Amyloidosis

 

Amyloidosis is a group of diseases in which abnormal protein, known as amyloid fibrils, builds up in tissue.[4]Symptoms depend on the type and are often variable.[2] They may include diarrhea, weight loss, feeling tired, enlargement of the tongue, bleeding, numbness, feeling faint with standing, swelling of the legs, or enlargement of the spleen.[2]

There are about 30 different types of amyloidosis, each due to a specific protein misfolding.[5] Some are genetic while others are acquired.[3] They are grouped into localized and systemic forms.[2] The four most common types of systemic disease are light chain (AL), inflammation (AA), dialysis (Aβ2M), and hereditary and old age (ATTR).[2]

Diagnosis may be suspected when protein is found in the urine, organ enlargement is present, or problems are found with multiple peripheral nerves and it is unclear why.[2] Diagnosis is confirmed by tissue biopsy.[2] Due to the variable presentation, a diagnosis can often take some time to reach.[3]

Treatment is geared towards decreasing the amount of the involved protein.[2] This may sometimes be achieved by determining and treating the underlying cause.[2] AL amyloidosis occurs in about 3–13 per million people per year and AA amyloidosis in about 2 per million people per year.[2] The usual age of onset of these two types is 55 to 60 years old.[2] Without treatment, life expectancy is between six months and four years.[2] In the developed world about 1 per 1,000 people die from amyloidosis.[3] Amyloidosis has been described since at least 1639.[2]

Skin features of amyloidosis cutis dyschromica. Hyperpigmented and hypopigmented macules on (A) lower legs, (B) back and waist, (C) waist. (D) Individual blisters on upper arm

The presentation of amyloidosis is broad and depends on the site of amyloid accumulation. The kidney and heart are the most common organs involved.

Amyloid deposition in the kidneys can cause nephrotic syndrome, which results from a reduction in the kidney’s ability to filter and hold on to proteins. The nephrotic syndrome occurs with or without elevations in creatinine and blood urea concentration,[6]two biochemical markers of kidney injury. In AA amyloidosis, the kidneys are involved in 91–96% of people,[7]symptoms ranging from protein in the urine to nephrotic syndrome and rarely renal insufficiency.

Amyloid deposition in the heart can cause both diastolic and systolic heart failure. EKG changes may be present, showing low voltage and conduction abnormalities like atrioventricular block or sinus node dysfunction. On echocardiography, the heart shows a restrictive filling pattern, with normal to mildly reduced systolic function.[6] AA amyloidosis usually spares the heart.[7]

People with amyloidosis do not get central nervous system involvement but can develop sensory and autonomic neuropathies. Sensory neuropathy develops in a symmetrical pattern and progresses in a distal to proximal manner. Autonomic neuropathy can present as orthostatic hypotension but may manifest more gradually with nonspecific gastrointestinal symptoms like constipation, nausea, or early satiety.[6]

Accumulation of amyloids in the liver can lead to elevations in serum aminotransferases and alkaline phosphatase, two biomarkers of liver injury, which is seen in about one third of people.[7] Liver enlargement is common. In contrast, spleen enlargement is rare, occurring in 5% of people. Splenic dysfunction, leading to the presence of Howell-Jolly bodies on blood smear, occurs in 24% of people with amyloidosis.[6] Malabsorption is seen in 8.5% of AL amyloidosis and 2.4% of AA amyloidosis. One suggested mechanism for the observed malabsorption is that amyloid deposits in the tips of intestinal villi (fingerlike projections that increase the intestinal area available for absorption of food), begin to erode the functionality of the villi, presenting a sprue-like picture.[7]

A rare development is a susceptibility to bleeding with bruising around the eyes, termed “raccoon-eyes”, caused by amyloid deposition in the blood vessels and a reduced activity of thrombin and factor X, two clotting proteins that lose their function after binding with amyloid.[6]

Amyloid deposits in tissue can cause enlargement of structures. Twenty percent of people with AL amyloidosis have a enlarged tongue, that can lead to obstructive sleep apnea, difficulty swallowing, and altered taste.[7] Tongue enlargement does not occur in ATTR or AA amyloidosis.[6] Enlarged shoulders, “shoulder pad sign”, results from amyloid deposition in synovial space. Deposition of amyloid in the throat can cause hoarseness.[6] Aβ2MG amyloidosis (Hemodialysis associated amyloidosis) likes to deposit in synovial tissue, causing chronic synovitis, which can lead to repeated carpal tunnel syndrome.[7]

Both the thyroid and adrenal gland can be infiltrated. It is estimated that 10–20% of individuals with amyloidosis have hypothyroidism. Adrenal infiltration may be harder to appreciate given that its symptoms of orthostatic hypotension and low blood sodium concentration may be attributed to autonomic neuropathy and heart failure.[6]

“Amyloid deposits occur in the pancreas of patients with diabetes mellitus, although it is not known if this is functionally important. The major component of pancreatic amyloid is a 37-amino acid residue peptide known as islet amyloid polypeptide or ‘amylin.’ This is stored with insulin in secretory granules in B cells and is co secreted with insulin.” (Rang and Dale’s Pharmacology, 2015.)

Uncommonly, a collection of amyloid can grow large enough to be classed as an amyloidoma, a macroscopic lump of amyloid that can cause mass effect.

The cells in the body have two different ways of making proteins. Some proteins are made of one single piece or sequence of amino acids; in other cases, protein fragments are produced, and the fragments come and join together to form the whole protein. But such a protein can sometimes fall apart into the original protein fragments. This process of “flip flopping” happens frequently for certain protein types, especially the ones that cause amyloidosis.

The fragments or actual proteins are at risk of misfolding as they are synthesized, to make a poorly functioning protein. This causes proteolysis, which is the directed breakdown of proteins by cellular enzymes called proteases or by intramolecular digestion; proteases come and digest the misfolded fragments and proteins. The problem occurs when the proteins do not dissolve in proteolysis because the misfolded proteins sometimes become robust enough so that they are not dissolved by normal proteolysis. When the fragments do not dissolve, they get spit out of proteolysis and aggregate to form oligomers. The reason they aggregate is that the parts of the protein that do not dissolve in proteolysis are hydrophobic β-pleated sheets. They are usually sequestered in the middle of the protein, while parts of the protein that are more soluble are found near the outside. When they are exposed to water, these hydrophobic pieces tend to aggregate with other hydrophobic pieces. This ball of fragments gets stabilized by GAGs (glycosaminoglycans) and SAP (serum amyloid P), a component found in amyloid aggregations that is thought to stabilize them and prevent proteolytic cleavage. The stabilized balls of protein fragments are called oligomers. The oligomers can aggregate together and further stabilize to make amyloid fibrils.

Both the oligomers and amyloid fibrils are toxic to cells and can interfere with proper organ function.[8]

Diagnosis of amyloidosis requires tissue biopsy. The biopsy is assessed for evidence of characteristic amyloid deposits. The tissue is treated with various stains. The most useful stain in the diagnosis of amyloid is Congo red, which, combined with polarized light, makes the amyloid proteins appear apple-green on microscopy. Also, thioflavin T stain may be used.[9]

Tissue can come from any involved organ, but in systemic disease the first-line site of the biopsy is subcutaneous abdominal fat, known as a “fat pad biopsy”, due to its ease of acquisition versus biopsy of the rectum, salivary gland or internal organs. An abdominal fat biopsy is not completely sensitive, and sometimes, biopsy of an involved organ (such as the kidney) is required to achieve a diagnosis.[9] For example, in AL amyloidosis only 85% of people will have a positive fatpad biopsy using Congo red stain.[6] By comparison, rectal biopsy has sensitivity of 74–94%.[7]

The type of the amyloid protein can be determined in various ways: the detection of abnormal proteins in the bloodstream (on protein electrophoresis or light chain determination); binding of particular antibodies to the amyloid found in the tissue (immunohistochemistry); or extraction of the protein and identification of its individual amino acids.[9] Immunohistochemistry can identify AA amyloidosis the majority of the time, but can miss many cases of AL amyloidosis.[7] Laser microdissection with mass spectrometry is the most reliable method of identifying the different forms of amyloidosis.[10]

AL is the most common form of amyloidosis, and a diagnosis often begins with a search for plasma cell dyscrasia, memory B cells producing aberrant immunoglobulins or portions of immunoglobulins. Immunofixation electrophoresis of urine or serum is positive in 90% of people with AL amyloidosis.[6] Immunofixation electrophoresis is more sensitive than regular electrophoresis but may not be available in all centers. Alternatively immunohistochemical staining of a bone marrow biopsy looking for dominant plasma cells can be sought in people with a high clinical suspicion for AL amyloidosis but negative electrophoresis.[6]

ATTR, or familial transthyretin-associated amyloidosis, is suspected in people with family history of idiopathic neuropathies or heart failure who lack evidence of plasma cell dyscrasias. ATTR can be identified using isoelectric focusing which separates mutated forms of transthyretin. Findings can be corroborated by genetic testing to look for specific known mutations in transthyretin that predispose to amyloidosis.[6]

AA is suspected on clinical grounds in individuals with longstanding infections or inflammatory diseases. AA can be identified by immunohistochemistry staining.[6]

Historical classification systems were based on clinical factors. Until the early 1970s, the idea of a single amyloid substance predominated. Various descriptive classification systems were proposed based on the organ distribution of amyloid deposits and clinical findings. Most classification systems included primary (i.e., idiopathic) amyloidosis, in which no associated clinical condition was identified, and secondary amyloidosis (i.e., secondary to chronic inflammatory conditions). Some classification systems included myeloma-associated, familial, and localized amyloidosis.

The modern era of amyloidosis classification began in the late 1960s with the development of methods to make amyloid fibrils soluble. These methods permitted scientists to study the chemical properties of amyloids. Descriptive terms such as primary amyloidosis, secondary amyloidosis, and others (e.g., senile amyloidosis), which are not based on cause, provide little useful information and are no longer recommended.

The modern classification of amyloid disease tends to use an abbreviation of the protein that makes the majority of deposits, prefixed with the letter A. For example, amyloidosis caused by transthyretin is termed “ATTR”. Deposition patterns vary between people but are almost always composed of just one amyloidogenic protein. Deposition can be systemic (affecting many different organ systems) or organ-specific. Many amyloidoses are inherited, due to mutations in the precursor protein.

Other forms are due to different diseases causing overabundant or abnormal protein production – such as with overproduction of immunoglobulin light chains (termed AL amyloidosis), or with continuous overproduction of acute phase proteins in chronic inflammation (which can lead to AA amyloidosis).

About 60 amyloid proteins have been identified so far.[11] Of those, at least 36 have been associated with a human disease.[12]

The names of amyloids usually start with the letter “A”. Here is a brief description of the more common types of amyloid:

Abbr. Amyloid type/Gene Description OMIM
AL amyloid light chain AL amyloidosis / multiple myeloma. Contains immunoglobulin light-chains (λ,κ) derived from plasma cells. 254500
AA SAA Serum amyloid A protein (SAA) is an acute-phase reactant that is produced in times of inflammation.
β amyloid/APP Found in Alzheimer disease brain lesions. 605714
ALECT2 LECT2 In LECT2 amyloidosis, the LECT2 protein deposits in the kidneys and various other tissues but only kidneys show signs or symptoms; these are typical those of kidney failure.[13]
ATTR transthyretin Transthyretin is a protein that is mainly formed in the liver that transports thyroxine and retinol binding protein.[6] A mutant form of a normal serum protein that is deposited in the genetically determined familial amyloid polyneuropathies. TTR is also deposited in the heart in wild-type transthyretin amyloidosis, also known as senile systemic amyloidosis.[14] Also found in leptomeningeal amyloidosis. 105210
2M β2microglobulin Not to be confused with Aβ, β2m is a normal serum protein, part of major histocompatibility complex (MHC) Class 1 molecules. Haemodialysis-associated amyloidosis
AIAPP amylin Found in the pancreas of people with type 2 diabetes.
APrP prion protein In prion diseases, misfolded prion proteins deposit in tissues and resemble amyloid proteins. Some examples are Creutzfeldt–Jakob disease (humans), BSE or “mad cow disease” (cattle), and scrapie (sheep and goats). A recently described familial prion disease presents with peripheral amyloidosis causing autonomic neuropathy and diarrhea.[15] 123400
AGel GSN Finnish type amyloidosis 105120
ACys CST3 Cerebral amyloid angiopathy, Icelandic-type 105150
AApoA1 APOA1 Familial visceral amyloidosis 105200
AFib FGA Familial visceral amyloidosis 105200
ALys LYZ Familial visceral amyloidosis 105200
? OSMR Primary cutaneous amyloidosis 105250
ABri
ADan
ITM2B Cerebral amyloid angiopathy, British-type
Danish-type
176500
117300
APro prolactin Prolactinoma
AKer keratoepithelin Familial corneal amyloidosis
AANF atrial natriuretic factor Senile amyloid of atria of heart
ACal calcitonin Medullary carcinoma of the thyroid

As of 2010, 27 human and 9 animal fibril proteins were classified, along with 8 inclusion bodies.[16]

An older clinical method of classification refers to amyloidoses as systemic or localised

Another classification is primary or secondary.

Additionally, based on the tissues in which it is deposited, it is divided into mesenchymal (organs derived from mesoderm) or parenchymal (organs derived from ectoderm or endoderm).

Treatment depends on the type of amyloidosis that is present. Treatment with high dose melphalan, a chemotherapy agent, followed by stem cell transplantation has showed promise in early studies and is recommended for stage I and II AL amyloidosis.[10] However, only 20–25% of people are eligible for stem cell transplant. Chemotherapy and steroids, with melphalan plus dexamethasone, is mainstay treatment in AL people not eligible for transplant.[10]

In AA, symptoms may improve if the underlying condition is treated; eprodisate has been shown to slow renal impairment by inhibiting polymerization of amyloid fibrils.

In ATTR, liver transplant is a curative therapy[6] because mutated transthyretin which forms amyloids is produced in the liver.

People affected by amyloidosis are supported by organizations, including the Amyloidosis Foundation, Amyloidosis Support Groups, and Amyloidosis Australia.[18][19]

Prognosis varies with the type of amyloidosis. Prognosis for untreated AL amyloidosis is poor with median survival of one to two years. More specifically, AL amyloidosis can be classified as stage I, II or III based on cardiac biomarkers like troponin and BNP. Survival diminishes with increasing stage, with estimated survival of 26, 11 and 3.5 months at stages I, II and III, respectively.[10]

Outcomes in a person with AA amyloidosis depend on the underlying disease and correlate with the concentration of serum amyloid A protein.[7]

People with ATTR have better prognosis and may survive for over a decade.[6]

Senile systemic amyloidosis was determined to be the primary cause of death for 70% of people over 110 who have been autopsied.[20][21]

The three most common forms of amyloidosis are AL, AA, and ATTR amyloidoses. The median age at diagnosis is 64.[7]

In the western hemisphere, AL is the most prevalent, comprising 90% of cases.[10] In the United States it’s estimated that there are 1,275 to 3,200 new cases of AL amyloidoses a year.[6]

AA amyloidoses is the most common form in developing countries and can complicate longstanding infections with tuberculosis, osteomyleitis, and bronchiectesis. In the west, AA is more likely to occur from autoimmune inflammatory states.[6] The most common causes of AA amyloidosis in the West are rheumatoid arthritis, inflammatory bowel disease, psoriasis, and familial Mediterranean fever.

People undergoing long term hemodialysis (14–15 years) can develop amyloidosis from accumulation of light chains of the HLA 1 complex which is normally filtered out by the kidneys.[7]

Senile amyloidosis resulting from deposition of normal transthyretin, mainly in the heart, is found in 10–36% of people over 80.[7]

Treatments for ATTR-related neuropathy include TTR-specific oligonucleotides in the form of small interfering RNA (patirsiran) or antisense inotersen,[22] the former having recently received FDA approval.[23]

  1. ^ Hawkins, P (29 April 2015). “AL amyloidosis”. Wikilite.com. Archived from the original on 22 December 2015. Retrieved 19 December 2015.
  2. ^ Jump up to: a b c d e f g h i j k l m n o p Hazenberg, BP (May 2013). “Amyloidosis: a clinical overview”. Rheumatic Diseases Clinics of North America. 39 (2): 323–45. doi:10.1016/j.rdc.2013.02.012. PMID 23597967.
  3. ^ Jump up to: a b c d e f g Pepys, MB (2006). “Amyloidosis”. Annual Review of Medicine. 57: 223–41. doi:10.1146/annurev.med.57.121304.131243. PMID 16409147.
  4. ^ “AL amyloidosis”. rarediseases.info.nih.gov. Genetic and Rare Diseases Information Center (GARD). Archived from the original on 24 April 2017. Retrieved 22 April 2017.
  5. ^ Sipe, Jean D.; Benson, Merrill D.; Buxbaum, Joel N.; Ikeda, Shu-ichi; Merlini, Giampaolo; Saraiva, Maria J. M.; Westermark, Per (2014-12-01). “Nomenclature 2014: Amyloid fibril proteins and clinical classification of the amyloidosis”. Amyloid. 21 (4): 221–224. doi:10.3109/13506129.2014.964858. ISSN 1744-2818. PMID 25263598.
  6. ^ Jump up to: a b c d e f g h i j k l m n o p q r Falk, Rodney H.; Comenzo, Raymond L.; Skinner, Martha (25 September 1997). “The Systemic Amyloidoses”. New England Journal of Medicine. 337 (13): 898–909. doi:10.1056/NEJM199709253371306.
  7. ^ Jump up to: a b c d e f g h i j k l Ebert, Ellen C.; Nagar, Michael (March 2008). “Gastrointestinal Manifestations of Amyloidosis”. The American Journal of Gastroenterology. 103 (3): 776–787. doi:10.1111/j.1572-0241.2007.01669.x.
  8. ^ [1], Karp, Judith E., ed. Amyloidosis Diagnosis and Treatment. Rochester: Humana, 2010. Online Source.
  9. ^ Jump up to: a b c Dember LM (December 2006). “Amyloidosis-associated kidney disease”. Journal of the American Society of Nephrology. 17 (12): 3458–3471. doi:10.1681/ASN.2006050460. PMID 17093068. Archived from the original on 2011-12-05.
  10. ^ Jump up to: a b c d e Rosenzweig, Michael; Landau, Heather (2011). “Light chain (AL) amyloidosis: update on diagnosis and management”. Journal of Hematology & Oncology. 4 (1): 47. doi:10.1186/1756-8722-4-47.
  11. ^ Mok KH, Pettersson J, Orrenius S, Svanborg C (March 2007). “HAMLET, protein folding, and tumor cell death”. Biochemical and Biophysical Research Communications Communications. 354 (1): 1–7. doi:10.1016/j.bbrc.2006.12.167. PMID 17223074.
  12. ^ Pettersson-Kastberg J, Aits S, Gustafsson L, et al. (November 2008). “Can misfolded proteins be beneficial? The HAMLET case”. Annals of Medicine. 41 (3): 1–15. doi:10.1080/07853890802502614. PMID 18985467.
  13. ^ Slowik V, Apte U (2017). “Leukocyte Cell-Derived Chemotaxin-2: It’s Role in Pathophysiology and Future in Clinical Medicine”. Clinical and Translational Science. 10 (4): 249–259. doi:10.1111/cts.12469. PMC 5504477. PMID 28466965.
  14. ^ Hassan W, Al-Sergani H, Mourad W, Tabbaa R (2005). “Amyloid heart disease. New frontiers and insights in pathophysiology, diagnosis, and management”. Texas Heart Institute Journal. 32 (2): 178–184. PMC 1163465. PMID 16107109.
  15. ^ Mead, Simon; Gandhi, Sonia; et al. (2013). “A Novel Prion Disease Associated with Diarrhea and Autonomic Neuropathy”. New England Journal of Medicine. 369 (20): 1904–1914. doi:10.1056/NEJMoa1214747. ISSN 0028-4793. PMC 3863770.
  16. ^ Sipe JD, Benson MD, Buxbaum JN, et al. (September 2010). “Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis”. Amyloid. 17 (3–4): 101–104. doi:10.3109/13506129.2010.526812. PMID 21039326.
  17. ^ Jump up to: a b c Table 5-12 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN 1-4160-2973-7. 8th edition.
  18. ^ “Amyloidosis – NORD (National Organization for Rare Disorders)”. NORD (National Organization for Rare Disorders). Archived from the original on 2016-03-16. Retrieved 2016-03-15.
  19. ^ “Amyloidosis primary cutaneous – Disease – Organizations – Genetic and Rare Diseases Information Center (GARD) – NCATS Program”. rarediseases.info.nih.gov. Archived from the original on 2016-03-15. Retrieved 2016-03-15.
  20. ^ Coles LS, Young RD (2012). “Supercentenarians and transthyretin amyloidosis: the next frontier of human life extension”. Preventive Medicine. 54 (Suppl): s9–s11. doi:10.1016/j.ypmed.2012.03.003. PMID 22579241.
  21. ^ “Searching for the Secrets of the Super Old”. Science. 26 September 2008. pp. 1764–1765. Archived from the original on 9 March 2013. Retrieved 22 February 2013.
  22. ^ Buxbaum, Joel N. (5 July 2018). “Oligonucleotide Drugs for Transthyretin Amyloidosis”. New England Journal of Medicine. 379 (1): 82–85. doi:10.1056/nejme1805499. ISSN 0028-4793.
  23. ^ Commissioner, Office of the. “Press Announcements – FDA approves first-of-its kind targeted RNA-based therapy to treat a rare disease”. www.fda.gov. Retrieved 2018-08-11.

Classification
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Amyloid

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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. 20X

Amyloids are aggregates of proteins that become folded into a shape that allows many copies of that protein to stick together, forming fibrils. In the human body, amyloids have been linked to the development of various diseases. Pathogenic amyloids form when previously healthy proteins lose their normal physiological functions and form fibrous deposits in plaques around cells which can disrupt the healthy function of tissues and organs.

Such amyloids have been associated with (but not necessarily as the cause of) more than 50[1] human diseases, known as amyloidoses, and may play a role in some neurodegenerative disorders.[2] Some amyloid proteins are infectious; these are called prions in which the infectious form can act as a template to convert other non-infectious proteins into infectious form.[3] Amyloids may also have normal biological functions; for example, in the formation of fimbriae in some genera of bacteria, transmission of epigenetic traits in fungi, as well as pigment deposition and hormone release in humans.[4]

Amyloids have been known to arise from many different proteins and polypeptides.[5] These polypeptide chains generally form β-sheet structures that aggregate into long fibers; however, identical polypeptides can fold into multiple distinct amyloid conformations. The diversity of the conformations may have led to different forms of the prion diseases.[4]

The name amyloid comes from the early mistaken identification by Rudolf Virchow of the substance as starch (amylum in Latin, from Greek ἄμυλον amylon), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits are fatty deposits or carbohydrate deposits until it was finally found (in 1859) that they are, in fact, deposits of albumoid proteinaceous material.[6]

  • The classical, histopathological definition of amyloid is an extracellular, proteinaceous deposit exhibiting beta sheet structure. Common to most cross-beta-type structures, in general, they are 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.[7] Recently this definition has come into question as some classic, amyloid species have been observed in distinctly intracellular locations.[8]
  • A more recent, biophysical definition is broader, including any polypeptide that 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,[9][10] leading to some conflict in the biological community over an issue of language.

The remainder of this article will use the biophysical context.

Disease Protein featured Official abbreviation
Alzheimer’s disease Beta amyloid from Amyloid precursor protein[11][12][13][14] Aβ, APP
Diabetes mellitus type 2 IAPP (Amylin)[15][16] AIAPP
Parkinson’s disease Alpha-synuclein[12] none
Transmissible spongiform encephalopathy (e.g. bovine spongiform encephalopathy) PrPSc[17] APrP
Fatal familial insomnia PrPSc APrP
Huntington’s disease Huntingtin[18][19] none
Medullary carcinoma of the thyroid Calcitonin[20] ACal
Cardiac arrhythmias, isolated atrial amyloidosis Atrial natriuretic factor AANF
Atherosclerosis Apolipoprotein AI AApoA1
Rheumatoid arthritis Serum amyloid A AA
Aortic medial amyloid Medin AMed
Prolactinomas Prolactin APro
Familial amyloid polyneuropathy Transthyretin ATTR
Hereditary non-neuropathic systemic amyloidosis Lysozyme ALys
Dialysis related amyloidosis Beta-2 microglobulin Aβ2M
Finnish amyloidosis Gelsolin AGel
Lattice corneal dystrophy Keratoepithelin AKer
Cerebral amyloid angiopathy Beta amyloid[21]
Cerebral amyloid angiopathy (Icelandic type) Cystatin ACys
Systemic AL amyloidosis Immunoglobulin light chain AL[20] AL
Sporadic Inclusion body myositis S-IBM none

The International Society of Amyloidosis classifies amyloid fibrils based upon associated proteins.[22]

  • Native amyloids in organisms[23]
    • Curli 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.[24] This suggest that many more bacteria may express curli fibrils.
    • Gas vesicles, the buoyancy organelles of aquatic archaea and eubacteria[25]
    • Functional amyloids in Pseudomonas (Fap)[26][27]
    • Chaplins from Streptomyces coelicolor
    • Podospora anserina prion het-s
    • Malarial coat protein
    • Spider silk (some but not all spiders)
    • Mammalian melanosomes (PMEL)
    • Tissue-type plasminogen activator (tPA), a hemodynamic factor
    • ApCPEB protein and its homologues with a glutamine-rich domain
    • Peptide/protein hormones stored as amyloids within endocrine secretory granules[28]
    • Proteins and peptides engineered to make amyloid that display specific properties, such as ligands that target cell surface receptors[29]
    • Several yeast prions are based on an infectious amyloid, e.g. [PSI+] (Sup35p); [URE3] (Ure2p); [PIN+] (Rnq1p); [SWI1+] (Swi1p) and [OCT8+] (Cyc8p)
    • Functional amyloids are abundant in most environmental biofilms according to staining with amyloid specific dyes and antibodies[30]
    • Fungal cell adhesion proteins aggregate on the surface of the fungi to form cell surface amyloid regions with greatly increased binding strength [31][32]
    • The tubular sheaths encasing Methanosaeta thermophila filaments are the first functional amyloids to be reported from archeal domain of life [33]

“Amyloid deposits occur in the pancreas of patients with diabetes mellitus, although it is not known if this is functionally important. The major component of pancreatic amyloid is a 37-amino acid residue peptide known as islet amyloid polypeptide or amylin. This is stored with insulin in secretory granules in B cells and is co secreted with insulin” (Rang and Dale’s Pharmacology, 2015).

ATTR amyloid deposits from transthyretin occur not only in Transthyretin-related hereditary amyloidosis, but also in advanced cases of aging in many tissues, in many mammalian species. They are a common result in supercentenarian autopsies. A proposal is that they may mediate some tissue pathologies seen in advanced aging, and pose a limit to human life span.[34]

Amyloids are formed of long unbranched fibers that are characterized by a cross-beta sheet quaternary structure in which antiparallel chains of β-stranded peptides are arranged in an orientation perpendicular to the axis of the fiber. Each individual fiber may be 5–15 nanometres in width and a few micrometres in length.[4] While amyloid is usually identified using fluorescent dyes, stain polarimetry, circular dichroism, or FTIR (all indirect measurements), the “gold-standard” test to see whether a structure contains cross-β fibres is by placing a sample in an X-ray diffraction beam. 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.[35] 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.[36] 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. The cross-beta pattern is considered a diagnostic hallmark of amyloid structure.[4]

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 that now enable direct data on the internal structure of different types of amyloid fibrils. Two prominent methods include the use of 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.[37][38]

X-ray diffraction studies of microcrystals revealed atomistic details of core region of amyloid.[39][40] 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.[4] 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.

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 β-sandwich, or a β-solenoid which may be either β-helix or β-roll. One complicating factor in studies of amyloidogenic polypeptides is that identical polypeptides can fold into multiple distinct amyloid conformations.[4] This phenomenon is typically described as amyloid polymorphism. It has notable biological consequences given that it is thought to explain the prion strain phenomenon, for example.

Amyloid is formed through the polymerization of hundreds to thousands of monomeric peptides into long fibers. In general, amyloid polymerization (aggregation or non-covalent polymerization) is 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 or non-coded alpha-aminoisobutyric acid.[41] 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.[citation needed] Studies comparing synthetic to recombinant Amyloid beta 1-42 in assays measuring rate of fibrillation, fibril homogeneity, and cellular toxicity showed that recombinant Amyloid beta 1-42 has a faster fibrillation rate and greater toxicity than synthetic Amyloid beta 1-42 peptide.[42] This observation combined with the irreproducibility of certain Amyloid beta 1-42 experimental studies has been suggested to be responsible for the lack of progress in Alzheimer’s research.[43] Consequently, there have been renewed efforts to manufacture Amyloid beta 1-42 and other amyloid peptides at unprecedented (>99%) purity.[44]

There are multiple classes of amyloid-forming polypeptide sequences. 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 sequence, with analogous findings in a C. elegans model system with engineered polyglutamine peptides.[45]

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.[citation needed] Among the hydrophobic residues, aromatic amino-acids are found to have the highest amyloidogenic propensity.[46][47]

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.[citation needed] 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.[48] 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] Polypeptides will not cross-polymerize their mirror-image counterparts, indicating that the phenomenon involves specific binding and recognition events.[citation needed]

The fast aggregation process, rapid conformational changes as well as solvent effects provide challenges in measuring monomeric and oligomeric amyloid peptide structures in solution. Theoretical and computational studies complement experiments and provide insights that are otherwise difficult to obtain using conventional experimental tools. Several groups have successfully studied the disordered structures of amyloid and reported random coil structures with specific structuring of monomeric and oligomeric amyloid as well as how genetics and oxidative stress impact the flexible structures of amyloid in solution.[49]

Oligomeric intermediates of insulin during fibrillation (more toxic than other intermediates: native, protofibril, and fibril) decreased the surface tension of solution which indicated to detergent-like properties of oligomers and significant role of hydrophobic forces in cytotoxicity of oligomers.[50]

The reasons for amyloid association disease 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.[13][51]

Calcium dysregulation has been observed in cells exposed to amyloid oligomers. These small aggregates can form ion channels planar lipid bilayer membranes. Channel formation has been hypothesized to account for calcium dysregulation and mitochondrial dysfunction by allowing indiscriminate leakage of ions across cell membranes.[52]

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.[53]

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.[54]

In the clinical setting, amyloid diseases are typically identified by a change in the fluorescence intensity of planar aromatic dyes such as thioflavin T, congo red or NIAD-4.[55] In general, this is attributed to the environmental change, as these dyes intercalate between beta-strands to confine their structure.[56] 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[57] and oligomers.[58] 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; in general, an amyloid protein structure is a different conformation from the one that the antibody recognizes.

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