'''Amyloid''' describes various types of [[protein]]aggregationsthatsharespecifictraits when examined [[light microscopy|microscopically]].The name ''amyloid'' comes from the early mistaken identification of the substance as [[starch]] (''amylum'' in [[Latin]]), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits were [[lipid|fatty]] deposits or [[carbohydrate]] deposits until it was finally resolved that it was neither, but rather a deposition of proteinaceous mass.
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[[Image:Smallbowelduodenumwithamyloiddeposition20X.jpg|thumb|right|[[Micrograph]] showing'''amyloid''' deposits (pink) in [[small bowel]]. [[H&E stain]].]]
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'''Amyloids''' are insoluble fibrous [[protein]] aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to [[amyloidosis]], and may play a role in various other neurodegenerative diseases.
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To be specific, amyloid deposits are extracellular, [[thioflavin|thioflavin]]-positive, and exhibit apple-green [[birefringence]] when stained with [[congo red]]. Other indicators exist, such as [[serum amyloid p-component]] binding. Since these are indirect indicators, biophysicists have redefined amyloid using a canonical set of biophysical characteristics (see below), and this seems to cause a low level of conflict between histologists and biophysicists.
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==Definition==
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The name ''amyloid'' comes from the early mistaken identification of the substance as [[starch]] (''amylum'' in [[Latin]]), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits were [[lipid|fatty]] deposits or [[carbohydrate]] deposits until it was finally resolved that it was neither, but rather a deposition of proteinaceous mass.<ref>Kyle, R.A. (2001) Amyloidosis: a convoluted story. ''Brit. J. Haem.'' 114:529-538. PMID 11552976</ref>
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The phenotypes of genetically transmitted amyloid diseases are often inherited in an [[autosomal dominant]] fashion. Sometimes, the difference between aggressive amyloid diseasesandsenescentamyloid diseases is due to a mutation that makes the protein more prone to aggregation. Mostcommonlyseen are point mutations, which affect the cohesiveness of the protein and promote misfolding; other mutations cause aggregation-prone pieces of the protein to be cleaved off from the rest of the protein.
* The classical, [[histopathology|histopathological]] definition of amyloid is an extracellular, proteinaceous deposit exhibiting [[beta sheet]] structure. Common to most cross-beta type structures they are generally identified by apple-green [[birefringence]] when stained with [[congo red]] and seen under [[polarization|polarized light]]. These deposits often recruit various sugars and other components such as [[Serum Amyloid P component]], resulting in complex, and sometimes inhomogeneous structures.<ref>Sipe, J. D. and Cohen, A.S. (2000) Review: History of the Amyloid Fibril. ''J. Struct. Biol.'' 130:88-98. PMID 10940217</ref> Recently this definition has come into question as some classic, amyloid species have been observed in distinctly intracellular locations.<ref name="pmid17353506">{{cite journal |author=Lin CY, Gurlo T, Kayed R, ''et al'' |title=Toxic human islet amyloid polypeptide (h-IAPP) oligomers are intracellular, and vaccination to induce anti-toxic oligomer antibodies does not prevent h-IAPP-induced beta-cell apoptosis in h-IAPP transgenic mice |journal=Diabetes |volume=56 |issue=5 |pages=1324–32 |year=2007 |month=May |pmid=17353506 |doi=10.2337/db06-1579 |url=}}</ref>
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==Diseasesfeaturing amyloid==
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* A more recent, ''biophysical'' definition is broader, including any polypeptide which polymerizes to form a cross-beta structure, ''in vivo'', or ''in vitro''. Some of these, although demonstrably cross-beta sheet, do not show some classic histopathological characteristics such as the Congo red birefringence. Microbiologists and biophysicists have largely adopted this definition,<ref name="pmid15283924">{{cite journal |author=NilssonMR |title=Techniques to study amyloid fibril formation in vitro |journal=Methods (San Diego, Calif.) |volume=34 |issue=1 |pages=151–60 |year=2004 |month=September |pmid=15283924 |doi=10.1016/j.ymeth.2004.03.012 |url=}}</ref><ref name="pmid17530168">{{cite journal |author=Fändrich M |title=On the structural definition of amyloid fibrils and other polypeptide aggregates |journal=Cellular and molecular life sciences : CMLS |volume=64 |issue=16 |pages=2066–78 |year=2007 |month=August |pmid=17530168 |doi=10.1007/s00018-007-7110-2 |url=}}</ref> leading to some conflict in the biological community over an [[Linguistic prescription|issue of language]].
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It should be noted that, in almost all of the organ-specific pathologies, there is significant debate as to whether the amyloid plaques are the causal agent of the disease or instead a symptom downstream of a common ideopathic agent. The associated proteins are indicated in parentheses. Note that ''amyloidosis'' by itself ususally refers to ''AA amyloidosis'', but any disease which presents amyloid deposition is technically an amyloidosis. CJD, alzheimer's and diabetes are almost never referred to as amyloidoses.
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*Systemicamyloidosis
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Theremainderof this article will use the biophysical context.
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** Primary amyloidosis
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*** Mutations in [[lysozyme]], [[transthyretin]], [[apolipoprotein B]], [[fibrinogen]]
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** Secondary amyloidosis
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*** ''AA amyloidosis'' (amyloid A protein, an [[acute-phase protein]] due to chronic [[inflammation]])
***Most commonly caused by mutations in the [[transthyretin]] protein, but in rare occurrences can also be caused by [[apolipoprotein A1]], [[gelsolin]], [[fibrinogen]], and [[lysozyme]] mutations.
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***Primarily caused by genetics, believed to be [[Autosome|autosomal dominant]], high probability of passage to offspring
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***[[Appalachian type amyloidosis]]
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* Organ-specific amyloidosis
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** [[Diabetes mellitus type 2]] ([[amylin]], also known as IAPP)
| [[Beta amyloid]]<ref name="pmid18781964">{{cite journal |author=Chiang PK, Lam MA, Luo Y |title=The many faces of amyloid beta in Alzheimer's disease |journal=Current molecular medicine |volume=8 |issue=6 |pages=580–4 |year=2008 |month=September |pmid=18781964 |doi= |url=http://www.bentham-direct.org/pages/content.php?CMM/2008/00000008/00000006/0013M.SGM}}</ref><ref name="pmid18368143">{{cite journal |author=Irvine GB, El-Agnaf OM, Shankar GM, Walsh DM |title=Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseases |journal=Molecular medicine (Cambridge, Mass.) |volume=14 |issue=7-8 |pages=451–64 |year=2008 |pmid=18368143 |pmc=2274891 |doi=10.2119/2007-00100.Irvine |url=}}</ref><ref name="pmid17505973">{{cite journal |author=Ferreira ST, Vieira MN, De Felice FG |title=Soluble protein oligomers as emerging toxins in Alzheimer's and other amyloid diseases |journal=IUBMB life |volume=59 |issue=4-5 |pages=332–45 |year=2007 |pmid=17505973 |doi=10.1080/15216540701283882 |url=}}</ref>
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|-
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|[[Type 2 diabetes mellitus]]
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|[[Amylin|IAPP (Amylin)]]<ref name="pmid18314421">{{cite journal |author=Haataja L, Gurlo T, Huang CJ, Butler PC |title=Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis |journal=Endocrine reviews |volume=29 |issue=3 |pages=303–16 |year=2008 |month=May |pmid=18314421 |doi=10.1210/er.2007-0037 |url=}}</ref><ref name="pmid10933741">{{cite journal |author=Höppener JW, Ahrén B, Lips CJ |title=Islet amyloid and type 2 diabetes mellitus |journal=The New England journal of medicine |volume=343 |issue=6 |pages=411–9 |year=2000 |month=August |pmid=10933741 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=10933741&promo=ONFLNS19}}</ref>
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|-
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|[[Parkinson's disease]]
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|[[Alpha-synuclein]]<ref name="pmid18368143">{{cite journal |author=Irvine GB, El-Agnaf OM, Shankar GM, Walsh DM |title=Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseases |journal=Molecular medicine (Cambridge, Mass.) |volume=14 |issue=7-8 |pages=451–64 |year=2008 |pmid=18368143 |pmc=2274891 |doi=10.2119/2007-00100.Irvine |url=}}</ref>
|[[Prion]]<ref>[http://www.nature.com/nsmb/journal/v8/n4/full/nsb0401_281.html "More than just mad cow desease", Nature Structural Biology 8, 281 (2001)] doi:10.1038/86132</ref>
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|-
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|[[Huntington's Disease]]
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|[[Huntingtin]]<ref name="pmid18637947">{{cite journal |author=Truant R, Atwal RS, Desmond C, Munsie L, Tran T |title=Huntington's disease: revisiting the aggregation hypothesis in polyglutamine neurodegenerative diseases |journal=The FEBS journal |volume=275 |issue=17 |pages=4252–62 |year=2008 |month=September |pmid=18637947 |doi=10.1111/j.1742-4658.2008.06561.x |url=}}</ref><ref name="pmid16848688">{{cite journal |author=Weydt P, La Spada AR |title=Targeting protein aggregation in neurodegeneration--lessons from polyglutamine disorders |journal=Expert opinion on therapeutic targets |volume=10 |issue=4 |pages=505–13 |year=2006 |month=August |pmid=16848688 |doi=10.1517/14728222.10.4.505 |url=}}</ref>
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|-
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|[[Medullary thyroid cancer|Medullary carcinoma of the thyroid]]
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|[[Calcitonin]]<ref>[http://emedicine.medscape.com/article/335414-overview "Amyloidosis, Overview" by Bruce A Baethge and Daniel R Jacobson]</ref>
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|-
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|[[Cardiac arrhythmias]]
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|[[Atrial natriuretic factor]]
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|-
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|[[Atherosclerosis]]
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|[[Apolipoprotein AI]]
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|-
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|[[Rheumatoid arthritis]]
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|[[Serum amyloid A]]
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|-
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|Aortic medial amyloid
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|[[Medin]]
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|-
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|Prolactinomas
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|Prolactin
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|-
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|Familial amyloid polyneuropathy
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|[[Transthyretin]]
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|-
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|Hereditary non-neuropathic systemic amyloidosis
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|[[Lysozyme]]
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|-
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|[[Dialysis related amyloidosis]]
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|b2-Microglobulin
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|-
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|Finnish amyloidosis
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|Gelsolin
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|-
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|Lattice corneal dystrophy
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|Kerato-epithelin
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|-
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|[[Cerebral amyloid angiopathy]]
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|[[Beta amyloid]]<ref name="pmid19188916">{{cite journal |author=Dotti CG, De Strooper B |title=Alzheimer's dementia by circulation disorders: when trees hide the forest |journal=Nat. Cell Biol. |volume=11 |issue=2 |pages=114–6 |year=2009 |month=February |pmid=19188916 |doi=10.1038/ncb0209-114 |url=}}</ref>
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|-
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|Cerebral amyloid angiopathy (Icelandic type)
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|[[Cystatin]]
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|-
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|[[systemic AL amyloidosis]]
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|Immunoglobulin light chain AL<ref>[http://emedicine.medscape.com/article/335414-overview "Amyloidosis, Overview" by Bruce A Baethge and Daniel R Jacobson]</ref>
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|-
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|Yeast Prions [Sup35],<ref name="pmid16024723">{{cite journal |author=Nakayashiki T, Kurtzman CP, Edskes HK, Wickner RB |title=Yeast prions [URE3] and [PSI+] are diseases |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=102 |issue=30 |pages=10575–80 |year=2005 |month=July |pmid=16024723 |pmc=1180808 |doi=10.1073/pnas.0504882102 |url=}}</ref> Rnq1 (parastitic type infection in yeast)
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|
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|-
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|Sporadic [[Inclusion body myositis|Inclusion Body Myositis]]
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|S-IBM
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|-
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|[[pheochromocytoma]]
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|
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|-
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|Osteomyelitis
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|
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|-
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|Multiple myeloma
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|
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|-
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|}
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==Non-disease and functional amyloids==
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* Native amyloids in organisms<ref name="pmid18487849">{{cite journal |author=Hammer ND, Wang X, McGuffie BA, Chapman MR |title=Amyloids: friend or foe? |journal=Journal of Alzheimer's disease : JAD |volume=13 |issue=4 |pages=407–19 |year=2008 |month=May |pmid=18487849 |doi= |url=http://iospress.metapress.com/openurl.asp?genre=article&issn=1387-2877&volume=13&issue=4&spage=407}}</ref>
** Curli [[E. coli]] Protein (curlin)
** Curli [[E. coli]] Protein (curlin)
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** YeastPrion[Sup35]{Ref Nakayashiki, PNAS, 2005}
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** Chaplinsfrom''Streptomycescoelicolor''
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** Podospora Anserina Prion Het-s
** [[Malaria]]l coat protein
** [[Malaria]]l coat protein
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** [[Spider silk]]
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** [[Spider silk]] (some but not all spiders)
** Mammalian [[melanosome]]s (pMel)
** Mammalian [[melanosome]]s (pMel)
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** Tissue plasminogen a (tPA), a hemodynamic factor
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** Tissue-type plasminogen activator (tPA), a hemodynamic factor
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* Proteins and peptides known to make amyloid without any known disease
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** Calcitonin
* Proteins and peptides engineered to make amyloid
* Proteins and peptides engineered to make amyloid
==Amyloid biophysics==
==Amyloid biophysics==
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The amyloid fold is characterized by a cross-[[beta sheet]] [[quaternary structure]]; that is, amonomericunitcontributesa beta strandtoabetasheet,whichspansacrossmorethanonemolecule. While amyloid is usually identified using fluorescent dyes, stain polarimetry, circular dichroism, or FTIR (all indirect measurements), the "gold-standard" test to see if a structure isamyloid is by placing a sample in an [[X-ray]] diffraction beam;there are two characteristic scattering bands produced at 4 and 10 [[angstrom]]s (0.4 nm and 1.0 nm}, corresponding to the interstrand and stacking distances in beta sheets. It should be noted that the "stacks" of beta sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned strands.
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Amyloid is characterized by a cross-[[beta sheet]] [[quaternary structure]]; that is, thebeta-strandsofthestacked beta-sheetscomefromdifferentproteinmonomersandalignperpendiculartotheaxisofthe fibril. While amyloid is usually identified using fluorescent dyes, stain polarimetry, [[circular dichroism]], or [[Fourier transform infrared spectroscopy|FTIR]] (all indirect measurements), the "gold-standard" test to see if a structure containscross-beta fibres is by placing a sample in an [[X-ray]] diffraction beam.There are two characteristic scattering diffraction signals produced at 4.7 and 10 [[Ångstrom]]s (0.47 nm and 1.0 nm), corresponding to the interstrand and stacking distances in beta sheets.{{Fact|date=November2008}} It should be noted that the "stacks" of beta sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned strands.
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Amyloid [[polymer]]ization is generally sequence-sensitive, that is, causing mutations in the sequence can prevent self-assembly, especially if the mutation is a beta-sheet breaker, such as proline. For example, [[human]]s produce an amyloidogenic peptide associated with type II diabetes, but, in [[rodentia]],aprolineis substituted in a critical location and amyloidogenesis does not occur.
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Amyloid [[polymer]]ization (aggregation or non-covalent polymerization) is generally sequence-sensitive, that is, causing mutations in the sequence can prevent self-assembly, especially if the mutation is a beta-sheet breaker, such as proline. For example, humans produce [[amylin]], an amyloidogenic peptide associated with type II diabetes, but in ratsandmiceprolines are substituted in critical locations and amyloidogenesis does not occur.{{Fact|date=November 2008}}
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There are two broad classes of amyloid-forming polypeptide sequences. '''Glutaminerich''' polypeptides are important in the amyloidogenesis of Yeast and mammalian prions, as well as Huntington's disease. Glutamines can aggregate peptides into a beta-sheet conformation, where the structureisbraced by intrastrand hydrogen bonding between glutamine amide carbonyls and nitrogens. In general, for these diseases toxicity correlates with glutamine content. This has been observed in studies of onset age for Huntington's disease (the longer the polyglutamine sequence, the sooner the symptoms appear), and has been confirmed in a [[c. elegans]] model system with engineered polyglutamine peptides.
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There are two broad classes of amyloid-forming polypeptide sequences. '''Glutamine-rich''' polypeptides are important in the amyloidogenesis of Yeast and mammalian [[prions]], as well as Huntington's disease. When peptides are in a beta-sheet conformation, particularly when the residuesareparallel and in-register (causing alignment), glutamines can brace the structure by forming intrastrand hydrogen bonding between its amide carbonyls and nitrogens. In general, for this class of diseases, toxicity correlates with glutamine content.{{Fact|date=November2008}} This has been observed in studies of onset age for [[Huntington's disease]] (the longer the [[polyglutamine tract|polyglutamine sequence]], the sooner the symptoms appear), and has been confirmed in a ''[[C. elegans]]'' model system with engineered polyglutamine peptides.{{Fact|date=November2008}}
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Other polypeptides and proteins such as [[amylin]] and the Alzheimer's beta protein do not have a simple consensus sequence and are thought to operate by '''hydrophobic association'''.
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Other polypeptides and proteins such as [[amylin]] and the Alzheimer's beta protein do not have a simple consensus sequence and are thought to operate by '''hydrophobic association'''.{{Fact|date=November 2008}} Among the hydrophobic residues, aromatic amino-acids are found to have the highest amyloidogenic propensity. {{Fact|date=November 2008}}
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For these peptides, cross-polymerization (fibrils of one polypeptide sequence causing other fibrils of another sequence to form) is a phenomenon observed in vitro. This phenomenon is important since it would explain interspecies [[prion]] propagation and differential rates of propagation, as well as a statistical link between alzheimer's and diabetes. In general, cross-polymerization is more efficient the more similar the peptide sequence, though entirely dissimilar sequences can cross-polymerize and highly similar sequences can even be "blockers" which prevent polymerization. Polypeptides will not polymerize their mirror-image counterparts.
+
For these peptides, cross-polymerization (fibrils of one polypeptide sequence causing other fibrils of another sequence to form) is observed in vitro and possibly in vivo.{{Fact|date=November2008}} This phenomenon is important since it would explain interspecies [[prion]] propagation and differential rates of prion propagation, as well as a statistical link between Alzheimer's and type 2 diabetes.{{Fact|date=December2008}} In general, the more similar the peptide sequence the more efficient cross-polymerization is, though entirely dissimilar sequences can cross-polymerize and highly similar sequences can even be "blockers" which prevent polymerization.{{Fact|date=November2008}} Polypeptides will not cross-polymerize their mirror-image counterparts, indicating that the phenomenon involves specific binding and recognition events.{{Fact|date=November 2008}}
+
+
==Amyloid pathology==
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+
The reasons for amyloid association with disease is unclear. In some cases, the deposits physically disrupt tissue architecture, suggesting disruption of function by some bulk process. An emerging consensus implicates prefibrillar intermediates, rather than mature amyloid fibers, in causing cell death.<ref>{{cite journal |author=Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG |title=Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers |journal=The Journal of biological chemistry |volume=280 |issue=17 |pages=17294–300 |year=2005 |month=April |pmid=15722360 |doi=10.1074/jbc.M500997200 |url=}}></ref>
+
<ref name="pmid17505973">{{cite journal |author=Ferreira ST, Vieira MN, De Felice FG |title=Soluble protein oligomers as emerging toxins in Alzheimer's and other amyloid diseases |journal=IUBMB life |volume=59 |issue=4-5 |pages=332–45 |year=2007 |pmid=17505973 |doi=10.1080/15216540701283882 |url=}}</ref>
+
+
Studies have shown that amyloid deposition is associated with mitochondrial dysfunction and a resulting generation of reactive oxygen species (ROS), which can initiate a signaling pathway leading to [[apoptosis]] <ref> Kadowaki et al., 2005. Amyloid bold italic beta induces neuronal cell death through ROS-mediated ASK1 activation. Cell Death and Differentiation 12:19-24. [http://www.nature.com/cdd/journal/v12/n1/full/4401528a.html] </ref>.
==Histological staining==
==Histological staining==
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Amyloidis typically identified by a change in the fluorescence intensity of planar aromatic dyes such as Thioflavin T or [[Congo red|Congo Red]]. This is generally attributed to the environmental change, as these dyes intercolate between beta-strands. Congophillic amyloid plaques generally cause apple-green birefringence, when viewed through crossed polarimetric filters. To avoid nonspecific staining, [[histology]] stains, such as [[haematoxylin]] and [[eosin]] stain, are used to quench the dyes' activity in other places where the dye might bind, such as the nucleus. The dawn of antibody technology and [[immunohistochemistry]] has made specific staining easier, but often this can cause trouble because epitopes can be concealed in the amyloid fold; an amyloid protein structure is generally a different conformation from that which the antibody recognizes.
+
Clinically,amyloid diseases are typically identified by a change in the [[fluorescence]] intensity of planar [[aromatic]][[dye]]s such as [[thioflavin T]] or [[congo red]]. Congo red positivity remains the gold standard for diagnosis of [[amyloidosis]]. This is generally attributed to the environmental change, as these dyes [[Intercalation_(chemistry)|intercalate]] between beta-strands. Congophilic amyloid plaques generally cause apple-green [[birefringence]] when viewed through crossed polarimetric filters. To avoid nonspecific staining, other [[histology]] stains, such as the [[H&E stain|hematoxylin and eosin]] stain, are used to quench the dyes' activity in other places such as the nucleus where the dye might bind. Modern antibody technology and [[immunohistochemistry]] has made specific staining easier, but often this can cause trouble because epitopes can be concealed in the amyloid fold; an amyloid protein structure is generally a different conformation from that which the antibody recognizes.
* [http://www.bu.edu/amyloid Amyloid Treatment and Research Program] at [[Boston University]]
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* [http://www.informaworld.com/damy Amyloid: Journal of Protein Folding Disorders web page] at InformaWorld
* [http://www.amyloidosisaustralia.org Information, support and advice to anyone with Amyloidosis, particularly in Australia] (www.amyloidosisaustralia.org)
* [http://www.amyloidosisaustralia.org Information, support and advice to anyone with Amyloidosis, particularly in Australia] (www.amyloidosisaustralia.org)
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* [http://www.amyloidosissupport.com Amyloidosis Support GroupInformation](www.amyloidosissupport.com)
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* [http://amyloidosis.org/whatisit.asp Amyloidosis Support Network]atamyloidosis.org
* [http://www.ucl.ac.uk/medicine/amyloidosis/nac/ UK National Amyloidosis Centre- one of the largest amyloid diagnosis and research centres] at ucl.ac.uk
* [http://www.pathologyatlas.roColoreAtlas of Pathology]
+
* [http://kidney.niddk.nih.gov National Kidney and Urologic Diseases Information Clearinghouse] at[[NationalInstitute of Health]]
+
* [http://www.physorg.com/news88943328.html Role of anesthetics in Alzheimer's disease: Molecular details revealed]
+
* [http://www.physics.uwaterloo.ca/research/zleonenko/data/amyloidosis%20review.pdf Mini Review Amyloidosis] Covering strucutre, mechanisms of action and kinetics of amyloid fibrils.
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various other neurodegenerative diseases.
The name amyloid comes from the early mistaken identification of the substance as starch (amylum in Latin), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits were fatty deposits or carbohydrate deposits until it was finally resolved that it was neither, but rather a deposition of proteinaceous mass.[1]
The classical, histopathological definition of amyloid is an extracellular, proteinaceous deposit exhibiting beta sheet structure. Common to most cross-beta type structures they are generally identified by apple-green birefringence when stained with congo red and seen under polarized light. These deposits often recruit various sugars and other components such as Serum Amyloid P component, resulting in complex, and sometimes inhomogeneous structures.[2] Recently this definition has come into question as some classic, amyloid species have been observed in distinctly intracellular locations.[3]
A more recent, biophysical definition is broader, including any polypeptide which polymerizes to form a cross-beta structure, in vivo, or in vitro. Some of these, although demonstrably cross-beta sheet, do not show some classic histopathological characteristics such as the Congo red birefringence. Microbiologists and biophysicists have largely adopted this definition,[4][5] leading to some conflict in the biological community over an issue of language.
The remainder of this article will use the biophysical context.
Amyloid is characterized by a cross-beta sheetquaternary structure; that is, the beta-strands of the stacked beta-sheets come from different protein monomers and align perpendicular to the axis of the fibril. While amyloid is usually identified using fluorescent dyes, stain polarimetry, circular dichroism, or FTIR (all indirect measurements), the "gold-standard" test to see if a structure contains cross-beta fibres is by placing a sample in an X-ray diffraction beam. There are two characteristic scattering diffraction signals produced at 4.7 and 10 Ångstroms (0.47 nm and 1.0 nm), corresponding to the interstrand and stacking distances in beta sheets.[How to reference and link to summary or text] It should be noted that the "stacks" of beta sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned strands.
Amyloid polymerization (aggregation or non-covalent polymerization) is generally sequence-sensitive, that is, causing mutations in the sequence can prevent self-assembly, especially if the mutation is a beta-sheet breaker, such as proline. For example, humans produce amylin, an amyloidogenic peptide associated with type II diabetes, but in rats and mice prolines are substituted in critical locations and amyloidogenesis does not occur.[How to reference and link to summary or text]
There are two broad classes of amyloid-forming polypeptide sequences. Glutamine-rich polypeptides are important in the amyloidogenesis of Yeast and mammalian prions, as well as Huntington's disease. When peptides are in a beta-sheet conformation, particularly when the residues are parallel and in-register (causing alignment), glutamines can brace the structure by forming intrastrand hydrogen bonding between its amide carbonyls and nitrogens. In general, for this class of diseases, toxicity correlates with glutamine content.[How to reference and link to summary or text] This has been observed in studies of onset age for Huntington's disease (the longer the polyglutamine sequence, the sooner the symptoms appear), and has been confirmed in a C. elegans model system with engineered polyglutamine peptides.[How to reference and link to summary or text]
Other polypeptides and proteins such as amylin and the Alzheimer's beta protein do not have a simple consensus sequence and are thought to operate by hydrophobic association.[How to reference and link to summary or text] Among the hydrophobic residues, aromatic amino-acids are found to have the highest amyloidogenic propensity. [How to reference and link to summary or text]
For these peptides, cross-polymerization (fibrils of one polypeptide sequence causing other fibrils of another sequence to form) is observed in vitro and possibly in vivo.[How to reference and link to summary or text] This phenomenon is important since it would explain interspecies prion propagation and differential rates of prion propagation, as well as a statistical link between Alzheimer's and type 2 diabetes.[How to reference and link to summary or text] In general, the more similar the peptide sequence the more efficient cross-polymerization is, though entirely dissimilar sequences can cross-polymerize and highly similar sequences can even be "blockers" which prevent polymerization.[How to reference and link to summary or text] Polypeptides will not cross-polymerize their mirror-image counterparts, indicating that the phenomenon involves specific binding and recognition events.[How to reference and link to summary or text]
The reasons for amyloid association with disease is unclear. In some cases, the deposits physically disrupt tissue architecture, suggesting disruption of function by some bulk process. An emerging consensus implicates prefibrillar intermediates, rather than mature amyloid fibers, in causing cell death.[19][8]
Studies have shown that amyloid deposition is associated with mitochondrial dysfunction and a resulting generation of reactive oxygen species (ROS), which can initiate a signaling pathway leading to apoptosis[20].
Clinically, amyloid diseases are typically identified by a change in the fluorescence intensity of planar aromaticdyes such as thioflavin T or congo red. Congo red positivity remains the gold standard for diagnosis of amyloidosis. This is generally attributed to the environmental change, as these dyes intercalate between beta-strands. Congophilic amyloid plaques generally cause apple-green birefringence when viewed through crossed polarimetric filters. To avoid nonspecific staining, other histology stains, such as the hematoxylin and eosin stain, are used to quench the dyes' activity in other places such as the nucleus where the dye might bind. Modern antibody technology and immunohistochemistry has made specific staining easier, but often this can cause trouble because epitopes can be concealed in the amyloid fold; an amyloid protein structure is generally a different conformation from that which the antibody recognizes.
↑Kyle, R.A. (2001) Amyloidosis: a convoluted story. Brit. J. Haem. 114:529-538. PMID 11552976
↑Sipe, J. D. and Cohen, A.S. (2000) Review: History of the Amyloid Fibril. J. Struct. Biol. 130:88-98. PMID 10940217
↑Lin CY, Gurlo T, Kayed R, et al (May 2007). Toxic human islet amyloid polypeptide (h-IAPP) oligomers are intracellular, and vaccination to induce anti-toxic oligomer antibodies does not prevent h-IAPP-induced beta-cell apoptosis in h-IAPP transgenic mice. Diabetes56 (5): 1324–32.
↑Nilsson MR (September 2004). Techniques to study amyloid fibril formation in vitro. Methods (San Diego, Calif.)34 (1): 151–60.
↑Fändrich M (August 2007). On the structural definition of amyloid fibrils and other polypeptide aggregates. Cellular and molecular life sciences : CMLS64 (16): 2066–78.
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