beta-amyloid

• βアミロイド、βアミロイドタンパク質

関

Abeta、beta-amyloid peptide、beta-amyloid protein

WordNet

1. to remain unmolested, undisturbed, or uninterrupted -- used only in infinitive form; "let her be"
2. work in a specific place, with a specific subject, or in a specific function; "He is a herpetologist"; "She is our resident philosopher" (同)follow
3. have life, be alive; "Our great leader is no more"; "My grandfather lived until the end of war" (同)live
4. be identical to; be someone or something; "The president of the company is John Smith"; "This is my house"
5. happen, occur, take place; "I lost my wallet; this was during the visit to my parents house"; "There were two hundred people at his funeral"; "There was a lot of noise in the kitchen"
6. have the quality of being; (copula, used with an adjective or a predicate noun); "John is rich"; "This is not a good answer"
7. occupy a certain position or area; be somewhere; "Where is my umbrella?" "The toolshed is in the back"; "What is behind this behavior?"
8. spend or use time; "I may be an hour"
9. stake on the outcome of an issue; "I bet $100 on that new horse"; "She played all her money on the dark horse" (同)wager, play
10. the act of gambling; "he did it on a bet" (同)wager
11. maintain with or as if with a bet; "I bet she will be there!" (同)wager
12. second in order of importance; "the candidate, considered a beta male, was perceived to be unable to lead his party to victory"
13. the 2nd letter of the Greek alphabet
14. preliminary or testing stage of a software or hardware product; "a beta version"; "beta software"
15. (pathology) a waxy translucent complex protein resembling starch that results from degeneration of tissue
16. a non-nitrogenous food substance consisting chiefly of starch; any substance resembling starch
17. beets (同)genus Beta

PrepTutorEJDIC

1. 《連結語として補語を伴なって…『である』,…だ,…です / 《位置・場所を表す語句を伴って》(…に)『ある』,いる(occupy a place or situation) / 〈物事が〉『存在する』,ある(exist);〈生物が〉生存する,生きている(live) / 行われる,起こる,発生する(take place, occur) / 存続する,そのままでいる(remain as before) / 《『be to』 do》 / …する予定である,…することになっている / …すべきだ / 《受動態の不定詞を伴って》…できる / 《命令》…するのだ / 《条件節に》…する意図がある / 《『if…were to』 do》…するとしたなら / 《『be』 do『ing』》《進行形》 / 《進行中の動作》…している,しつつある / 《近い未来》…しようとしている,するつもり / 《動作の反復》(いつも)…している / 《『be』+『他動詞の過去分詞』》《受動態》…される,されている / 《『be』+『自動詞の過去分詞』》《完了形》…した[状態にある]
2. 『かけ』・(…との)かけ《+『with』+『名』》 / かけた物(金) / かけの対象 / 〈金・物〉'を'『かける』 / (かけ事・ゲームなどで)〈人〉‘と'『かけをする』《+『名』〈人〉+『on』+『名』》 / (…に)『かける』《+『on』(『against』)+『名』(one's do『ing』)》
3. ベータ(ギリシア語アルファベットの第2文字;B,β;英語のB,b に遭当)

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/08/20 01:27:48」(JST)

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[Wiki en表示]

Beta-amyloid peptide (beta-APP)
A partially folded structure of amyloid-beta(1 40) in an aqueous environment (pdb 2lfm)
Identifiers
Symbol	Beta-APP
Pfam	PF03494
InterPro	IPR013803
SCOP	2lfm
SUPERFAMILY	2lfm
TCDB	1.C.50
OPM superfamily	369
OPM protein	2y3k
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)
Processing of the amyloid precursor protein
Identifiers
Symbol	APP
Alt. symbols	AD1
Entrez	351
HUGO	620
OMIM	104760
RefSeq	NM_000484
UniProt	P05067
Other data
Locus	Chr. 21 q21.2

Amyloid beta (Aβ or Abeta) is a peptide of 36–43 amino acids that is processed from the amyloid precursor protein (APP). While best known as a component of amyloid plaques in association with Alzheimer's disease, as Aβ is the main component of certain deposits found in the brains of patients with Alzheimer's disease, evidence has been found that Aβ is a highly multifunctional peptide with significant non-pathological activity. A recent study suggested that APP and its amyloid potential is of ancient origins, dating as far back as early deuterostomes.

Normal activity

The normal function of Aβ is not well understood. Though some animal studies have shown that the absence of Aβ does not lead to any loss of physiological function, several potential activities have been discovered for Aβ, including activation of kinase enzymes, protection against oxidative stress, regulation of cholesterol transport, functioning as a transcription factor, and anti-microbial activity (potentially associated with Aβ's pro-inflammatory activity).

Disease associations

Aβ is the main component of amyloid plaques (deposits found in the brains of patients with Alzheimer's disease). Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis (a muscle disease), while Aβ can also form the aggregates that coat cerebral blood vessels in cerebral amyloid angiopathy. The plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers, a protein fold shared by other peptides such as the prions associated with protein misfolding diseases. Recent research suggests that soluble oligomeric forms of the peptide may be causative agents in the development of Alzheimer's disease. A number of genetic, cell biology, biochemical and animal studies support the concept that Aβ plays a central role in the development of Alzheimer’s disease pathology.

Brain Aβ is elevated in patients with sporadic Alzheimer’s disease. Aβ is the main constituent of brain parenchymal and vascular amyloid; it contributes to cerebrovascular lesions and is neurotoxic. It is unresolved how Aβ accumulates in the central nervous system and subsequently initiates the disease of cells. Some researchers have found that the Aβ oligomers induce some of the symptoms of Alzheimer's Disease by competing with insulin for binding sites on the insulin receptor, thus impairing glucose metabolism in the brain. Significant efforts have been focused on the mechanisms responsible for Aβ production, including the proteolytic enzymes alpha- and β-secretases which generate Aβ from its precursor protein, APP (amyloid precursor protein). Aβ circulates in plasma, cerebrospinal fluid (CSF) and brain interstitial fluid (ISF) mainly as soluble Aβ40 Senile plaques contain both Aβ40 and Aβ42, while vascular amyloid is predominantly the shorter Aβ40. Several sequences of Aβ were found in both lesions. Generation of Aβ in the CNS may take place in the neuronal axonal membranes after APP-mediated axonal transport of β-secretase and presenilin-1.

Formation

Aβ is formed after sequential cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein of undetermined function. APP can be cleaved by the proteolytic enzymes α-, β- and γ-secretase; Aβ protein is generated by successive action of the β and γ secretases. The γ secretase, which produces the C-terminal end of the Aβ peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 36-43 amino acid residues in length. The most common isoforms are Aβ₄₀ and Aβ₄₂; the longer form is typically produced by cleavage that occurs in the endoplasmic reticulum, while the shorter form is produced by cleavage in the trans-Golgi network. The Aβ₄₀ form is the more common of the two, but Aβ₄₂ is the more fibrillogenic and is thus associated with disease states. Mutations in APP associated with early-onset Alzheimer's have been noted to increase the relative production of Aβ₄₂, and thus one suggested avenue of Alzheimer's therapy involves modulating the activity of β and γ secretases to produce mainly Aβ₄₀. Aβ is destroyed by several amyloid-degrading enzymes including neprilysin.

Genetics

Autosomal-dominant mutations in APP cause hereditary early-onset Alzheimer's disease (familial AD). This form of AD accounts for no more than 10% of all cases, and the vast majority of AD is not accompanied by such mutations. However, familial Alzheimer disease is likely to result from altered proteolytic processing. Increases in either total Aβ levels or the relative concentration of both Aβ₄₀ and Aβ₄₂ (where the former is more concentrated in cerebrovascular plaques and the latter in neuritic plaques) have been implicated in the pathogenesis of both familial and sporadic Alzheimer's disease. Due to its more hydrophobic nature, the Aβ₄₂ is the most amyloidogenic form of the peptide. However the central sequence KLVFFAE is known to form amyloid on its own, and probably forms the core of the fibril.

The "amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is by no means conclusively established. An alternative hypothesis is that amyloid oligomers rather than plaques are responsible for the disease. Mice that are genetically engineered to express oligomers but not plaques (APP^E693Q) develop the disease. Furthermore mice that are in addition engineered to convert oligomers into plaques (APP^E693Q X PS1ΔE9), are no more impaired than the oligomer only mice. Intra-cellular deposits of tau protein are also seen in the disease, and may also be implicated, as has aggregation of alpha synuclein.

Structure

Amyloid beta is commonly thought to be intrinsically unstructured, meaning that in solution it does not acquire a unique tertiary fold but rather populates a set of structures. As such, it cannot be crystallized and most structural knowledge on amyloid beta comes from NMR and molecular dynamics. Early NMR-derived models of a 26-aminoacid polypeptide from amyloid beta (Aβ 10-35) show a collapsed coil structure devoid of significant secondary structure content, however, the most recent (2012) NMR structure of (Aβ 1-40) has significant secondary and tertiary structure. Replica exchange molecular dynamics studies suggested that amyloid beta can indeed populate multiple discrete structural states; more recent studies identified a multiplicity of discrete conformational clusters by statistical analysis. By NMR-guided simulations, amyloid beta 1-40 and amyloid beta 1-42 also seem to feature highly different conformational states, with the C-terminus of amyloid beta 1-42 being more structured than that of the 1-40 fragment.

Structural information on the oligomeric state of amyloid beta is still sparse as of 2010. Low-temperature and low-salt conditions allowed to isolate pentameric disc-shaped oligomers devoid of beta structure. In contrast, soluble oligomers prepared in the presence of detergents seem to feature substantial beta sheet content with mixed parallel and antiparallel character, different from fibrils; computational studies suggest an antiparallel beta-turn-beta motif instead for membrane-embedded oligomers.

Intervention strategies

Researchers in Alzheimer's disease have identified five strategies as possible interventions against amyloid:

• β-Secretase inhibitors. These work to block the first cleavage of APP outside of the cell.
• γ-Secretase inhibitors (e. g. semagacestat). These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of Aβ and its toxic fragments.
• Selective Aβ₄₂ lowering agents (e. g. tarenflurbil). These modulate γ-secretase to reduce Aβ₄₂ production in favor of other (shorter) Aβ versions.

β- and y-secretase are responsible for the generation of Aβ from the release of the intracellular domain of APP, meaning that compounds that can partially inhibit the activity of either β- and y-secretase are highly sought after. In order to initiate partial inhibition of β- and y-secretase, a compound is needed that can block the large active site of aspartyl proteases while still being capable of bypassing the blood-brain barrier. To date, human testing has been avoided due to concern that it might interfere with signaling via Notch proteins and other cell surface receptors.

• Immunotherapy. This stimulates the host immune system to recognize and attack Aβ, or provide antibodies that either prevent plaque deposition or enhance clearance of plaques or Aβ oligomers. Oligomerization is a chemical process that converts individual molecules into a chain consisting of a finite number of molecules. Prevention of oligomerization of Aβ has been exemplified by active or passive Aβ immunization. In this process antibodies to Aβ are used to decrease cerebral plaque levels. This is accomplished by promoting microglial clearance and/or redistributing the peptide from the brain to systemic circulation. One such beta-amyloid vaccine that is currently in clinical trials is CAD106. Immunization with synthetic Aβ1-42 has been shown to be beneficial in mice and displays low toxicity; however human trials have shown no significant differences. Thus, it is not yet effective in humans and requires further research. Specific findings show that the 20 amino acid SDPM1 protein binds tetramer forms of Aβ(1-40)- and Aβ(1-42)-amyloids and blocks subsequent Aβ amyloid aggregation. It is important to note that this study was done in mice and that while it prevents further development of neuropathology it did not result in an improvement in cognitive performance. Lastly, Aβ42 immunization resulted in the clearance of amyloid plaques in patients with Alzheimer's disease but did not prevent progressive neurodegeneration.

• Anti-aggregation agents such as apomorphine. These prevent Aβ fragments from aggregating or clear aggregates once they are formed. Studies comparing synthetic to recombinant Aβ₄₂ in assays measuring rate of fibrillation, fibril homogeneity, and cellular toxicity showed that recombinant Aβ₄₂ had a faster fibrillation rate and greater toxicity than synthetic Amyloid beta 1-42 peptide. This observation combined with the irreproducibility of certain Aβ₄₂ experimental studies has been suggested to be responsible for the lack of progress in Alzheimer’s research. Consequently, there has been renewed efforts to manufacture Aβ₄₂ and other amyloid peptides at unprecedented (>99%) purity

There is some indication that supplementation of the hormone melatonin may be effective against amyloid. Melatonin interacts with amyloid beta and inhibits its aggregation This anti-aggregatory activity occurs only through an interaction with dimers of the soluble amyloid beta peptide. Melatonin does not reverse fibril formation or oligomers of amyloid beta once they are formed. This is supported by experiments in transgenic mice which suggest that melatonin has the potential to prevent amyloid deposition if administered early in life, but it may not be efficacious to revert amyloid deposition or treat Alzheimer's disease.

This connection with melatonin, which regulates sleep, is strengthened by the recent research showing that the wakefulness inducing hormone orexin influences amyloid beta (see below). Interestingly, animal experiments show that melatonin may also correct mild elevations of cholesterol which is also an early risk factor for amyloid formation.

The cannabinoid HU-210 has been shown to prevent amyloid beta-promoted inflammation. The endocannabinoids anandamide and noladin ether have also been shown to be neuroprotective against amyloid beta in vitro.

It has been shown that high-cholesterol diets tend to increase Aβ pathology in animals. Modulating cholesterol homeostasis has yielded results that show that chronic use of cholesterol-lowering drugs, such as the statins, is associated with a lower incidence of AD. In APP genetically modified mice, cholesterol-lowering drugs have been shown to reduce overall pathology. While the mechanism is poorly understood it appears that cholesterol-lowering drugs have a direct effect on APP processing.

Chelation therapy, which involves the removal of heavy metals from the body, has also been shown to be beneficial in lowering amyloid plaque levels. This is because Aβ aggregation is somewhat dependent on the metal ions copper and zinc. Zinc in synaptic vesicles, which is under the control of the zinc transporter ZnT3, plays a major role in Aβ formation. The expression of the ZnT3 is significantly lower in Alzheimer’s patients compared to healthy patients. Mice without ZnT3 were found to have much lower plaque formation. Further promoting this concept, Aβ deposition was impeded in APP transgenic mice treated with the antibiotic clioquinol, a known copper/zinc chelator.

Drug therapy has been another approach to treatment. Memantine is an Alzheimer’s drug which has received widespread approval. It is a non-competitive N-methyl-D-aspartate (NMDA) channel blocker. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. It is an option for the management of patients with moderate to severe Alzheimer's Disease (modest effect). The study showed that 20 mg/day improved cognition, functional ability and behavioural symptoms in patient population. Another drug that is currently under research is victoza, which is typically used as a diabetes drug. Treatment with victoza yielded cognitive benefits that included improved object and spatial recognition. Additionally victoza enhances induction and maintenance of long term potentiation (LTP) and paired-pulse facilitation (PPF) in both APP/PS1 and non-genetically altered mice. Other histological benefits include a reduced inflammatory response and an increase in the number of young neurons in the dentate gyrus. The β-amyloid level was also found to be significantly reduced.

Circadian rhythm of amyloid beta

A 2009 report demonstrated that amyloid beta production follows a circadian rhythm, rising when an animal (mouse) or person is awake and falling during sleep. The wakefulness-promoting neuroprotein orexin was shown to be necessary for the circadian rhythm of amyloid beta production. The report suggested that excessive periods of wakefulness (i.e. due to sleep debt) could cause chronic build-up of amyloid beta, which could hypothetically lead to Alzheimer's disease. This is consistent with recent findings that chronic sleep deprivation is associated with early onset Alzheimer's disease.

Melatonin is also involved in circadian rhythm maintenance. Notably, melatonin has been connected with the "sundowning" phenomenon, in which Alzheimer's disease patients that have amyloid plaques in the hypothalamus exhibit exacerbation of Alzheimer's disease symptoms late in the day. This "sundowning" phenomenon could be directly or indirectly related to the recently discovered continuous increase in amyloid beta throughout the day.

Measuring amyloid beta

Micrograph showing amyloid beta (brown) in senile plaques of the cerebral cortex (upper left of image) and cerebral blood vessels (right of image) with immunostaining.

There are many different ways to measure Amyloid beta. It can be measured semi-quantitatively with immunostaining, which also allows one to determine location. Amyloid beta may be primarily vascular, as in cerebral amyloid angiopathy, or in senile plaques and vascular.

One highly sensitive method is ELISA which is an immunosorbent assay which utilizes a pair of antibodies that recognize Amyloid beta.

Imaging compounds, notably Pittsburgh compound B, (6-OH-BTA-1, a thioflavin), can selectively bind to amyloid beta in vitro and in vivo. This technique, combined with PET imaging, has been used to image areas of plaque deposits in Alzheimer's patients.

Atomic force microscopy, which can visualize nanoscale molecular surfaces, can be used to determine the aggregation state of Amyloid beta in vitro.

Dual polarisation interferometry is an optical technique which can measure the very earliest stages of aggregration and inhibition by measuring the molecular size and densities as the fibrils elongate. These aggregate processes can also be studied on lipid bilayer constructs.

References

Further reading

• Martins IC, Kuperstein I, Wilkinson H, Maes E, Vanbrabant M, Jonckheere W, Van Gelder P, Hartmann D, D'Hooge R, De Strooper B, Schymkowitz J, Rousseau F (January 2008). "Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice". EMBO J. 27 (1): 224–33. doi:10.1038/sj.emboj.7601953. PMC 2206134. PMID 18059472. 
• Istrate AN, Tsvetkov PO, Mantsyzov AB, Kulikova AA, Kozin SA, Makarov AA, Polshakov VI (January 2012). "NMR solution structure of rat Aβ(1-16): toward understanding the mechanism of rats' resistance to Alzheimer's disease". Biophys J. 102 (1): 136–43. Bibcode:2012BpJ...102..136I. doi:10.1016/j.bpj.2011.11.4006. PMC 3250693. PMID 22225807. 

External links

• Online 'Mendelian Inheritance in Man' (OMIM) 104300

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. アミロイドーシスの概要 an overview of amyloidosis
• 2. アルツハイマー病の遺伝学 genetics of alzheimer disease
• 3. アルツハイマー病の臨床症状および診断 clinical manifestations and diagnosis of alzheimer disease
• 4. アミロイド心筋症の治療 treatment of amyloid cardiomyopathy
• 5. 腎アミロイドーシス renal amyloidosis

English Journal

• Phenolic contents and bioactive potential of peach fruit extracts.

• Mokrani A1, Krisa S2, Cluzet S2, Da Costa G2, Temsamani H2, Renouf E3, Mérillon JM4, Madani K5, Mesnil M6, Monvoisin A6, Richard T7.
• Food chemistry.Food Chem.2016 Jul 1;202:212-20. doi: 10.1016/j.foodchem.2015.12.026. Epub 2015 Dec 8.
• Several cultivars of peach fruit (Prunus persica L.) were investigated. Their phenolic composition and concentration were assessed by LC-MS. Concentrations were calculated in mg per g of dry weight extract. Their antioxidant capacity (Folin-Ciocalteu, ORAC, DPPH, ABTS, PFRAP and ICA), inhibitory pro
• PMID 26920287

• Nano-biosensors to detect beta-amyloid for Alzheimer's disease management.

• Kaushik A1, Jayant RD2, Tiwari S2, Vashist A2, Nair M3.
• Biosensors & bioelectronics.Biosens Bioelectron.2016 Jun 15;80:273-87. doi: 10.1016/j.bios.2016.01.065. Epub 2016 Jan 28.
• Beta-amyloid (β-A) peptides are potential biomarkers to monitor Alzheimer's diseases (AD) for diagnostic purposes. Increased β-A level is neurotoxic and induces oxidative stress in brain resulting in neurodegeneration and causes dementia. As of now, no sensitive and inexpensive method is available
• PMID 26851586

• On the physiological/pathological link between Aβ peptide, cholesterol, calcium ions and membrane deformation: A molecular dynamics study.

• Pannuzzo M1.
• Biochimica et biophysica acta.Biochim Biophys Acta.2016 Jun;1858(6):1380-9. doi: 10.1016/j.bbamem.2016.03.018. Epub 2016 Mar 19.
• The dynamic interplay between cholesterol, asymmetrically (at physiological condition) or symmetrically (hallmark of aging) distributed in membrane, and β amyloid peptides is investigated by a computational approach. The drawn overall picture, starting from the very appearance of β amyloid peptide
• PMID 27003127

Japanese Journal

• アミロイドイメージングによる認知症の診断 (特集 認知症の診断と治療 : 最近の進歩)

• 臨床精神医学 45(4), 433-439, 2016-04
• NAID 40020782505

• The relation between canine cognitive dysfunction and age-related brain lesions

• Journal of Veterinary Medical Science advpub(0), 2016
• NAID 130005127218

• PET検査のこれまでとこれから

• 医学物理 35(1), 2-9, 2015
• NAID 130005123784

Related Links

• Beta amyloidとは - goo Wikipedia (ウィキペディア)

^ a b Vivekanandan S, Brender JR, Lee SY, Ramamoorthy A (July 2011). "A partially folded structure of amyloid-beta(1-40) in an aqueous environment". Biochem. Biophys. Res. Commun. 411 (2): 312–6. doi:10.1016/j.bbrc.2011.06.133.

• アミロイドベータ蛋白 (amyloid beta protein)

アミロイドβ蛋白 (amyloidβprotein) アミロイドβ蛋白(Aβ)は40-42(3)アミノ酸からなるペプチドであり、β-及びγ-セクレターゼの働きにより前駆体蛋白(APP: amyloid β protein precursor)から切り出されてくる。APPはα-セクレターゼによっても切断 ...

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★リンクテーブル★

リンク元	「βアミロイドタンパク質」「ベータアミロイド」「βアミロイド」「Abeta」
拡張検索	「beta-amyloid protein」「beta-amyloid peptide」
関連記事	「amyloid」「beta」「be」

「βアミロイドタンパク質」

　　[★]

英

beta-amyloid protein、beta-amyloid peptide、beta-amyloid

関

アミロイドβタンパク質、βアミロイド、βアミロイドペプチド、β-アミロイド、β-アミロイドペプチド、β-アミロイドタンパク質

「ベータアミロイド」

　　[★]

英

beta-amyloid, beta amyloid, β-amyloid, β amyloid

同

βアミロイド

関

アミロイド

「βアミロイド」

　　[★]

英

beta-amyloid, β-amyloid

同

amyloidタンパク

関

βアミロイドタンパク質

「Abeta」

　　[★]

• βアミロイド

関

beta-amyloid

「beta-amyloid protein」

　　[★]

• βアミロイドタンパク質

関

amyloid beta-protein、beta-amyloid、beta-amyloid peptide

「beta-amyloid peptide」

　　[★]

• βアミロイドペプチド

関

beta-amyloid、beta-amyloid protein

「amyloid」

　　[★]

アミロイド

関

amyloid fibril、amyloid protein

　 　

「beta」

　　[★]

β、ベータ 　 　 　 　

「be」

　　[★]