin hiiriltä  ensinnäkin, että metamfetamiini ohentaa niiden  selkäytimen myeliinituppeja. Jos hiireen siirrettiin (transgeenisesti)  trx-1- geenin yliesiintymä,  niillä  kuitenkin tuon  huumeen  heikentämä  myeliinituppi pystyi korjaantumaan normaaliin vahvuuteen.
Myeliiniproteiineja ovat MAG ( myeliiniin assosioituva glykoproteiini) ja  MBP ( myeliinin emäksinen proteiini). Niiden esiintymä vähenee  metamfetamiinista, samoin väheni kinaasientsyymi  CDK5. Mutta näitä muutoksia blokeerasi  Trx-1 hiirissä.

• In this study, we found that METH-induced thin myelin sheaths in spinal cord, whereas Trx-1 overexpression transgenic (TG) mice restored the myelin sheaths thickness. The expressions of myelin-associated glycoprotein, myelin basic protein, and cyclin-dependent kinase 5 were decreased by METH, whereas these alterations were blocked in Trx-1 TG mice.

 Metamfetamiini vähensi prokaspaasi-12- ja prokaspaasi-3- määriä ja lisäsi calpaiini-1 määrää. Näihin  muutoksiin vastavaikutti Trx-2 TG-hiirissä. Samoin metamfetamiini  indusoi  extrasellulaarissta signaalia säätelevän kinaasin, NF-kB tumatekijän, TNF-alfan ja IL1-betan . Näihinkin muutoksiin  Trx-1 vaikutti TG-hiirissä.

•  The expressions of procaspase-12 and procaspase-3 were decreased by METH, the expression of calpain1 was increased by METH, whereas the alterations were suppressed in Trx-1 TG mice. As same as, the expressions of the extracellular signal-regulated kinase, nuclear factor κB, tumor necrosis factor-alpha, and interleukin-1beta were induced by METH, which were suppressed in Trx-1 TG mice. 

 Johtopäätöksenä:  Trx-1  saattaa olla kehossa  metamfetamiininvälitteisen selkäydindemyelinisaation kriittinen vastavaikuttaja  säätelemällä  endoplasmisen retikulumin stressiä ja  tulehduksellisia teitä.

• These data suggest that Trx-1 may play a critical role in resisting the METH-mediated demyelination in spinal cord through regulating endoplasmic reticulum stress and inflammation pathways.

Avainsanoja,KEYWORDS:

demyelination; endoplasmic reticulum stress; inflammation; methamphetamine; spinal cord; thioredoxin-1

Luteiini , zeaxantiini, DHA, kognitio

https://www.ncbi.nlm.nih.gov/pubmed/29049383

PLoS One. 2017 Oct 19;12(10):e0186767. doi: 10.1371/journal.pone.0186767. eCollection 2017.

Lutein accumulates in subcellular membranes of brain regions in adult rhesus macaques: Relationship to DHA oxidation products.

Mohn ES¹, Erdman JW Jr², Kuchan MJ³, Neuringer M⁴, Johnson EJ¹.

Tiivistelmä, Abstract

 LUTEIINI on karotenoidi, jolla on antioksidatiivista funktiota ja kädellisillä sitä tapaa kertyä  aivoon;  ihmisellä se korreloi kognitioon. Omega3 rasvahappo DHA on myöskin kognitiolle edullista, mutta  se on altis oksidoitumaan. Tässä tutkimuksessa selvitetään luteiinin sijoittumista kognitiolle tärkeisiin  aivoalueisiin ja  määritetään, onko  se assosioitunut aivojen PUFA  rasvahappojen oksidoitumiseen jollain tavalla.

• Lutein, a carotenoid with anti-oxidant functions, preferentially accumulates in primate brain and is positively related to cognition in humans. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (PUFA), is also beneficial for cognition, but is susceptible to oxidation. The present study characterized the membrane distribution of lutein in brain regions important for different domains of cognitive function and determined whether membrane lutein was associated with brain PUFA oxidation.

 Aikuiselle rhesusapinoille  syötettiin kahta  rehulaatua, jossa toisessa  oli luteiini/zeaxantiinilisää.
a)   rehua (sisälsi   noin 2 mg luteiinia  kiloa kohden päivässä eli  0,5 umol/kg).
 b)  rehua ja   luteiinilisää 4.5 mg/ kg eli 1umol/kg päivässä ja zeaxantiinia 0.5 mg/painokilo tai 0,1 umol/painokilo. Tällaisia  dieettejä  syötettiin 6kk  -12 kk.
Siitten apinoista  tutkittiin tumakalvot,  myeliini, mitokondriakalvot ja neuronien plasmakalvot ja seuraavat aivojen osat:  prefrontaalinen kuorikerros, pikkuaivot,   striatum ( kuorikerroken allaoleva harmaa tumake)  ja hippocampus. Mitattiin karotenoidit,  monityydyttämättömät rasvahapot (PUFA)   ja niitten oksidaatiotuotteet.

• Adult rhesus monkeys were fed a stock diet (~2 mg/day lutein or ~0.5 μmol/kg body weight/day) (n = 9) or the stock diet plus a daily supplement of lutein (~4.5 mg/day or~1 μmol/kg body weight/day) and zeaxanthin (~0.5 mg/day or 0.1 μmol/kg body weight/day) for 6-12 months (n = 4).   Nuclear, myelin, mitochondrial, and neuronal plasma membranes were isolated using a Ficoll density gradient from prefrontal cortex (PFC), cerebellum (CER), striatum (ST), and hippocampus (HC). Carotenoids, PUFAs, and PUFA oxidation products were measured using HPLC, GC, and LC-GC/MS, respectively.

 Kaikista tutkituista  etuaivonkuoren   ja aivokuoren kalvoista  havaittiin all-trans-luteiinia (ng/mg proteiinia) ja se vaihteli suuresti eri yksilöiden kesken. Luteiini/zeaxantiinilisä  nosti merkitsevästi seerumin luteiinia sekä luteiinipitoisuuksia  etuaivojen ja kuorikerroksen  sekä mitokondrian kalvoissa, samoin kokonais DHA:n pitoisuus etuaivoissa kohosi . Etuaivoissa ja  striatumissa mitokondriaalinen  luteiini suhtautui käänteisesti DHA oksidaatiotuotteisiin, mutta ei arakidonihapon oksidaatiotuoteisiin. 

Mitä tästä pääteltiin ? Tieto on uutta subsellulaarisen  luteiinin kertymisestä ja sen suhteesta DHA rasvahappoon kädellisaivoissa.  Nämä löydöt  tukevat hypoteesia luteiinin osallistumsiesta  aivojen antioksidatiiviseen funktioon.

• All-trans-lutein (ng/mg protein) was detected in all regions and membranes and was highly variable among monkeys. Lutein/zeaxanthin supplementation significantly increased total concentrations of lutein in serum, PFC and CER, as well as lutein in mitochondrial membranes and total DHA concentrations in PFC only (P<0 .05="" acid="" and="" arachidonic="" but="" dha="" from="" in="" inversely="" li="" lutein="" mitochondrial="" not="" oxidation="" pfc="" products="" related="" st="" those="" to="" was="">

• This study provides novel data on subcellular lutein accumulation and its relationship to DHA oxidation in primate brain. These findings support the hypothesis that lutein may be associated with antioxidant functions in the brain.

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