Editing Amyloid

{{short description|Insoluble protein aggregate with a fibrillar morphology}}
{{Other uses}}
<!--[[File:Crossbeta.png|300px|thumb|right|Structural model of a section of cross-β amyloid fibril. The closest monomer units are highlighted. Note that each monomer contributes a β strand to a β sheet that extends the full length of the fibril. In this example, the fibril comprises four β sheets, with each monomer contributing two strands to two different sheets. Hydrogen bonding occurs in an intermolecular fashion. The strands are oriented perpendicular to long axis of the fibril.]]-->
[[File:Small bowel duodenum with amyloid deposition 20X.jpg|thumb|[[Micrograph]] showing amyloid deposits (pink) in [[small bowel]]. Duodenum with amyloid deposition in lamina propria. Amyloid shows up as homogeneous pink material in lamina propria and around blood vessels. 20× magnification. ]]
'''Amyloids''' are aggregates of [[protein]]s characterised by a [[fibril]]lar morphology of typically 7–13 [[Nanometer|nm]] in [[diameter]], a [[beta sheet|β-sheet]] [[Secondary structure of proteins|secondary structure]] (known as cross-β) and ability to be [[Staining|stained]] by particular dyes, such as [[Congo red]].<ref name="pmid9356260">{{cite journal | vauthors = Sunde M, Serpell LC, Bartlam M, Fraser PE, Pepys MB, Blake CC | s2cid = 19394482 | title = Common core structure of amyloid fibrils by synchrotron X-ray diffraction | journal = Journal of Molecular Biology | volume = 273 | issue = 3 | pages = 729–39 | date = October 1997 | pmid = 9356260 | doi = 10.1006/jmbi.1997.1348 }}</ref> In the [[human body]], amyloids have been linked to the development of various [[disease]]s.<ref name="pmid28498720"/> Pathogenic amyloids form when previously healthy proteins lose their normal [[Protein structure|structure]] and [[physiology|physiological]] functions ([[Protein misfolding|misfolding]]) and form fibrous deposits within and around cells. These protein misfolding and deposition processes disrupt the healthy function of tissues and organs.

Such amyloids have been associated with (but not necessarily as the cause of) more than 50<ref name="pmid28498720">{{cite journal | vauthors = Chiti F, Dobson CM | title = Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade | journal = Annual Review of Biochemistry | volume = 86 | pages = 27–68 | date = June 2017 | pmid = 28498720 | doi = 10.1146/annurev-biochem-061516-045115 | hdl = 2158/1117236 | hdl-access = free }}</ref><ref name="pmid30614283">{{cite journal | vauthors = Benson MD, Buxbaum JN, Eisenberg DS, Merlini G, Saraiva MJ, Sekijima Y, Sipe JD, Westermark P | display-authors = 6 | title = Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee | journal = Amyloid | volume = 25 | issue = 4 | pages = 215–219 | date = December 2018 | pmid = 30614283 | doi = 10.1080/13506129.2018.1549825 | doi-access = free | hdl = 1805/20251 | hdl-access = free }}</ref> human diseases, known as [[amyloidosis]], and may play a role in some [[neurodegenerative diseases]].<ref name="pmid28498720"/><ref>{{cite journal | vauthors = Pulawski W, Ghoshdastider U, Andrisano V, Filipek S | title = Ubiquitous amyloids | journal = Applied Biochemistry and Biotechnology | volume = 166 | issue = 7 | pages = 1626–43 | date = April 2012 | pmid = 22350870 | pmc = 3324686 | doi = 10.1007/s12010-012-9549-3 }}</ref> Some of these diseases are mainly sporadic and only a few cases are [[Genetic disorder|familial]]. Others are only [[Genetic disorder|familial]]. Some [[iatrogenic|result from medical treatment]]. [[Prion]]s are an [[infectious]] form of amyloids that can act as a template to convert other non-infectious forms.<ref>{{cite journal | vauthors = Soto C, Estrada L, Castilla J | title = Amyloids, prions and the inherent infectious nature of misfolded protein aggregates | journal = Trends in Biochemical Sciences | volume = 31 | issue = 3 | pages = 150–5 | date = March 2006 | pmid = 16473510 | doi = 10.1016/j.tibs.2006.01.002 }}</ref> Amyloids may also have normal biological functions; for example, in the formation of [[fimbria (bacteriology)|fimbriae]] in some [[genus|genera]] of [[bacteria]], transmission of epigenetic traits in fungi, as well as pigment deposition and hormone release in humans.<ref name="ann rev biochem 2011"/>

Amyloids have been known to arise from many different proteins.<ref name="pmid28498720"/><ref>{{cite journal | vauthors = Ramirez-Alvarado M, Merkel JS, Regan L | title = A systematic exploration of the influence of the protein stability on amyloid fibril formation in vitro | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 16 | pages = 8979–84 | date = August 2000 | pmid = 10908649 | pmc = 16807 | doi = 10.1073/pnas.150091797 | bibcode = 2000PNAS...97.8979R | doi-access = free }}</ref> These polypeptide chains generally form [[beta sheet|β-sheet]] structures that aggregate into long fibers; however, identical polypeptides can fold into multiple distinct amyloid conformations.<ref name="pm11076514"/> The diversity of the conformations may have led to different forms of the [[prion]] diseases.<ref name="ann rev biochem 2011">{{cite journal | vauthors = Toyama BH, Weissman JS | title = Amyloid structure: conformational diversity and consequences | journal = Annual Review of Biochemistry | volume = 80 | pages = 557–85 | date = 2011 | pmid = 21456964 | pmc = 3817101 | doi = 10.1146/annurev-biochem-090908-120656 }}</ref>

An unusual secondary structure named [[alpha sheet|α sheet]] has been proposed as the toxic constituent of amyloid precursor proteins,<ref name="alphasheet">{{cite journal | vauthors = Armen RS, Demarco ML, Alonso DO, Daggett V | title = Pauling and Coreys α-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 1 | pages = 11622–11627 | date = 2004 | pmid = 15280548 | pmc = 511030 | doi = 10.1073/pnas.0401781101  | bibcode = 2004PNAS..10111622A | doi-access = free }}</ref> but this idea is not widely accepted at present.

[[File:2rnm.jpg|thumb|upright=1.1|Amyloid of HET-s(218-289) prion pentamer, ''Podospora anserina'' ({{PDB|2rnm}})]]

==Definition==
The name ''amyloid'' comes from the early mistaken identification by [[Rudolf Virchow]] of the substance as [[starch]] ({{Lang|la|amylum}} in [[Latin]], from {{Langx|grc|ἄμυλον|translit=amylon}}), based on crude [[iodine-staining]] techniques. For a period, the scientific community debated whether or not amyloid deposits are [[lipid|fatty]] deposits or [[carbohydrate]] deposits until it was finally found (in 1859) that they are, in fact, deposits of [[albumin|albumoid]] proteinaceous material.<ref>{{cite journal | vauthors = Kyle RA | title = Amyloidosis: a convoluted story | journal = British Journal of Haematology | volume = 114 | issue = 3 | pages = 529–38 | date = September 2001 | pmid = 11552976 | doi = 10.1046/j.1365-2141.2001.02999.x | s2cid = 23111535 | doi-access =  }}</ref>
* The classical, [[histopathology|histopathological]] definition of amyloid is an extracellular, proteinaceous [[fibrillar]] deposit exhibiting [[β-sheet]] [[Secondary structure of proteins|secondary structure]] and identified by apple-green [[birefringence]] when stained with [[congo red]] under [[Polarization (waves)|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>{{cite journal | vauthors = Sipe JD, Cohen AS | s2cid = 16442783 | title = Review: history of the amyloid fibril | journal = Journal of Structural Biology | volume = 130 | issue = 2–3 | pages = 88–98 | date = June 2000 | pmid = 10940217 | doi = 10.1006/jsbi.2000.4221 }}</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 | vauthors = Lin CY, Gurlo T, Kayed R, Butler AE, Haataja L, Glabe CG, Butler PC | 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 β-cell apoptosis in h-IAPP transgenic mice | journal = Diabetes | volume = 56 | issue = 5 | pages = 1324–32 | date = May 2007 | pmid = 17353506 | doi = 10.2337/db06-1579 | doi-access = free }}</ref>
* A more recent, [[biophysics|''biophysical'']] definition is broader, including any polypeptide that polymerizes to form a cross-β structure, ''in vivo'' or ''in vitro'', inside or outside [[Cell (biology)|cells]]. [[Microbiologists]], [[biochemists]], [[biophysicists]], [[chemists]] and [[physicists]] have largely adopted this definition,<ref name="pmid15283924">{{cite journal | vauthors = Nilsson MR | title = Techniques to study amyloid fibril formation in vitro | journal = Methods | volume = 34 | issue = 1 | pages = 151–60 | date = September 2004 | pmid = 15283924 | doi = 10.1016/j.ymeth.2004.03.012 }}</ref><ref name="pmid17530168">{{cite journal | vauthors = Fändrich M | title = On the structural definition of amyloid fibrils and other polypeptide aggregates | journal = Cellular and Molecular Life Sciences | volume = 64 | issue = 16 | pages = 2066–78 | date = August 2007 | pmid = 17530168 | doi = 10.1007/s00018-007-7110-2 | s2cid = 32667968 | pmc = 11138455 }}</ref> leading to some conflict in the biological community over an [[Linguistic prescription|issue of language]].

==Proteins forming amyloids in diseases==
To date, 37 human [[proteins]] have been found to form amyloid in [[pathology]] and be associated with well-defined [[diseases]].<ref name="pmid28498720"/> The International Society of Amyloidosis classifies amyloid fibrils and their associated diseases based upon associated proteins (for example ATTR is the group of diseases and associated fibrils formed by [[Transthyretin|TTR]]).<ref name="pmid30614283"/> A table is included below.

{| class="sortable wikitable"
|-
! Protein
! Diseases
! Official abbreviation
|-
|[[β amyloid|β amyloid peptide]] ([[Beta amyloid|Aβ]]) from [[Amyloid precursor protein]]<ref name="pmid18781964">{{cite journal | vauthors = Chiang PK, Lam MA, Luo Y | title = The many faces of amyloid β in Alzheimer's disease | journal = Current Molecular Medicine | volume = 8 | issue = 6 | pages = 580–4 | date = September 2008 | pmid = 18781964 | doi = 10.2174/156652408785747951 }}</ref><ref name="pmid18368143">{{cite journal | vauthors = 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 | volume = 14 | issue = 7–8 | pages = 451–64 | year = 2008 | pmid = 18368143 | pmc = 2274891 | doi = 10.2119/2007-00100.Irvine }}</ref><ref name="pmid17505973">{{cite journal | vauthors = Ferreira ST, Vieira MN, De Felice FG | s2cid = 7489461 | 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 | doi-access = free }}</ref><ref name="pmid22813427">{{cite journal | vauthors = Hamley IW | title = The amyloid β peptide: a chemist's perspective. Role in Alzheimer's and fibrillization | journal = Chemical Reviews | volume = 112 | issue = 10 | pages = 5147–92 | date = October 2012 | pmid = 22813427 | doi = 10.1021/cr3000994 | url = http://centaur.reading.ac.uk/30230/2/AbetaRevisednew%20-IWH%20%281%29.pdf }}</ref>
|[[Alzheimer's disease]], [[Hereditary cystatin C amyloid angiopathy|Hereditary cerebral haemorrhage with amyloidosis]]
| Aβ
|-
|[[α-synuclein]]<ref name="pmid18368143"/>
|[[Parkinson's disease]], [[Parkinson's disease dementia]], [[Dementia with Lewy bodies]], [[Multiple system atrophy]]
|AαSyn
|-
|[[Prion|PrP<sup>Sc</sup>]]<ref>{{cite journal | title = More than just mad cow disease | journal = Nature Structural Biology | volume = 8 | issue = 4 | pages = 281 | date = April 2001 | pmid = 11276238 | doi = 10.1038/86132 | doi-access = free }}</ref>
|[[Transmissible spongiform encephalopathy]] (e.g. [[Fatal familial insomnia]], [[Gerstmann-Sträussler-Scheinker disease]], [[Creutzfeldt–Jakob disease]], [[New variant Creutzfeldt-Jakob disease|New variant Creutzfeldt–Jakob disease]])
|APrP
|-
|[[Microtubule-associated protein tau]]
|Various forms of [[tauopathies]] (e.g. [[Pick's disease]], [[Progressive supranuclear palsy]], [[Corticobasal degeneration]], [[Frontotemporal dementia with parkinsonism|Frontotemporal dementia with parkinsonism linked to chromosome 17]], [[Argyrophilic grain disease]])
|ATau
|-
|[[Huntingtin|Huntingtin exon 1]]<ref name="pmid18637947">{{cite journal | vauthors = 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 | date = September 2008 | pmid = 18637947 | doi = 10.1111/j.1742-4658.2008.06561.x | s2cid = 11510408 | doi-access = free }}</ref><ref name="pmid16848688">{{cite journal | vauthors = 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 | date = August 2006 | pmid = 16848688 | doi = 10.1517/14728222.10.4.505 | s2cid = 24483289 }}</ref>
|[[Huntington's disease]]
|HTTex1
|-
|[[ITM2B|ABri peptide]]
|[[Familial British dementia]]
|ABri
|-
|[[ITM2B|ADan peptide]]
|[[Familial Danish dementia]]
|ADan
|-
|Fragments of [[immunoglobulin light chains]]<ref name="emedicine.medscape.com"/>
|[[Primary systemic amyloidosis|Light chain amyloidosis]]
|AL
|-
| Fragments of [[immunoglobulin heavy chains]]<ref name="emedicine.medscape.com"/>
|Heavy chain amyloidosis
|AH
|-
|full length of N-terminal fragments of [[Serum amyloid A protein]]
|[[AA amyloidosis]]
|AA
|-
|[[Transthyretin]]
|[[Senile systemic amyloidosis]], [[Familial amyloid polyneuropathy]], [[Familial amyloid cardiomyopathy]], [[Leptomeningeal amyloidosis]]
|ATTR
|-
|[[Beta-2 microglobulin|β-2 microglobulin]]
|[[Dialysis related amyloidosis]], [[Familial visceral amyloidosis|Hereditary visceral amyloidosis]] (familial)
|Aβ2M
|-
|N-terminal fragments of [[Apolipoprotein AI]]
|ApoAI amyloidosis
|AApoAI
|-
|C-terminally extended [[Apolipoprotein A2|Apolipoprotein AII]]
| ApoAII amyloidosis
|AApoAII
|-
|N-terminal fragments of [[Apolipoprotein A4|Apolipoprotein AIV]]
| ApoAIV amyloidosis
|AApoAIV
|-
|[[Apolipoprotein C2|Apolipoprotein C-II]]
| ApoCII amyloidosis
|AApoCII
|-
|[[Apolipoprotein C3|Apolipoprotein C-III]]
| ApoCIII amyloidosis
|AApoCIII
|-
|fragments of [[Gelsolin]]
|[[Finnish type amyloidosis|Familial amyloidosis, Finnish type]]
|AGel
|-
|[[Lysozyme]]
|[[Hereditary non-neuropathic systemic amyloidosis]]
|ALys
|-
|fragments of [[Fibrinogen α chain]]
|Fibrinogen amyloidosis
|AFib
|-
|N-terminally truncated [[Cystatin C]]
|Hereditary cerebral hemorrhage with amyloidosis, Icelandic type
|ACys
|-
|[[Amylin|IAPP (Amylin)]]<ref name="pmid18314421">{{cite journal | vauthors = 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 | date = May 2008 | pmid = 18314421 | pmc = 2528855 | doi = 10.1210/er.2007-0037 }}</ref><ref name="pmid10933741">{{cite journal | vauthors = 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 | date = August 2000 | pmid = 10933741 | doi = 10.1056/NEJM200008103430607 }}</ref>
|[[Diabetes mellitus type 2]], Insulinoma
| AIAPP
|-
|[[Calcitonin]]<ref name="emedicine.medscape.com">{{cite journal | vauthors = Holmes RO, Edison J, Baethge BA, Jacobson DR |url=https://emedicine.medscape.com/article/335414-overview|title=Amyloidosis: Definition of Amyloid and Amyloidosis, Classification Systems, Systemic Amyloidoses|date=10 October 2018 |website=Medscape}}</ref>
|[[Medullary thyroid cancer|Medullary carcinoma of the thyroid]]
| ACal
|-
|[[Atrial natriuretic factor]]
|[[Cardiac arrhythmias]], [[Isolated atrial amyloidosis]]
|AANF
|-
|[[Prolactin]]
|[[Prolactinoma|Pituitary prolactinoma]]
|APro
|-
|[[Insulin]]
|Injection-localized amyloidosis
|AIns
|-
|[[Lactadherin]] / [[Lactadherin|Medin]]
|[[Aortic medial amyloidosis]]
|AMed
|-
|[[Lactotransferrin]] / [[Lactoferrin]]
|[[Gelatinous drop-like corneal dystrophy]]
|ALac
|-
|Odontogenic ameloblast-associated protein
|Calcifying epithelial odontogenic tumors
|AOAAP
|-
|[[Pulmonary surfactant-associated protein C]] (SP-C)
|[[Pulmonary alveolar proteinosis]]
|ASPC
|-
|[[LECT2|Leukocyte cell-derived chemotaxin-2]] ([[LECT2|LECT-2]])
|[[LECT2 amyloidosis|Renal LECT2 amyloidosis]]
|ALECT2
|-
|[[Galectin-7]]
|[[Lichen amyloidosis]], [[Macular amyloidosis]]
|AGal7
|-
|[[Corneodesmosin]]
|[[Hypotrichosis simplex of the scalp]]
|ACor
|-
|C-terminal fragments of [[TGFBI]]/[[Keratoepithelin]]
|[[Lattice corneal dystrophy type I]], Lattice corneal dystrophy type 3A, Lattice corneal dystrophy Avellino type
|AKer
|-
|[[Semenogelin I|Semenogelin-1]] (SGI)
|Seminal vesicle amyloidosis
|ASem1
|-
|[[S100 protein|Proteins S100A8/A9]]
|[[Prostate cancer]]
|none
|-
|[[Enfuvirtide]]
|Injection-localized amyloidosis
|AEnf
|-
|}

==Non-disease and functional amyloids==
Many examples of non-pathological amyloid with a well-defined physiological role have been identified in various organisms, including [[Homo sapiens|human]]. These may be termed as functional or physiological or native amyloid.<ref name="pmid18487849">{{cite journal | vauthors = Hammer ND, Wang X, McGuffie BA, Chapman MR | title = Amyloids: friend or foe? | journal = Journal of Alzheimer's Disease | volume = 13 | issue = 4 | pages = 407–19 | date = May 2008 | pmid = 18487849 | pmc = 2674399 | doi = 10.3233/JAD-2008-13406 | url = http://iospress.metapress.com/openurl.asp?genre=article&issn=1387-2877&volume=13&issue=4&spage=407 | url-status = dead | archive-url = https://archive.today/20130103210811/http://iospress.metapress.com/openurl.asp?genre=article&issn=1387-2877&volume=13&issue=4&spage=407 | archive-date = 2013-01-03 }}</ref><ref name="pmid17412596">{{cite journal | vauthors = Fowler DM, Koulov AV, Balch WE, Kelly JW | title = Functional amyloid--from bacteria to humans | journal = Trends in Biochemical Sciences | volume = 32 | issue = 5 | pages = 217–24 | date = May 2007 | pmid = 17412596 | doi = 10.1016/j.tibs.2007.03.003 }}</ref><ref name="pmid28498720"/>
* Functional amyloid in [[Homo sapiens|''Homo sapiens'']]:
** Intralumenal domain of melanocyte protein [[PMEL (gene)|PMEL]]<ref name="pmid16300414">{{cite journal | vauthors = Fowler DM, Koulov AV, Alory-Jost C, Marks MS, Balch WE, Kelly JW | title = Functional amyloid formation within mammalian tissue | journal = PLOS Biology | volume = 4 | issue = 1 | pages = e6 | date = January 2006 | pmid = 16300414 | pmc = 1288039 | doi = 10.1371/journal.pbio.0040006 | doi-access = free }}</ref>
** Peptide/protein hormones stored as amyloids within endocrine secretory granules<ref>{{cite journal | vauthors = Maji SK, Perrin MH, Sawaya MR, Jessberger S, Vadodaria K, Rissman RA, Singru PS, Nilsson KP, Simon R, Schubert D, Eisenberg D, Rivier J, Sawchenko P, Vale W, Riek R | display-authors = 6 | title = Functional amyloids as natural storage of peptide hormones in pituitary secretory granules | journal = Science | volume = 325 | issue = 5938 | pages = 328–32 | date = July 2009 | pmid = 19541956 | pmc = 2865899 | doi = 10.1126/science.1173155 | bibcode = 2009Sci...325..328M }}</ref>
** Receptor-interacting serine/threonine-protein kinase 1/3 ([[RIP1 (protein)|RIP1]]/[[RIP3]])<ref name="pmid22817896">{{cite journal | vauthors = Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A, Chan FK, Wu H | display-authors = 6 | title = The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis | journal = Cell | volume = 150 | issue = 2 | pages = 339–50 | date = July 2012 | pmid = 22817896 | pmc = 3664196 | doi = 10.1016/j.cell.2012.06.019 }}</ref>
** Fragments of [[prostatic acid phosphatase]] and [[semenogelin]]s<ref name="pmid24691351">{{cite journal | vauthors = Usmani SM, Zirafi O, Müller JA, Sandi-Monroy NL, Yadav JK, Meier C, Weil T, Roan NR, Greene WC, Walther P, Nilsson KP, Hammarström P, Wetzel R, Pilcher CD, Gagsteiger F, Fändrich M, Kirchhoff F, Münch J | display-authors = 6 | title = Direct visualization of HIV-enhancing endogenous amyloid fibrils in human semen | journal = Nature Communications | volume = 5 | pages = 3508 | date = April 2014 | pmid = 24691351 | pmc = 4129123 | doi = 10.1038/ncomms4508 | bibcode = 2014NatCo...5.3508U }}</ref>
* Functional amyloid in other organisms:
** [[Pilus#Curli|Curli]] [[Fimbria (bacteriology)|fibrils]] produced by ''[[E. coli]],'' ''[[Salmonella]], ''and a few other members of the [[Enterobacteriales]] (Csg). The genetic elements ([[operons]]) encoding the curli system are phylogenetic widespread and can be found in at least four bacterial phyla.<ref>{{cite journal | vauthors = Dueholm MS, Albertsen M, Otzen D, Nielsen PH | title = Curli functional amyloid systems are phylogenetically widespread and display large diversity in operon and protein structure | journal = PLOS ONE | volume = 7 | issue = 12 | pages = e51274 | year = 2012 | pmid = 23251478 | pmc = 3521004 | doi = 10.1371/journal.pone.0051274 | veditors = Webber MA | bibcode = 2012PLoSO...751274D | doi-access = free }}</ref> This suggest that many more bacteria may express curli fibrils.
** GvpA, forming the walls of particular [[Gas vesicle]]s, i.e. the buoyancy organelles of aquatic archaea and eubacteria<ref>{{cite journal | vauthors = Bayro MJ, Daviso E, Belenky M, Griffin RG, Herzfeld J | title = An amyloid organelle, solid-state NMR evidence for cross-β assembly of gas vesicles | journal = The Journal of Biological Chemistry | volume = 287 | issue = 5 | pages = 3479–84 | date = January 2012 | pmid = 22147705 | pmc = 3271001 | doi = 10.1074/jbc.M111.313049 | doi-access = free }}</ref>
** Fap fibrils in various species of ''[[Pseudomonas]]''<ref>{{cite journal | vauthors = Dueholm MS, Petersen SV, Sønderkær M, Larsen P, Christiansen G, Hein KL, Enghild JJ, Nielsen JL, Nielsen KL, Nielsen PH, Otzen DE | display-authors = 6 | title = Functional amyloid in Pseudomonas | journal = Molecular Microbiology | volume = 77 | issue = 4 | pages = 1009–20 | date = August 2010 | pmid = 20572935 | doi = 10.1111/j.1365-2958.2010.07269.x | s2cid = 205368641 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Dueholm MS, Søndergaard MT, Nilsson M, Christiansen G, Stensballe A, Overgaard MT, Givskov M, Tolker-Nielsen T, Otzen DE, Nielsen PH | display-authors = 6 | title = Expression of Fap amyloids in Pseudomonas aeruginosa, P. fluorescens, and P. putida results in aggregation and increased biofilm formation | journal = MicrobiologyOpen | volume = 2 | issue = 3 | pages = 365–82 | date = June 2013 | pmid = 23504942 | pmc = 3684753 | doi = 10.1002/mbo3.81 }}</ref>
** Chaplins from ''[[Streptomyces coelicolor]]''<ref name="pmid12832396">{{cite journal | vauthors = Claessen D, Rink R, de Jong W, Siebring J, de Vreugd P, Boersma FG, Dijkhuizen L, Wosten HA | display-authors = 6 | title = A novel class of secreted hydrophobic proteins is involved in aerial hyphae formation in Streptomyces coelicolor by forming amyloid-like fibrils | journal = Genes & Development | volume = 17 | issue = 14 | pages = 1714–26 | date = July 2003 | pmid = 12832396 | pmc = 196180 | doi = 10.1101/gad.264303 }}</ref>
** [[Spidroin]] from ''[[Trichonephila edulis]]'' ([[spider]]) ([[Spider silk]])<ref name="pmid12180993">{{cite journal | vauthors = Kenney JM, Knight D, Wise MJ, Vollrath F | title = Amyloidogenic nature of spider silk | journal = European Journal of Biochemistry | volume = 269 | issue = 16 | pages = 4159–63 | date = August 2002 | pmid = 12180993 | doi = 10.1046/j.1432-1033.2002.03112.x | doi-access = free }}</ref>
** [[Hydrophobin]]s from [[Neurospora crassa]] and other fungi<ref name="pmid11250193">{{cite journal | vauthors = Mackay JP, Matthews JM, Winefield RD, Mackay LG, Haverkamp RG, Templeton MD | title = The hydrophobin EAS is largely unstructured in solution and functions by forming amyloid-like structures | journal = Structure | volume = 9 | issue = 2 | pages = 83–91 | date = February 2001 | pmid = 11250193 | doi = 10.1016/s0969-2126(00)00559-1 | doi-access = free }}</ref>
** Fungal cell adhesion proteins forming cell surface amyloid regions with greatly increased binding strength<ref>{{cite journal | vauthors = Garcia MC, Lee JT, Ramsook CB, Alsteens D, Dufrêne YF, Lipke PN | title = A role for amyloid in cell aggregation and biofilm formation | journal = PLOS ONE | volume = 6 | issue = 3 | pages = e17632 | date = March 2011 | pmid = 21408122 | pmc = 3050909 | doi = 10.1371/journal.pone.0017632 | bibcode = 2011PLoSO...617632G | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lipke PN, Garcia MC, Alsteens D, Ramsook CB, Klotz SA, Dufrêne YF | title = Strengthening relationships: amyloids create adhesion nanodomains in yeasts | journal = Trends in Microbiology | volume = 20 | issue = 2 | pages = 59–65 | date = February 2012 | pmid = 22099004 | pmc = 3278544 | doi = 10.1016/j.tim.2011.10.002 }}</ref>
** Environmental [[biofilm]]s according to staining with amyloid specific dyes and antibodies.<ref>{{cite journal | vauthors = Larsen P, Nielsen JL, Dueholm MS, Wetzel R, Otzen D, Nielsen PH | title = Amyloid adhesins are abundant in natural biofilms | journal = Environmental Microbiology | volume = 9 | issue = 12 | pages = 3077–90 | date = December 2007 | pmid = 17991035 | doi = 10.1111/j.1462-2920.2007.01418.x | bibcode = 2007EnvMi...9.3077L }}</ref>
** Tubular sheaths encasing [[Methanosaeta]] thermophila filaments<ref>{{cite journal | vauthors = Dueholm MS, Larsen P, Finster K, Stenvang MR, Christiansen G, Vad BS, Bøggild A, Otzen DE, Nielsen PH | display-authors = 6 | title = The Tubular Sheaths Encasing Methanosaeta thermophila Filaments Are Functional Amyloids | journal = The Journal of Biological Chemistry | volume = 290 | issue = 33 | pages = 20590–600 | date = August 2015 | pmid = 26109065 | pmc = 4536462 | doi = 10.1074/jbc.M115.654780 | doi-access = free }}</ref>
* Functional amyloid acting as prions
** Several [[yeast prions]] are based on an infectious amyloid, e.g. [PSI+] ([[Sup35p]]); [URE3] ([[Ure2p]]); [PIN+] or [RNQ+] (Rnq1p); [SWI1+] (Swi1p) and [OCT8+] (Cyc8p)
** Prion HET-s from ''[[Podospora anserina]]''<ref name="pmid9275200">{{cite journal | vauthors = Coustou V, Deleu C, Saupe S, Begueret J | title = The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 18 | pages = 9773–8 | date = September 1997 | pmid = 9275200 | pmc = 23266 | doi = 10.1073/pnas.94.18.9773 | bibcode = 1997PNAS...94.9773C | doi-access = free }}</ref>
** Neuron-specific isoform of CPEB from ''[[Aplysia californica]]'' (marine snail)<ref name="pmid14697205">{{cite journal | vauthors = Si K, Lindquist S, Kandel ER | title = A neuronal isoform of the aplysia CPEB has prion-like properties | journal = Cell | volume = 115 | issue = 7 | pages = 879–91 | date = December 2003 | pmid = 14697205 | doi = 10.1016/s0092-8674(03)01020-1 | s2cid = 3060439 | doi-access = free }}</ref>

== Structure ==
[[File:Protofilament of Beta Amyloid.jpg|thumb|Structure of a fibril, consisting of one single protofilament, of the amyloid β peptide viewed down the long axis of the fibril ({{PDB|2mlq}})<ref name="pmid19015532">{{cite journal | vauthors = Paravastu AK, Leapman RD, Yau WM, Tycko R | title = Molecular structural basis for polymorphism in Alzheimer's β-amyloid fibrils | journal = PNAS | volume = 105 | issue = 47 | pages = 18349–54 | date = 25 November 2008 | pmid = 19015532 | doi = 10.1073/pnas.0806270105 | pmc = 2587602 | bibcode = 2008PNAS..10518349P | doi-access = free }}</ref>]]

Amyloids are formed of long unbranched fibers that are characterized by an extended [[β sheet|β-sheet secondary structure]] in which individual [[beta strand|β strand]]s (β-strands) (coloured arrows in the adjacent figure) are arranged in an orientation perpendicular to the long axis of the fiber. Such a structure is known as cross-β structure. Each individual fiber may be 7–13 [[nanometre]]s in width and a few [[micrometre]]s in length.<ref name="ann rev biochem 2011"/><ref name="pmid28498720"/> The main hallmarks recognised by different disciplines to classify protein aggregates as amyloid is the presence of a fibrillar morphology with the expected diameter, detected using [[transmission electron microscopy]] (TEM) or [[atomic force microscopy]] (AFM), the presence of a cross-β secondary structure, determined with [[circular dichroism]], [[Fourier transform infrared spectroscopy|FTIR]], [[solid-state nuclear magnetic resonance]] (ssNMR), [[X-ray crystallography]], or [[X-ray diffraction|X-ray fiber diffraction]] (often considered the "gold-standard" test to see whether a structure contains cross-β fibres), and an ability to stain with specific dyes, such as [[Congo red]], [[thioflavin T]] or [[thioflavin S]].<ref name="pmid28498720"/>

The term "cross-β" was based on the observation of two sets of diffraction lines, one longitudinal and one transverse, that form a characteristic "cross" pattern.<ref>Wormell RL. ''New fibres from proteins''. Academic Press, 1954, p. 106.</ref> There are two characteristic scattering diffraction signals produced at 4.7 and 10&nbsp;[[Ångstrom|Å]] (0.47&nbsp;nm and 1.0&nbsp;nm), corresponding to the interstrand and stacking distances in β sheets.<ref name="pmid9356260"/> The "stacks" of β sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned β-strands. The cross-β pattern is considered a diagnostic hallmark of amyloid structure.<ref name="ann rev biochem 2011"/>

Amyloid fibrils are generally composed of 1–8 protofilaments (one protofilament also corresponding to a fibril is shown in the figure), each 2–7&nbsp;nm in diameter, that interact laterally as flat ribbons that maintain the height of 2–7&nbsp;nm (that of a single protofilament) and are up to 30&nbsp;nm wide; more often protofilaments twist around each other to form the typically 7–13&nbsp;nm wide fibrils.<ref name="pmid28498720"/> Each protofilament possesses the typical cross-β structure and may be formed by 1–6 β-sheets (six are shown in the figure) stacked on each other. Each individual protein molecule can contribute one to several β-strands in each protofilament and the strands can be arranged in antiparallel β-sheets, but more often in parallel β-sheets. Only a fraction of the polypeptide chain is in a β-strand conformation in the fibrils, the remainder forms structured or unstructured loops or tails.

For a long time our knowledge of the atomic-level structure of amyloid fibrils was limited by the fact that they are unsuitable for the most traditional methods for studying protein structures. Recent years have seen progress in experimental methods, including [[solid-state NMR]] spectroscopy and [[cryo-electron microscopy]]. Combined, these methods have provided 3D atomic structures of amyloid fibrils formed by amyloid β peptides, α-synuclein, tau, and the FUS protein, associated with various neurodegenerative diseases.<ref>{{cite journal | vauthors = Meier BH, Riek R, Böckmann A | title = Emerging Structural Understanding of Amyloid Fibrils by Solid-State NMR | journal = Trends in Biochemical Sciences | volume = 42 | issue = 10 | pages = 777–787 | date = October 2017 | pmid = 28916413 | doi = 10.1016/j.tibs.2017.08.001 | hdl = 20.500.11850/193533 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Fitzpatrick AW, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SH | display-authors = 6 | title = Cryo-EM structures of tau filaments from Alzheimer's disease | journal = Nature | volume = 547 | issue = 7662 | pages = 185–190 | date = July 2017 | pmid = 28678775 | pmc = 5552202 | doi = 10.1038/nature23002 | bibcode = 2017Natur.547..185F }}</ref>

[[X-ray crystallography|X-ray diffraction studies of microcrystals]] revealed [[Atomistics|atomistic]] details of core region of amyloid, although only for simplified peptides having a length remarkably shorter than that of peptides or proteins involved in disease.<ref name=Nelson2005>{{cite journal | vauthors = Nelson R, Sawaya MR, Balbirnie M, Madsen AØ, Riekel C, Grothe R, Eisenberg D | title = Structure of the cross-β spine of amyloid-like fibrils | journal = Nature | volume = 435 | issue = 7043 | pages = 773–8 | date = June 2005 | pmid = 15944695 | pmc = 1479801 | doi = 10.1038/nature03680 | bibcode = 2005Natur.435..773N }}</ref><ref name=Sawaya2007>{{cite journal | vauthors = Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA, Apostol MI, Thompson MJ, Balbirnie M, Wiltzius JJ, McFarlane HT, Madsen AØ, Riekel C, Eisenberg D | display-authors = 6 | title = Atomic structures of amyloid cross-β spines reveal varied steric zippers | journal = Nature | volume = 447 | issue = 7143 | pages = 453–7 | date = May 2007 | pmid = 17468747 | doi = 10.1038/nature05695 | bibcode = 2007Natur.447..453S | s2cid = 4400866 }}</ref> The crystallographic structures show that short stretches from amyloid-prone regions of amyloidogenic proteins run perpendicular to the filament axis, consistent with the "cross-β" feature of amyloid structure. They also reveal a number of characteristics of amyloid structures – neighboring β-sheets are tightly packed together via an interface devoid of water (therefore referred to as dry interface), with the opposing β-strands slightly offset from each other such that their side-chains interdigitate. This compact dehydrated interface created was termed a steric-zipper interface.<ref name="ann rev biochem 2011"/> There are eight theoretical classes of steric-zipper interfaces, dictated by the directionality of the β-sheets (parallel and anti-parallel) and symmetry between adjacent β-sheets. A limitation of X-ray crystallography for solving amyloid structure is represented by the need to form microcrystals, which can be achieved only with peptides shorter than those associated with disease.

Although bona fide amyloid structures always are based on intermolecular β-sheets, different types of "higher order" tertiary folds have been observed or proposed. The β-sheets may form a [[Beta-sandwich|β-sandwich]], or a β-solenoid which may be either [[Beta helix|β-helix]] or β-roll. Native-like amyloid fibrils in which native β-sheet containing proteins maintain their native-like structure in the fibrils have also been proposed.<ref name=PMID12219081>{{cite journal | vauthors = Serag AA, Altenbach C, Gingery M, Hubbell WL, Yeates TO | title = Arrangement of subunits and ordering of β-strands in an amyloid sheet | journal = Nature Structural Biology | volume = 9 | issue = 10 | pages = 734–9 | date = October 2002 | pmid = 12219081 | doi = 10.1038/nsb838 | s2cid = 23926428 }}</ref> There are few developed ideas on how the complex backbone topologies of disulfide-constrained proteins, which are prone to form amyloid fibrils (such as insulin and lysozyme), adopt the amyloid β-sheet motif. The presence of multiple constraints significantly reduces the accessible conformational space, making computational simulations of amyloid structures more feasible.<ref>{{cite journal |last1=Puławski |first1=W |last2=Dzwolak |first2=W |title=Virtual Quasi-2D Intermediates as Building Blocks for Plausible Structural Models of Amyloid Fibrils from Proteins with Complex Topologies: A Case Study of Insulin. |journal=Langmuir |date=7 June 2022 |volume=38 |issue=22 |pages=7024–7034 |doi=10.1021/acs.langmuir.2c00699 |pmid=35617668|pmc=9178918 }}</ref>

One complicating factor in studies of amyloidogenic polypeptides is that identical polypeptides can fold into multiple distinct amyloid conformations.<ref name="ann rev biochem 2011"/> This phenomenon is typically described as ''amyloid polymorphism''.<ref name="pm11076514">{{cite journal | vauthors = Balbach JJ, Ishii Y, Antzutkin ON, Leapman RD, Rizzo NW, Dyda F, Reed J, Tycko R | s2cid = 17232045 | display-authors = 6 | title = Amyloid fibril formation by Aβ16-22, a seven-residue fragment of the Alzheimer's β-amyloid peptide, and structural characterization by solid state NMR | journal = Biochemistry | volume = 39 | issue = 45 | pages = 13748–59 | date = November 2000 | pmid = 11076514 | doi = 10.1021/bi0011330 }}</ref><ref name="pm17056725">{{cite journal | vauthors = Bu Z, Shi Y, Callaway DJ, Tycko R | title = Molecular alignment within β-sheets in Aβ<sub>14-23</sub> fibrils: solid-state NMR experiments and theoretical predictions | journal = Biophysical Journal | volume = 92 | issue = 2 | pages = 594–602 | date = January 2007 | pmid = 17056725 | pmc = 1751388 | doi = 10.1529/biophysj.106.091017 | bibcode = 2007BpJ....92..594B | url = }}</ref><ref name="pm12023906">{{cite journal | vauthors = Tjernberg LO, Tjernberg A, Bark N, Shi Y, Ruzsicska BP, Bu Z, Thyberg J, Callaway DJ | display-authors = 6 | title = Assembling amyloid fibrils from designed structures containing a significant amyloid β-peptide fragment | journal = The Biochemical Journal | volume = 366 | issue = Pt 1 | pages = 343–51 | date = August 2002 | pmid = 12023906 | pmc = 1222771 | doi = 10.1042/BJ20020229 }}</ref> It has notable biological consequences given that it is thought to explain the [[prion]] strain phenomenon.

== Formation ==
[[File:Three phases of amyloid fibril formation.tif|thumb|upright=1.35|Three phases of amyloid fibril formation: [[Incubation period|lag phase]], [[exponential function|exponential phase]] and [[plateau effect|plateau phase]]]]
Amyloid is formed through the [[polymerization]] of hundreds to thousands of monomeric [[peptides]] or [[proteins]] into long fibers. Amyloid formation involves a ''[[Incubation period|lag]] phase'' (also called ''[[nucleation]] phase''), an ''[[Exponential growth|exponential]] phase'' (also called ''growth phase'') and a ''[[plateau effect|plateau]] phase'' (also called ''saturation phase''), as shown in the figure.<ref name="pmid8490014"> {{cite journal | vauthors = Jarrett JT, Berger EP, Lansbury PT | title = The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease | journal = Biochemistry | volume = 32 | issue = 18 | pages = 4693–7 | date = May 1993 | pmid = 8490014 | doi = 10.1021/bi00069a001 }}</ref><ref name="pmid10507029"> {{cite book | vauthors = Ferrone F | title = Amyloid, Prions, and Other Protein Aggregates | chapter = Analysis of protein aggregation kinetics | series = Methods in Enzymology | volume = 309 | pages = 256–74 | date = 1999 | pmid = 10507029 | doi = 10.1016/s0076-6879(99)09019-9 | isbn = 9780121822101 }}</ref><ref name="pmid19071235"> {{cite journal | vauthors = Morris AM, Watzky MA, Finke RG | title = Protein aggregation kinetics, mechanism, and curve-fitting: a review of the literature | journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics | volume = 1794 | issue = 3 | pages = 375–97 | date = March 2009 | pmid = 19071235 | doi = 10.1016/j.bbapap.2008.10.016 }}</ref><ref name="pmid20007899">{{cite journal | vauthors = Knowles TP, Waudby CA, Devlin GL, Cohen SI, Aguzzi A, Vendruscolo M, Terentjev EM, Welland ME, Dobson CM | s2cid = 6267152 | display-authors = 6 | title = An analytical solution to the kinetics of breakable filament assembly | journal = Science | volume = 326 | issue = 5959 | pages = 1533–7 | date = December 2009 | pmid = 20007899 | doi = 10.1126/science.1178250 | bibcode = 2009Sci...326.1533K }}</ref> Indeed, when the quantity of fibrils is plotted versus time, a [[sigmoid function|sigmoidal]] time course is observed reflecting the three distinct phases.

In the simplest model of 'nucleated polymerization' (marked by red arrows in the figure below), individual unfolded or partially unfolded [[polypeptide chains]] (monomers) convert into a [[Cell nucleus|nucleus]] ([[monomer]] or [[oligomer]]) via a [[thermodynamics|thermodynamically]] unfavourable process that occurs early in the lag phase.<ref name="pmid19071235"/> Fibrils grow subsequently from these [[Nucleation|nuclei]] through the addition of [[monomer]]s in the exponential phase.<ref name="pmid19071235"/>

A different model, called 'nucleated conformational conversion' and marked by blue arrows in the figure below, was introduced later on to fit some experimental observations: monomers have often been found to convert rapidly into misfolded and highly disorganized oligomers distinct from nuclei.<ref name="pmid10958771"> {{cite journal | vauthors = Serio TR, Cashikar AG, Kowal AS, Sawicki GJ, Moslehi JJ, Serpell L, Arnsdorf MF, Lindquist SL | display-authors = 6 | title = Nucleated conformational conversion and the replication of conformational information by a prion determinant | journal = Science | volume = 289 | issue = 5483 | pages = 1317–21 | date = August 2000 | pmid = 10958771 | doi = 10.1126/science.289.5483.1317 | bibcode = 2000Sci...289.1317S }}</ref> Only later on, will these aggregates reorganise structurally into nuclei, on which other disorganised oligomers will add and reorganise through a templating or induced-fit mechanism (this 'nucleated conformational conversion' model), eventually forming fibrils.<ref name="pmid10958771"/>

Normally [[folded proteins]] have to unfold partially before aggregation can take place through one of these mechanisms.<ref name="pmid19088715"> {{cite journal | vauthors = Chiti F, Dobson CM | title = Amyloid formation by globular proteins under native conditions | journal = Nature Chemical Biology | volume = 5 | issue = 1 | pages = 15–22 | date = January 2009 | pmid = 19088715 | doi = 10.1038/nchembio.131 }}</ref> In some cases, however, folded proteins can aggregate without crossing the major [[energy barrier]] for unfolding, by populating native-like conformations as a consequence of [[thermal fluctuations]], ligand release or local unfolding occurring in particular circumstances.<ref name="pmid19088715"/> In these native-like conformations, segments that are normally buried or structured in the fully folded and possessing a high propensity to aggregate become exposed to the solvent or flexible, allowing the formation of native-like aggregates, which convert subsequently into nuclei and fibrils. This process is called 'native-like aggregation' (green arrows in the figure) and is similar to the 'nucleated conformational conversion' model.

A more recent, modern and thorough model of amyloid fibril formation involves the intervention of secondary events, such as 'fragmentation', in which a fibril breaks into two or more shorter fibrils, and 'secondary nucleation', in which fibril surfaces (not fibril ends) catalyze the formation of new nuclei.<ref name="pmid20007899"/> Both secondary events increase the number of fibril ends able to recruit new monomers or oligomers, therefore accelerating fibril formation through a positive feedback mechanism. These events add to the well recognised steps of primary nucleation (formation of the nucleus from the monomers through one of models described above), fibril elongation (addition of monomers or oligomers to growing fibril ends) and dissociation (opposite process).

Such a new model is described in the figure on the right and involves the utilization of a [[master equation]] that includes all steps of amyloid fibril formation, i.e. primary nucleation, fibril elongation, secondary nucleation and fibril fragmentation.<ref name="pmid20007899"/><ref name=":0">{{cite journal | vauthors = Michaels TC, Šarić A, Habchi J, Chia S, Meisl G, Vendruscolo M, Dobson CM, Knowles TP | display-authors = 6 | title = Chemical Kinetics for Bridging Molecular Mechanisms and Macroscopic Measurements of Amyloid Fibril Formation | journal = Annual Review of Physical Chemistry | volume = 69 | issue = 1 | pages = 273–298 | date = April 2018 | pmid = 29490200 | doi = 10.1146/annurev-physchem-050317-021322 | bibcode = 2018ARPC...69..273M | doi-access = free }}</ref> The [[rate constant]]s of the various steps can be determined from a global fit of a number of time courses of aggregation (for example [[Thioflavin|ThT fluorescence]] emission versus time) recorded at different protein concentrations.<ref name="pmid20007899"/> The general master equation approach to amyloid fibril formation with secondary pathways has been developed by [[Tuomas Knowles|Knowles]], [[Michele Vendruscolo|Vendruscolo]], Cohen, Michaels and coworkers and considers the time evolution of the concentration <math>f(t,j)</math> of fibrils of length <math>j</math> (here <math>j</math> represents the number of monomers in an aggregate).<ref name=":0" /> <math display="block">\begin{align}
\frac{\partial f(t,j)}{\partial t}  & = 2k_+ m(t)f(t,j-1) - 2k_+ m(t)f(t,j) \\ & + 2k_{\rm{off}}f(t,j+1)-2k_{\rm{off}}f(t,j) \\ & + k_-\sum_{i=j+1}^\infty f(t,i)-k_-(j-1)f(t,j) \\ &  +k_1m(t)^{n_1}\delta_{j,n_1}+k_2m(t)^{n_2}M(t)\delta_{j,n_2}  \\
\\
\end{align}  </math>where <math>\delta_{i,j}  </math> denotes the [[Kronecker delta]]. The physical interpretation of the various terms in the above master equation is straight forward: the terms on the first line describe the growth of fibrils via monomer addition with rate constant <math>k_+  </math> (elongation). The terms on the second line describe monomer dissociation, i.e. the inverse process of elongation. <math>k_{\rm{off}}  </math> is the rate constant of monomer dissociation. The terms on the third line describe the effect of fragmentation, which is assumed to occur homogeneously along fibrils with rate constant <math>k_-  </math>. Finally, the terms on the last line describe primary and secondary nucleation respectively. Note that the rate of secondary nucleation is proportional to the mass of aggregates, defined as <math>M(t)=\sum_{j=n_1}^\infty jf(t,j)  </math>.

Following this analytical approach, it has become apparent that the lag phase does not correspond necessarily to only nucleus formation, but rather results from a combination of various steps. Similarly, the exponential phase is not only fibril elongation, but results from a combination of various steps, involving primary nucleation, fibril elongation, but also secondary events. A significant quantity of fibrils resulting from primary nucleation and fibril elongation may be formed during the lag phase and secondary steps, rather than only fibril elongation, can be the dominant processes contributing to fibril growth during the exponential phase. With this new model, any perturbing agents of amyloid fibril formation, such as putative [[drugs]], [[metabolites]], [[Amino acid replacement|mutations]], [[molecular chaperones|chaperones]], etc., can be assigned to a specific step of fibril formation.

== Amino acid sequence and amyloid formation ==
In general, amyloid [[polymer]]ization (aggregation or non-covalent polymerization) is sequence-sensitive, that is mutations in the sequence can induce or prevent self-assembly.<ref name=pmid12917692>{{cite journal | vauthors = Chiti F, Stefani M, Taddei N, Ramponi G, Dobson CM | title = Rationalization of the effects of mutations on peptide and protein aggregation rates | journal = Nature | volume = 424 | issue = 6950 | pages = 805–8 | date = August 2003 | pmid = 12917692 | doi = 10.1038/nature01891 | bibcode = 2003Natur.424..805C | s2cid = 4421180 }}</ref><ref>{{cite journal | vauthors = Gilead S, Gazit E | title = Inhibition of amyloid fibril formation by peptide analogues modified with α-aminoisobutyric acid | journal = Angewandte Chemie | volume = 43 | issue = 31 | pages = 4041–4 | date = August 2004 | pmid = 15300690 | doi = 10.1002/anie.200353565 }}</ref> 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.<ref>Lutz, T.A.: Creating the amylin story. Appetite 172 (2022) 105965, doi:10.1016/j.appet.2022.105965</ref> Studies comparing synthetic to recombinant [[β amyloid|β amyloid peptide]] in assays measuring rate of fibrillation, fibril homogeneity, and cellular toxicity showed that recombinant β amyloid peptide has a faster fibrillation rate and greater toxicity than synthetic β amyloid peptide.<ref>{{cite journal | vauthors = Finder VH, Vodopivec I, Nitsch RM, Glockshuber R | title = The recombinant amyloid-β peptide Aβ1-42 aggregates faster and is more neurotoxic than synthetic Aβ-42 | journal = Journal of Molecular Biology | volume = 396 | issue = 1 | pages = 9–18 | date = February 2010 | pmid = 20026079 | doi = 10.1016/j.jmb.2009.12.016 }}</ref>

There are multiple classes of amyloid-forming polypeptide sequences.<ref name="pm11076514"/><ref name="pm17056725"/><ref name="pm12023906"/> Glutamine-rich polypeptides are important in the amyloidogenesis of Yeast and mammalian [[prions]], as well as [[trinucleotide repeat disorders]] including [[Huntington's disease]]. When glutamine-rich polypeptides are in a β-sheet conformation, glutamines can brace the structure by forming inter-strand hydrogen bonding between its amide carbonyls and nitrogens of both the backbone and side chains. The onset age for Huntington's disease shows an inverse correlation with the length of the [[polyglutamine tract|polyglutamine sequence]], with analogous findings in a ''[[Caenorhabditis elegans|C. elegans]]'' model system with engineered polyglutamine peptides.<ref>{{cite journal | vauthors = Morley JF, Brignull HR, Weyers JJ, Morimoto RI | title = The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 16 | pages = 10417–22 | date = August 2002 | pmid = 12122205 | pmc = 124929 | doi = 10.1073/pnas.152161099 | bibcode = 2002PNAS...9910417M | doi-access = free }}</ref>

Other polypeptides and proteins such as [[amylin]] and the β amyloid peptide do not have a simple consensus sequence and are thought to aggregate through the sequence segments enriched with hydrophobic residues, or residues with high propensity to form β-sheet structure.<ref name="pmid12917692"/> Among the hydrophobic residues, aromatic amino-acids are found to have the highest amyloidogenic propensity.<ref>{{cite journal | vauthors = Gazit E | title = A possible role for pi-stacking in the self-assembly of amyloid fibrils | journal = FASEB Journal | volume = 16 | issue = 1 | pages = 77–83 | date = January 2002 | pmid = 11772939 | doi = 10.1096/fj.01-0442hyp | doi-access = free | s2cid = 27896962 }}</ref><ref name="PMID15925383">{{cite journal | vauthors = Pawar AP, Dubay KF, Zurdo J, Chiti F, Vendruscolo M, Dobson CM | title = Prediction of "aggregation-prone" and "aggregation-susceptible" regions in proteins associated with neurodegenerative diseases | journal = Journal of Molecular Biology | volume = 350 | issue = 2 | pages = 379–92 | date = July 2005 | pmid = 15925383 | doi = 10.1016/j.jmb.2005.04.016 }}</ref>

Cross-polymerization (fibrils of one polypeptide sequence causing other fibrils of another sequence to form) is observed in vitro and possibly in vivo. 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.<ref name="pmid23794448">{{cite journal | vauthors = Jackson K, Barisone GA, Diaz E, Jin LW, DeCarli C, Despa F | title = Amylin deposition in the brain: A second amyloid in Alzheimer disease? | journal = Annals of Neurology | volume = 74 | issue = 4 | pages = 517–26 | date = October 2013 | pmid = 23794448 | pmc = 3818462 | doi = 10.1002/ana.23956 }}</ref> 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" that prevent polymerization.{{Citation needed|date=November 2008}}

==Amyloid toxicity==

The reasons why amyloid cause diseases are 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, particularly in neurodegenerative diseases.<ref name="pmid17505973"/><ref>{{cite journal | vauthors = 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 | date = April 2005 | pmid = 15722360 | doi = 10.1074/jbc.M500997200 | doi-access =  free}}</ref> The fibrils are, however, far from innocuous, as they keep the protein homeostasis network engaged, release oligomers, cause the formation of toxic oligomers via secondary nucleation, grow indefinitely spreading from district to district<ref name="pmid28498720"/> and, in some cases, may be toxic themselves.<ref>{{cite journal | vauthors = Gath J, Bousset L, Habenstein B, Melki R, Böckmann A, Meier BH | title = Unlike twins: an NMR comparison of two α-synuclein polymorphs featuring different toxicity | journal = PLOS ONE | volume = 9 | pages = e90659 | date = March 5, 2014 | issue = 3 | pmid = 24599158| doi = 10.1371/journal.pone.0090659| pmc = 3944079 | bibcode = 2014PLoSO...990659G | doi-access = free }}</ref>

Calcium dysregulation has been observed to occur early in cells exposed to protein oligomers. These small aggregates can form ion channels through lipid bilayer membranes and activate NMDA and AMPA receptors. Channel formation has been hypothesized to account for calcium dysregulation and mitochondrial dysfunction by allowing indiscriminate leakage of ions across cell membranes.<ref>{{cite journal | vauthors = Kagan BL, Azimov R, Azimova R | title = Amyloid peptide channels | journal = The Journal of Membrane Biology | volume = 202 | issue = 1 | pages = 1–10 | date = November 2004 | pmid = 15702375 | doi = 10.1007/s00232-004-0709-4 | s2cid = 23771650 }}</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 signalling pathway leading to [[apoptosis]].<ref>{{cite journal | vauthors = Kadowaki H, Nishitoh H, Urano F, Sadamitsu C, Matsuzawa A, Takeda K, Masutani H, Yodoi J, Urano Y, Nagano T, Ichijo H | display-authors = 6 | title = Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation | journal = Cell Death and Differentiation | volume = 12 | issue = 1 | pages = 19–24 | date = January 2005 | pmid = 15592360 | doi = 10.1038/sj.cdd.4401528 | doi-access = free }}</ref> There are reports that indicate amyloid polymers (such as those of huntingtin, associated with Huntington's disease) can induce the polymerization of essential amyloidogenic proteins, which should be deleterious to cells. Also, interaction partners of these essential proteins can also be sequestered.<ref>{{cite journal | vauthors = Kochneva-Pervukhova NV, Alexandrov AI, Ter-Avanesyan MD | title = Amyloid-mediated sequestration of essential proteins contributes to mutant huntingtin toxicity in yeast | journal = PLOS ONE | volume = 7 | issue = 1 | pages = e29832 | year = 2012 | pmid = 22253794 | pmc = 3256205 | doi = 10.1371/journal.pone.0029832 | veditors = Tuite MF | bibcode = 2012PLoSO...729832K | doi-access = free }}</ref>

All these mechanisms of toxicity are likely to play a role. In fact, the aggregation of a protein generates a variety of aggregates, all of which are likely to be toxic to some degree. A wide variety of biochemical, physiological and cytological perturbations has been identified following the exposure of cells and animals to such species, independently of their identity. The oligomers have also been reported to interact with a variety of molecular targets. Hence, it is unlikely that there is a unique mechanism of toxicity or a unique cascade of cellular events. The misfolded nature of protein aggregates causes a multitude of aberrant interactions with a multitude of cellular components, including membranes, protein receptors, soluble proteins, RNAs, small metabolites, etc.

== Histological staining ==
In the clinical setting, amyloid diseases are typically identified by a change in the spectroscopic properties of planar [[aromatic]] [[dye]]s such as [[thioflavin T]], [[congo red]] or NIAD-4.<ref>{{cite journal | vauthors = Nesterov EE, Skoch J, Hyman BT, Klunk WE, Bacskai BJ, Swager TM | s2cid = 42217289 | title = In vivo optical imaging of amyloid aggregates in brain: design of fluorescent markers | journal = Angewandte Chemie | volume = 44 | issue = 34 | pages = 5452–6 | date = August 2005 | pmid = 16059955 | doi = 10.1002/anie.200500845 }}</ref> In general, this is attributed to the environmental change, as these dyes [[Intercalation (biochemistry)|intercalate]] between β-strands to confine their structure.<ref>{{cite journal | vauthors = Bae S, Lim E, Hwang D, Huh H, Kim SK |year=2015 |title=Torsion-dependent fluorescence switching of amyloid-binding dye NIAD-4 |journal=Chemical Physics Letters |volume=633 |pages=109–13 |doi=10.1016/j.cplett.2015.05.010 |bibcode=2015CPL...633..109B }}</ref>

Congo Red positivity remains the gold standard for diagnosis of [[amyloidosis]]. In general, binding of Congo Red to amyloid plaques produces a typical apple-green [[birefringence]] when viewed under cross-polarized light. Recently, significant enhancement of fluorescence quantum yield of NIAD-4 was exploited to [[super-resolution]] fluorescence imaging of amyloid fibrils<ref>{{cite journal | vauthors = Ries J, Udayar V, Soragni A, Hornemann S, Nilsson KP, Riek R, Hock C, Ewers H, Aguzzi AA, Rajendran L | display-authors = 6 | title = Superresolution imaging of amyloid fibrils with binding-activated probes | journal = ACS Chemical Neuroscience | volume = 4 | issue = 7 | pages = 1057–61 | date = July 2013 | pmid = 23594172 | pmc = 3715833 | doi = 10.1021/cn400091m }}</ref> and oligomers.<ref>{{cite journal | vauthors = Huh H, Lee J, Kim HJ, Hohng S, Kim SK |year=2017 |title=Morphological analysis of oligomeric vs. fibrillar forms of α-synuclein aggregates with super-resolution BALM imaging |journal=Chemical Physics Letters |volume=690 |pages=62–67 |doi=10.1016/j.cplett.2017.10.034 |bibcode=2017CPL...690...62H }}</ref> 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; in general, an amyloid protein structure is a different conformation from the one that the antibody recognizes.

== See also ==
* [[JUNQ and IPOD]]
* [[Proteopathy]]
* [[Protein aggregation predictors]]
* [[Alzheimer's disease]]
* [[Amyloid plaque]]

== References ==
{{Reflist|30em}}

== External links ==
{{Commons category|Amyloid}}
* [https://web.archive.org/web/20081210070634/http://scivee.tv/node/7266 Bacterial Inclusion Bodies Contain Amyloid-Like Structure] at [[SciVee]]
* [https://web.archive.org/web/20090219204637/http://wiki.iop.kcl.ac.uk/default.aspx/Neurodegeneration/Amyloid%20Cascade%20Hypothesis.html Amyloid Cascade Hypothesis]
* [https://www.tandfonline.com/journals/iamy20 Amyloid: Journal of Protein Folding Disorders web page]
* [https://medicalxpress.com/news/2007-01-role-anesthetics-alzheimer-disease-molecular.html Role of anesthetics in Alzheimer's disease: Molecular details revealed]

{{Amyloidosis}}

[[Category:Amyloidosis]]
[[Category:Histopathology]]
[[Category:Structural proteins]]