Leta i den här bloggen

fredag 6 maj 2016

Retinolia sitova proteiini RBP Alzheimerin taudissa

Hakusana, 6 vastausta, PubMed haku 5.5. 2016
Cascella R, Conti S, Mannini B, Li X, Buxbaum JN, Tiribilli B, Chiti F, Cecchi C.
Biochim Biophys Acta. 2013 Dec;1832(12):2302-14. doi: 10.1016/j.bbadis.2013.09.011. Epub 2013 Sep 25.
Suomennosta: "Transtyretiini vaimentaa proteiinien väärinlaskostumalla muodostuneitten   oligomeerien myrkyllisyyttä koeputkessa "
Vaikka ihmisen transthyretiini (h-TTR)   liittyy systeemiseen amyloidoosiin, on havaittu myös antiamyloidogeenistä vaikutusta, joka estää Abeta-oligomeerimuodostusta koeputkessa ja eläinmallissa. Tämä tutkimus selvittää kolmea eri TTR-tyyppiä, ihmisen  tetrameeriä h-TTR, hiiren tetrameeriä mTTR ja ihmisen  proteiinista  tehtyä monomeeria M-TTR   ja niiden vaimentavaa vaikutusta oligomeeritoksisuuteen kahta amyloidogeenista peptidiä/proteiinia vastaan ( HypF-N ja Abeta42). Hiiren mTTR oli stabiilein molekyyli, h-TTR voi dissosioitua osittain laskostumattomiksi monomeereiksi ja M-TTR pysyi monomeeritilassa. 
Toksisten peptidien esimuotoja inkuboitiin tutkittujen TTR- lajien kanssa ja lisättiin sitten viljelyalustaan. 
h-TTR ja vielä enemmän M-TTR suojasi ihmisen neuroblastoma- soluja ja rotan primäärejä neuroneita   oligomeerien aiheuttamalta toksisuudelta, kun taas mTTR ei omannut mitään suojavaikutusta. 
 ...Havaittiin oligomeerien tiivis sitoutuma h-TTR- ja erityisesti M-TTR- proteiiniin. Lisäksi muodostui laaja koostuma oligomeerejä M-TTR- läsnolosta  ja vähemmän h-TTR läsnäolosta. 
Yhteenvetona TTR ( transthyretiini) omaa geneeristä kykyä neutralisoida tehokkaasti sitä oligomeeritoksisuuta, mitä tulee väärin laskostuneista proteiineista  ja paljastuu, että sellaista neutralisoitumista tapahtuu kautta transtyretiinivälitteisen proteiinioligomeerien kokoamisen   laajemmiksi lajeiksi ja se tehokkuus korreloi käänteisesti TTR-tetrameerien stabiliteettiin.

Abstract. Although human transthyretin (TTR) is associated with systemic amyloidoses, an anti-amyloidogenic effect that prevents Aβ fibril formation in vitro and in animal models has been observed. Here we studied the ability of three different types of TTR, namely human tetramers (hTTR), mouse tetramers (muTTR) and an engineered monomer of the human protein (M-TTR), to suppress the toxicity of oligomers formed by two different amyloidogenic peptides/proteins (HypF-N and Aβ42). muTTR is the most stable homotetramer, hTTR can dissociate into partially unfolded monomers, whereas M-TTR maintains a monomeric state. Preformed toxic HypF-N and Aβ42 oligomers were incubated in the presence of each TTR then added to cell culture media. hTTR, and to a greater extent M-TTR, were found to protect human neuroblastoma cells and rat primary neurons against oligomer-induced toxicity, whereas muTTR had no protective effect. --      Moreover, atomic force microscopy (AFM), light scattering and turbidimetry analyses indicated that larger assemblies of oligomers are formed in the presence of M-TTR and, to a lesser extent, with hTTR. Overall, the data suggest a generic capacity of TTR to efficiently neutralize the toxicity of oligomers formed by misfolded proteins and reveal that such neutralization occurs through a mechanism of TTR-mediated assembly of protein oligomers into larger species, with an efficiency that correlates inversely with TTR tetramer stability.KEYWORDS: 

 AD; Alzheimer's disease  
Aβ, amyloid-beta peptide;
DTT dithiothreitol; 
HypF-N, N-terminal domain of the HypF protein from Escherichia coli;
FAC  familial amyloid cardiomyopathy; 
NBM, neurobasal medium; 
PSD-95,  postsynaptic density protein 95; 
RBP,  retinol binding protein charged with retinol
SSA, senile systemic amyloidosis; 
ThT thioflavin T; 
T4  thyroxine;
TTR,  transthyretin
TTR protective effect
TTR-mediated oligomer clsutering

Ando Y.Rinsho Byori. 2009 Mar;57(3):228-35. Review. Japanese.

AbstractTransthyretin (TTR) was previously called prealbumin because the band it formed on agarose gel electrophoresis at pH 8.6 was at the prealbumin position. However, it has been well documented that TTR of rodents does not show a prealbumin position on electrophoresis. Now, its name describes its function, binding to retinol binding protein (RBP) and T4. The serum concentration of the protein is 20-40 mg/dl, and TTR forms a tetramer. The plasma half life of the protein is 1.9 days. TTR is synthesized by the liver, retina, pancreas, and choroid plexus. In cerebro-spinal fluid (CSF), it is the second most abundant protein, and is considered as an important protein in the pathogenesis of Alzheimer's disease, depression, and lead intoxication. In addition, TTR is a tryptophan-rich protein, it is used as one of the nutrition assessment proteins, it acts as an anti acute phase protein, and its plasma concentration decreases during inflammation and bacterial infection. Since TTR is a highly amyloidogenic protein because it contains a beta-sheet structure, it becomes a precursor protein in familial amyloidotic polyneuropathy(FAP). Moreover, TTR plays important roles in various CNS disorders, diabetes melitus, and lipid metabolism.

Jung SM, Lee K, Lee JW, Namkoong H, Kim HK, Kim S, Na HR, Ha SA, Kim JR, Ko J, Kim JW.
Neurosci Lett. 2008 May 9;436(2):153-7. doi: 10.1016/j.neulet.2008.03.010. Epub 2008 Mar 18.

Abstract Cerebrospinal fluid (CSF) may be of valuable for exploring protein markers for the diagnosis of Alzheimer's disease (AD). The prospect of early detection and treatment, to slow progression, holds hope for aging populations with increased average lifespan. The aim of the present study was to investigate candidate CSF biological markers in patients with mild cognitive impairment (MCI) and AD and compare them with age-matched normal control subjects. In this report, we applied proteomics approaches to analyze 60 CSF samples derived from patients with neurodegenerative diseases such as MCI and AD. We classified patients by three groups: normal controls without cognitive dysfunction, MCI and AD. The AD group was subdivided into three groups by clinical severity according to clinical dementia rating (CDR), a well known clinical scale for dementia.We demonstrated a gradual decrease or absent of plasma retinol-binding protein (RBP) and haptoglobin precursor allele 1 in CSF from patients with MCI and AD compared to the age-matched normal subjects. Moreover, expression levels of both RBP and haptoglobin precursor allele 1 were observed to be very high in age-matched normal subjects.

In contrast, the RBP and haptoglobin precursor allele 1 were much decreased in the MCI group; those expressions were more weak or absent in AD group, and correlated with disease severity and progression. These findings suggest that the CSF levels of both RBP and haptoglobin precursor allele 1 may be candidate biomarkers for the progression of normal to MCI to AD.

Goodman AB.
J Cell Physiol. 2006 Dec;209(3):598-603. Review.
Vitamin A (retinoid) is required in the adult brain to enable cognition, learning, and memory. While brain levels of retinoid diminish over the course of normal ageing, retinoid deficit is greater in late onset Alzheimer disease (LOAD) brains than in normal-aged controls. This paper reviews recent evidence supporting these statements and further suggests that genes necessary for the synthesis, transport and function of retinoid to and within the ageing brain are appropriate targets for treatment of LOAD. These genes tend to be clustered with genes that have been proposed as candidates in LOAD, are found at chromosomal regions linked to LOAD, and suggest the possibility of an overall coordinated regulation. This phenomenon is termed Chromeron and is analogous to the operon mechanism observed in prokaryotes. Suggested treatment targets are the retinoic-acid inactivating enzymes (CYP26)s, the retinol binding and transport proteins, retinol-binding protein (RBP)4 and transthyretin (TTR), and the retinoid receptors.
 TTR as a LOAD target is the subject of active investigation. The retinoid receptors and the retinoid-inactivating enzymes have previously been proposed as targets. 
This is the first report to suggest that RBP4 is an amenable treatment target in LOAD. RBP4 is elevated in type-2 diabetes and obesity, conditions associated with increased risk for LOAD.
 Fenretinide, a novel synthetic retinoic acid (RA) analog lowers RBP4 in glucose intolerant obese mice. The feasibility of using fenretinide either as an adjunct to present LOAD therapies, or on its own as an early prevention strategy should be determined.
(c) 2006 Wiley-Liss, Inc.
Ando Y.
Rinsho Byori. 2005 Jun;53(6):554-7. Review. Japanese.
Abstract Transthyretin (TTR) is a beta-sheet rich protein whose plasma half life is 1.9 days. It behaves as a tetramer and binds to retinol binding protein (RBP) and thyroxin in plasma. Since TTR is a tryptophan-rich-protein, the protein is used as a useful marker protein for nutrition supporting team (NST). However, TTR is also an anti-acute phase protein, and the concentration is influenced by various conditions, such as inflammation and infection, Mutated forms of TTR are the precursor protein of familial amyloidotic polyneuropathy (FAP). Since plasma TTR is predominantly synthesized by the liver, liver transplantation has been performed as an effective therapy for FAP. Recent research revealed that TTR plays important roles in various central nervous system disorders, such as Alzheimer disease, depression, and lead intoxication. To elucidate the pathogenesis of those disorders, an accurate me surement of TTR concentrations in plasma and cerebrospinal fluids is of vital importance.
McCaddon A, Davies G, Hudson P, Tandy S, Cattell H.
Int J Geriatr Psychiatry. 1998 Apr;13(4):235-9.

Inga kommentarer:

Skicka en kommentar