Part I Overview of Amyloidosis and Amyloid Proteins · SAP was shown to be identical to the AP...

Part IOverview of Amyloidosis and Amyloid Proteins

Amyloid Proteins. The Beta Sheet Conformation and Disease. J. D. SipeCopyright © 2005 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-31072-X

Es gibt fast kein Problem in der allgemeinen und speziellenPathologie, das sich über Jahrhunderte in einer so sphinxhaftenWeise verhalten hat wie die Amyloidose. [There is almostno problem in general and systemic pathology that overthe centuries has behaved in such a sphinx-like wayas amyloidosis.] Letterer (1966) [1]

1.1Early History

History is not an absolute science. It is rather a somewhat subjective interpreta-tion of available data and, when it comes to more recent history, of ones ownmemories, all set on a background of the spirit of the age. This should be re-membered when reading this short history.

1.1.1Initial Studies

The early history of amyloid and amyloidosis is fascinating, and the definitionand nature of the amyloid-related alteration was the subject of intense debateduring the 19th century. The interested reader is referred to several comprehen-sive and well-written reviews (e.g. [2–5]). This chapter addresses, primarily, therecent history of the amyloid proteins. However, it is hardly possible, or particu-larly fruitful, to distinguish between the history of amyloid proteins and that ofamyloid itself. Anyone who wants an insight into the modern history of amyloidand amyloidosis will find an invaluable source in the volumes of the proceed-ings of the 10 international symposia on amyloid and amyloidosis, starting withthat covering the First International Symposium on Amyloidosis, Groningen,The Netherlands (1967). The most recent volume covers the 10th InternationalSymposium on Amyloidosis, Tours, France (2004). In addition, the excellent vol-

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Amyloid Proteins. The Beta Sheet Conformation and Disease. J. D. SipeCopyright © 2005 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-31072-X

1Amyloidosis and Amyloid Proteins:Brief History and DefinitionsPer Westermark

ume resulting from the International Course on Amyloidosis, Groningen, TheNetherlands (1986) contains a wealth of historical information [6].

When we talk about the history of amyloidosis, we often start with a reference toRudolf Virchow (Fig. 1.1), who first used the term “amyloid” for a structural bodyin human tissues [7, 8]. “Amyloid”, however, had been coined earlier and had beenused in botany, and the disease amyloidosis, without this name, was well knownamong post-mortem tissue dissectors. It is apparent from Virchow’s papers, whichreference his own studies and those of pathologists such as von Rokitansky andMeckel, that systemic amyloidosis was well known at that time; conditions suchas “lardaceous or cholesterin disease” (Speck- oder Cholesterin-krankheit) [9]and “wax-spleen” (Wachs-milz) were mentioned [7]. Malpighi recognized “sagospleen” and other investigators the “lardaceous spleen”, referring to the distinctmacroscopic appearances of two variant patterns of amyloid deposition.

1 Amyloidosis and Amyloid Proteins: Brief History and Definitions4

Fig. 1.1 Rudolf Virchow.

Virchow used a water solution of iodine in combination with hydrated sulfu-ric acid as a stain for cellulose in the human body [10, 11]. A cellulose-like sub-stance had earlier been described in lower animals. Virchow found that corporaamylacea in ependyme and choroid plexus showed a typical cellulose reactionwith iodine, and stated in his first report that “no doubt regarding the cellulosenature is possible” [10]. Afterwards, Virchow and also Meckel [7] tested tissuescorresponding to what we today call systemic amyloidosis and found a similarreaction to iodine as had been observed with corpora amylacea. Thus, Virchowfound that the wax-like deposits and degeneration of spleen, liver and kidneys,in cases of what must have been amyloid A (AA) amyloidosis due to chronic in-fectious diseases, showed a starch-like reaction with iodine. This initiated a de-bate as to whether the iodine reaction depended on cellulose or on cholesterin.

The hypothesis of the cellulose nature of amyloid did not stand for long. Fried-reich and Kekulé dissected out amyloid-rich segments from the spleen of a pa-tient with amyloidosis, probably AA in nature [12]. In contrast to Virchow, theyperformed quite elegant direct chemical analyses of material extracted in differ-ent ways and came to the definitive conclusion that the main substance wasprotein in nature. This was confirmed by Hanssen [13], who showed that amy-loid is digestible with pepsin. Ironically, 100 years later it was found that cor-pora amylacea in reality contain little protein and are essentially polysaccharidein nature [14].

The nature of the amyloid protein or proteins was a puzzle for a long time.Furthermore, it was debated whether the amyloid substance developed locallyfrom underlying cells. It was also suggested that the protein originated fromblood and that the specific protein was precipitated in organs by abnormalamounts of sulfuric acid present locally [15]. This is not too far from today’s the-ory that circulating proteins interact, not with sulfuric acid, but with glycosami-noglycans [16, 17].

1.1.2Different Chemical Forms of Amyloid: Early Studies

Systemic amyloidosis was initially regarded as a complication of chronic infec-tious diseases such as tuberculosis, syphilis and osteomyelitis. Later, it becameclear that amyloidosis could also occur after the onset of non-infectious chronicinflammatory disorders, e.g. rheumatoid arthritis. However, quite early, singlecases of amyloidosis without any obvious predisposing disease were described[18, 19]. In one case, Wild noted that, in addition to the absence of any addi-tional disease in his patient, the distribution of amyloid was quite remarkable[19], best comparable with what is today known as AL amyloidosis. Interestingly,Soyka described cardiac amyloidosis without predisposing diseases, particularlyat a high age [18]. Certainly, these cases must have been examples of transthyre-tin-derived senile systemic amyloidosis. Remarkable variation in the clinicalmanifestation of primary amyloidosis was noted quite early [20, 21]. The first in-vestigator to identify “primary amyloidosis” as a distinctive group was Lubarsch

1.1 Early History 5

[20]. We now know that this group originally included not only AL amyloidosis,but also different familial forms of amyloidosis, derived from several proteins,and the transthyretin-derived senile systemic amyloidosis.

Although, after Virchow’s initial studies, amyloidosis was typically found to begeneralized, there are early descriptions of characteristic localized AL amyloido-sis, particularly from the conjunctiva [22]. For example, Vossius described twocases of localized, tumor-like amyloidosis of the conjunctiva [23]. Very large in-ter-individual variation is also evident in the localized forms of AL amyloidosisand this is the obvious reason for the large number of case reports of AL amy-loidosis appearing in the medical literature over the years.

One popular theory of the origin of amyloid was that amyloid represents anantigen–antibody precipitate [24], perhaps depending on an autoantigen [25]. Itwas possible to identify immunoglobulin and complement proteins in amyloiddeposits by immunohistochemistry [26]. However, in extracts of amyloid, it wasnot possible to demonstrate �-globulin (immunoglobulin) in reasonableamounts to explain the nature of amyloid [27, 28]. For a long time it was be-lieved that the composition of all amyloids is one and the same, and, in the old-er literature, other possibilities are not discussed. However, Gellerstedt, in 1938,noted that amyloid in the islets of Langerhans differed in tinctorial propertiesas compared with vascular secondary amyloid in cases where both alterationswere observed [29]. He obviously understood that the two types of deposits weredifferent, although he did not explicitly state that they must contain differentproteins. It was not until the first direct protein sequence analyses were per-formed (Section 1.2.1) that the complex chemical nature of the amyloid depositsstarted to become apparent.

1.1.3Amyloid Staining Methodology

The initial method used to identify amyloid was that of iodine staining, intro-duced by Virchow. This method was soon replaced by metachromatic stains likecrystal violet. The use of the most important histological staining marker foramyloid, Congo red, was introduced by Bennhold [30]. This direct dye for cottonhad been used in the textile industry since 1884. Congo red was observed tohave a strong affinity for amyloid deposits and there was the observation thatits clearance from plasma could be used as a diagnostic method for amyloidosis.However, the value of Congo red in histology turned out to be much higher. Animportant discovery was made by Divry and Florkin in 1927 who noticed theenhanced birefringence of amyloid deposits after staining with Congo red [31].It was suggested that this property of amyloid depends on an ordered arrange-ment of the elongated Congo red molecules in the amyloid, indicating that, infact, the substance is not amorphous, as earlier described, but has an organizedsubstructure [31–34]. A standardized Congo red staining method was introducedby Puchtler et al. [35] and is still used. Additional staining methods have beenand are still used. The most important of these is probably Thioflavin T or S.


There were once divided opinions as to which of the two stainings Congo redor Thioflavin S is more specific for amyloid, but each method now has its ownrole today in the study of amyloidosis [36].

1.2Amyloid Proteins – Modern History

The modern history of amyloidosis can be said to have started with the discov-ery by Cohen and Calkins, using electron microscopy, that amyloid, which ishyaline and structureless under the light microscopy, has a characteristic fine fi-brillar ultrastructure [37]. This finding was confirmed in several other studies[38–42] and pointed to a specific structural organization of the constituent mole-cules – a concept that at that time was completely unknown.

The amyloid was found to contain “rigid”, unbranched fibrils, around 10 nmin diameter and of undetermined length. The fibrils were usually without orien-tation, but when close to cells appeared in parallel bundles, sometimes perpen-dicular and close to cell membranes [43, 44]. This fibrillar organization wastaken by some researchers as an indication that the fibrils were made by thesecells [45], but others were hesitant about this. This situation gave rise to the fa-mous argument raised by Bywaters that on pictures of San Sebastian transfixedwith arrows “he looked a bit sick too, but nobody had suggested he was secret-ing them” [46]. Careful electron microscopic studies by Shirahama and Cohenshowed that the amyloid fibrils, irrespective of origin, were composed of eventhinner subelements, designated protofibrils [47–49].

1.2.1The Amyloid Proteins

The first amyloid component to be identified, although not based on amino acidsequence data, was a soluble protein, which could be extracted from amyloid-la-den tissues. When rabbits were immunized with extracted amyloid fibrils, anti-bodies to this protein were detected [50] that also recognized an immunoreactivecomponent in plasma. The amyloid protein in tissues was consequently desig-nated amyloid plasma component or P component (later AP). The circulatingplasma counterpart, later shown to be identical, was called “serum amyloid Pcomponent” (SAP). SAP was shown to be identical to the AP particle that hadbeen identified in tissue amyloid deposits by electron microscopy and describedas a pentagonal structure [51]. SAP has been shown to be a ubiquitous part ofall of the chemical types of amyloid deposits. The SAP protein binds non-cova-lently and calcium dependently to ligands [52] such as �-pleated sheet fibrils.SAP is a normal constituent of the glomerular basement membrane [53] andelastic microfibrils [54].

The nature of the amyloid fibril was long an enigma. Methods to concentrateamyloid fibrils and to make good, representative fibrillar extracts of systemic

1.2 Amyloid Proteins – Modern History 7

amyloid deposits were developed by Cohen et al. [48] and Pras et al. [55].Further advancement and analysis of constitutive fibril subunits was difficult,however. Benditt et al. extracted secondary amyloid materials directly from tis-sues, without prior purification of fibrils [27]. They identified a protein compo-nent that was soluble in 6 M urea and exhibited an unusual amino acid compo-sition, in that both cysteine and threonine were lacking. At the time, it was notpossible to characterize this protein further and the investigators discussedmany different possibilities, including a virus protein.

Amyloid was long believed to be a singular substance, perhaps of some un-specific degenerative origin. The relationship to other structureless deposits,particularly “hyaline”, was often discussed in the literature and a process oftransformation from hyaline to amyloid was suggested. Even when it had beenshown by electron microscopy that the light microscopically amorphous amyloidconsists of fine fibrils of a characteristic appearance, amyloid deposits wereusually regarded as one unique kind of substance. The demonstration of a con-sistent cross-�-pleated sheet structure in amyloid fibrils was an important stepin our understanding how amyloid is formed [56, 57]. The �-pleated sheet struc-tured fibril seems to be the basis of the unusual resistance of all kinds of amy-loid to degradation and, therefore, the progressive deposition of the material. Ithad been shown already that insulin could be converted into a fibrous form un-der conditions that are denaturing to the secondary structure of proteins [58]. Itwas shown that insulin fibrils [59] as well as synthetic fibrils made from othersmall proteins [60] all had the properties of amyloid fibrils, including affinityfor Congo red and green birefringence when viewed under polarizing light mi-croscopy. Glenner incorporated the characteristic X-ray diffraction pattern ofamyloid fibrils into the definition of amyloid and proposed that the term “amy-loid” be used primarily as a generic adjectival term to indicate the presence ofnon-branching, 80- to 100-Å fibrillar (linear or concentric) proteinaceous depos-its demonstrated to have either Congo red birefringence or a �-pleated sheet X-ray diffraction pattern, together with the chemical nature of the fibril (if known)and the site or tissue of origin or deposition noted [60].

The first definitive proof of a chemically specific protein constituent of amyloidfibrils came from the studies of Glenner et al. They showed that, in cases of pri-mary and myeloma-associated systemic amyloidosis, the fibril protein originatedfrom homogeneous immunoglobulin light chains [61]. Glenner et al.’s workhad an enormous immediate impact and, since, at the time, amyloid was widelybelieved to be a single substance, all of the clinical forms of amyloid were initiallyregarded to be of immunoglobulin origin. When reading the literature from theearly 1970s, it is evident that there was a very high degree of international compe-tition between four or five prominent amyloid research groups and the citationsdo not always seem to be fully correct. Later, Benditt wrote [62] that he had diffi-culties with the publication of an important paper in which he presented evidencefor the existence of multiple chemical classes of amyloid substance [63]. Benditt’sgroup showed that a unique protein, which had a characteristic amino acid com-position and a uniform electrophoretic mobility, was present in all cases of typical


“secondary” amyloidosis, but absent in cases with other kinds of amyloid. Theycalled this component protein A and the protein(s) extracted from other kindsof amyloidosis, such as what is now known as AL, protein B [63]. Protein A (laterdesignated as amyloid A or AA) was characterized by amino acid sequence in 1971(see below). Based on varying amino acid compositions and electrophoretic mobi-lities, Benditt et al. also suggested that, in fact, there would likely be several differ-ent protein B forms [63]. Subsequent developments in amyloid research haveshown that they were absolutely right.

The pioneering work of the laboratories of Benditt and Glenner showed thatthe most fruitful method for elucidation of the nature of the amyloidosesshould be recognition of putative clinically specific amyloid diseases, and isola-tion from tissues and purification of the corresponding amyloid fibril proteins,followed by their chemical identification by amino acid sequence analysis. Thisapproach was immediately initiated. A third amyloid fibril protein was soonidentified by amino acid sequence analysis and was shown to be derived fromcalcitonin (or possibly procalcitonin), occurring in the amyloid of medullary thy-roid carcinoma [64]. This observation was clear evidence of the diversity in thenature of the amyloid fibril.

1.2.2Specific Amyloid Fibril Proteins

1.2.2.1 Protein AA and its Precursor, Serum AABenditt et al.’s pioneering papers from the pre-amyloid protein sequencing eraclearly showed that the major protein associated with amyloidosis secondary toinflammatory diseases has specific properties, including a constant electrophoret-ic mobility and unusual amino acid composition [27, 63, 65, 66]. Most remark-able was the lack of threonine. The definitive proof of a unique nature camewith the purification of the major protein and the demonstration of a unique N-terminal amino acid sequence of the protein designated protein A [67]. Thiswas soon verified by several other groups [68–70]. The full amino acid sequenceof amyloid protein A from several patients was soon published, indicating a 76-amino-acid protein [70, 71]. However, it has subsequently become clear that pro-tein A of different lengths, but with the same N-terminus, exists [68, 72–74].

The nomenclature for this unique protein varied in publications from differ-ent groups. Since a Staphylococcus protein already was called “protein A”, alter-native names were proposed, such as protein AS [69], ASF [70] or AUO [68].This confusion was ultimately resolved at the Second International Symposiumon Amyloidosis, Helsinki (1975), where the foundation of a modern amyloid no-menclature based on biochemistry was created [75]. At this time, protein A be-came protein AA.

Protein AA was soon found to have a circulating counterpart in plasma [76,77] now called serum AA (SAA). SAA, today known to be a protein family withseveral members of which two are circulating acute-phase reactants, was thusdiscovered through the ability of structurally related protein(s) to aggregate into


amyloid fibrils. In plasma fractionated by gel filtration under physiological con-ditions, SAA appeared as a large protein, around 180–200 kDa [78], but a low-molecular-weight component, around 12 kDa, could be isolated by gel filtrationunder denaturing conditions [79, 80]. The explanation for this difference in pro-tein mass came when it was found that SAA is an apolipoprotein, mainly asso-ciated with high-density lipoprotein, in humans [81], mice [82] and rabbits [83].The blood plasma protein SAA was shown to be about 40% larger than the 76-amino-acid residue AA protein that was first described. This larger size appar-ently depended on a C-terminal extension in the SAA molecule [84]. Subse-quently, it was established that human SAA is a 104-amino-acid molecule ofwhich amyloid protein A corresponds to the major N-terminal part [85]. Theacute-phase SAA is produced by the liver, but extrahepatic expression of SAAwas demonstrated. Thus, it was not immediately accepted that the circulatingSAA is the precursor of the amyloid protein. Eventually, however, direct animalexperimental work showed unequivocally that circulating SAA is converted intoamyloid fibrils [86, 87].

A systemic form of amyloidosis, resembling human secondary amyloidosis,had long been known to occur in many different mammals (for reviews, see[88, 89]), the most well known being that seen in mice. Secondary amyloidosiswas also a common outcome in horses which had been immunized for antiser-um production. At an early date, it was found to be possible to induce second-ary amyloidosis in laboratory animals, including rabbits, hens [90] and mice [91,92]. Protein AA was shown to be the major amyloid fibril component also inthese species ([93]; for review, see [89]). Most important for future experimentalstudies was the finding that the experimentally inducible amyloid in mice is as-sociated with protein AA [94]. As with human, a plasma component, antigeni-cally identical to the tissue-derived protein AA, could be extracted in several ani-mal species after induction of inflammation [95]. Also, as in humans, the plas-ma component appeared in a high-molecular-weight form in its native state, butcould be extracted as a 12-kDa protein after denaturation [96]. Sipe et al. [96]seem to be the first to name SAA as an acute-phase protein. Today we knowSAA as one of the most sensitive acute-phase reactants.

1.2.2.2 Immunoglobulin-derived Amyloid (AL and AH)Cases with simultaneous occurrence of multiple myeloma and amyloidosis weredescribed at an early date. The chemical nature of this amyloid was the subjectof many studies and immunoglobulin was a natural candidate. Many attemptsto extract significant amounts of immunoglobulin from the corresponding amy-loidotic tissues were unsuccessful. Added to the difficulties was the still wide-spread belief that, chemically, amyloid was either one specific substance or anon-specific degeneration product. To make the situation even more confusing,the amyloid associated with myelomatosis was sometimes called “secondary”.

One of the most important advances in amyloid history was the purificationof the fibrillar protein from tissues of a patient with primary amyloidosis and


the subsequent demonstration by Edman degradation that the N-terminal ami-no acid sequence corresponded to a monoclonal immunoglobulin light chain[97]. Several N-terminal sequences obtained from other individuals with thesame technique confirmed the initial report [61, 98]. The findings fitted nicelywith the demonstration that immunoglobulin light chains contain two sets of �-sheets, of which one comprises most of the variable region [99]. Some princi-ples rapidly became clear. The amyloid in primary and myeloma-associated amy-loidosis is biochemically identical, and consists of an N-terminal fragment of amonoclonal immunoglobulin chain. The fragment varies in length and, in rareoccasions, whole light chains constitute the major fibril protein. A novel immu-noglobulin light chain subtype was discovered by its unusual preponderance toform amyloid fibrils [100–102]. Later, it was shown that, in rare instances,monoclonal immunoglobulin heavy chains may make up amyloid [103, 104]and that also the constant region of light chains is amyloidogenic [105–107].

1.2.2.3 TransthyretinFamilial amyloidosis with varying clinical manifestations was described frommany parts of the world long before biochemical characterization of amyloidwas possible [108]. The first description of a familial amyloidosis was probablythat of Ostertag [109]. Many familial amyloid forms from Portugal, Japan, Swe-den, the USA and other countries had a progressive polyneuropathy as a majorindication. In 1978, Costa et al. [110] showed that the fibrils in the Portuguesetype were associated with prealbumin, which was the earlier name for transthyr-etin. The name prealbumin refers to the electrophoretic mobility of the protein.The primary structure of human transthyretin had been determined in 1974[111] and its crystal structure was published in 1978 [112]. Transthyretin wasfound to have a high degree of �-structure. Soon, many reports verified thetransthyretin nature of the amyloid fibril in many, but not all, of the hereditaryamyloid forms [113–115]. Further analyses showed that in all of the cases ofATTR there was a mutation creating an amino acid substitution. The most com-mon was found to be V30M [116–120]. A continuous stream of publications onnew transthyretin variants, amyloidogenic or even protective against amyloido-sis, has appeared until the present [121]. It has become increasingly clear thatfamilial transthyretin amyloidosis is spread all over the world.

In addition to the different familial forms, including the common V122I mu-tation [120, 122], transthyretin was found to be the fibril protein identified in se-nile systemic amyloidosis [123]. Senile systemic amyloidosis is probably themost common of all the systemic amyloidoses and is of great theoretical inter-est since it is so obviously connected to aging. In contrast to the familial forms,transthyretin in this senile systemic amyloid form is of the wild-type [124].


1.2.2.4 Other Biochemical Forms of Familial AmyloidosisThe identification throughout the world of more families with amyloid syn-dromes and the development of more efficient, sensitive methods in proteinanalyses, combined with molecular biologic methods, led to the identificationnot only of new transthyretin variants associated with amyloidosis, but also newand unexpected amyloid proteins. The strategy was generally the same: identifi-cation of the family, purification of the major amyloid fibril protein and aminoacid sequence analysis followed by sequencing of the specific gene. In this wayit has become relatively easy to rapidly determine the specific genetic cause ofmany familial amyloidoses. These include amyloidosis derived from cystatin C[125, 126], apolipoprotein A-I [127], apolipoprotein A-II [128], fibrinogen [129],gelsolin [130, 131], lysozyme [132], ABri [133] and ADan [134].

1.2.2.5 �2-Microglobulin (�2M)�2M shares strong structural similarities with immunoglobulin light and heavychain constant regions [135], and is part of the HLA class I complex. The pro-tein has a high degree of �-sheet conformation and is a small molecule, thus fit-ting well as an amyloid fibril protein precursor. Indeed, in 1985, Gejyo et al.[136] and directly afterwards Gorevic et al. [137] showed that �2M is the fibrilprotein in amyloidosis occurring as a complication to long-term hemodialysis, adisease that was described almost simultaneously [138–140]. Both full-length�2M and fragments thereof were found in the amyloid deposits [141]. The amy-loid disease had a peculiar systemic distribution, with destructive arthropathy asa major manifestation. An important cause of the disease is increased plasmaconcentration of �2M in individuals on dialysis. Fortunately, this is an amyloidthat is disappearing due to better treatment of kidney failure.

1.2.2.6 Specific Amyloid Forms in the Central Nervous System

Alzheimer and Amyloid The plaques in the cerebral cortex, described by Alzhei-mer [142], and the cerebral amyloid angiopathy, associated with Alzheimer’s dis-ease and aging [143], were entities known for long time, but not initially the sub-ject of any intense interest. Amyloid was rarely, if ever, mentioned as important inthe pathogenesis of the disease. The turning point came with the biochemicalcharacterization of the amyloid fibril protein, initially from the vascular amyloid[144, 145]. Purification of cerebral plaque amyloid was more difficult, but, by ap-plication of wool technology with solubilization in formic acid, Masters et al. [146]succeeded in characterizing the fibril protein, which turned out to be the same asGlenner had found in angiopathy. Glenner called the protein A�, while the nameused by Masters was A4. After some confusion, the name of the protein has be-come A�. A� was found to be an internal fragment of a much larger protein,the A� protein precursor (A�PP). The further development of the field has putA� protein at the center of the pathogenesis of Alzheimer’s disease [147, 148].


Spongiform Encephalopathies Amyloid itself is probably more of an epipheno-menon in the different spongiform encephalopathies (kuru, Creutzfeldt-Jakobdisease, Gerstmann-Sträussler-Scheinker disease), but is characteristic of sometypes [149]. The history of the causative agent in these and in related animaldiseases is very fascinating, and contains some of the most beautiful achieve-ments in medicine. It started with Gajdusek’s field studies in New Guineawhere the disease kuru was identified in a small isolated Papuan population[150]. Gajdusek found evidence that the disease was transmitted by ritualisticcannibalism and he was also able to transmit the disease from human to chim-panzees [151], thereby proving its contagious properties. Later, Prusiner foundthat the transmissible agent, prion, is not a virus but a protein [152]. The prionprotein aggregates and forms amyloid-like fibrils in vitro, and is the major com-ponent of spongiform plaques amyloid [153].

1.2.2.7 Polypeptide Hormone-derived (“Endocrine”) AmyloidIt has been known for a long time that amyloid may be deposited in some hor-mone-producing tissues. The first described example was amyloid in the isletsof Langerhans, although this was initially called hyaline [154, 155] and the amy-loid nature was accepted much later [29, 156]. Later, amyloid was described inother endocrine tissues and in polypeptide hormone-producing tumors, such asmedullary carcinoma of the thyroid. This “endocrine” amyloid was suggested byPearse et al. [157] to be derived from non-functional parts of pro-hormones. Athird class of amyloid fibril proteins was therefore suggested [157, 158]. Pearseet al. based this assumption on histochemical and microspectrofluorometricstudies of amyloid in an insulinoma and in three medullary carcinomas, whichindicated lack of both tyrosine and tryptophan. At that time the structure ofpro-insulin had been determined [159] and the C-peptide shown to lack aro-matic amino acid residues [160], but the more complicated precursor of calcito-nin was unknown. However, further studies on amyloid from a medullary carci-noma clearly showed the presence of tyrosine [161] and amino acid sequenceanalysis of the amyloid protein from the same case showed identity with calcito-nin [64]. A larger size of the fibril protein and an amino acid composition diverg-ing from that of calcitonin was interpreted as a sign of the presence of pro-calci-tonin in the amyloid, but no further amino acid sequence was obtained.

1.2.2.8 Islet Amyloid PolypeptideThe initial studies with medullary carcinoma showed that polypeptide hor-mones may give rise to amyloid fibrils in vivo. A close contact occurred betweenbundles of amyloid fibrils and � cells, resembling that seen between suspectedfibril-forming cells and amyloid in experimental AA amyloidosis [162], andtherefore islet amyloid was believed to be derived from proinsulin. The strongassociation between localized amyloid in the islets of Langerhans and Type 2diabetes [156, 163, 164] made analysis of this kind of amyloid highly warranted.


It took a long time and hard work to purify the amyloid protein, and this wasfirst done from an insulin-producing tumor [165]. Surprisingly, the major amy-loid fibril protein was a previously unknown polypeptide with partial identitywith calcitonin gene-related peptide (CGRP), initially called islet amyloid pep-tide and later islet amyloid polypeptide (IAPP). Further analyses showed thatIAPP consists of 37 amino acid residues, and that it is the major protein also inamyloid of human and feline islets of Langerhans [166, 167]. The findings wereverified by another group, which called the protein “diabetes-associated peptide”[168]. A later name has been “amylin”. IAPP was found to be a normal productof islet � cells, and is stored and released together with insulin [169, 170]. Sev-eral structural features of IAPP indicated a hormonal nature including C-termi-nal amidation [171, 172] and it is now accepted as a �-cell hormone, the firstdiscovered since insulin [173]. The identification of IAPP started a new branchin diabetes mellitus research. The interested can go to several reviews [174–176]and to Chapter 28 in this book. IAPP, together with A�, became popular modelmolecules for amyloid fibril formation.

1.3Classification of Amyloid Diseases

Until affinity for Congo red and green birefringence after this staining, com-bined with a characteristic fine fibrillar ultrastructure, were generally acceptedto be diagnostic for amyloidosis, there was a discussion about what should beincluded in the group of amyloidoses. The designation “amyloid” was usuallyreserved for systemic amyloidosis and for tumoral localized amyloid (todayknown to be of immunoglobulin origin). For many years there was a discussionof the nature of hyaline and its relationship to amyloid. It was even suggestedthat hyaline (which we know today is usually composed of collagen) could be-come transformed into amyloid. Scattered, small hyaline alterations were shownto occur in certain organs and some, but not all, of them are today included inthe amyloid group. A good example is the amyloid of the islets of Langerhans,initially described as hyalinization [154]. The similarity of the histological ap-pearance of the islet alteration and deposits in systemic amyloidosis was real-ized early, and the designation “para-amyloidosis” was coined for these altera-tions [29]. The following are the previously most commonly used categorizationsof amyloid deposits.

1.3.1Reimann’s Classification

An early classification, that is partly used even today, is that of Reimann et al.[177] who divided the amyloid types into four categories:(1) Primary amyloidosis(2) Secondary amyloidosis


(3) Tumor-forming amyloidosis(4) Amyloidosis associated with multiple myeloma.

1.3.2King’s Classification

Another classification, which is less commonly referred to, is that of King [178],who divided the amyloidoses into two groups, one with “typical amyloidosis”,i.e. with an organ distribution seen in what we today know as AA amyloidosis,and “atypical amyloidosis”, which is a group including all other cases. The des-ignation “atypical amyloidosis”, discriminating an amyloid from the depositionpattern of systemic amyloidosis in conjunction with a chronic inflammatory dis-ease, was already used earlier (e.g. [25]) and is still seen occasionally. With mod-ern knowledge, these designations should be avoided.

1.3.3Classification of Missmahl et al.

A third classification is that of Missmahl et al. This was also suggested beforethe biochemical era of amyloidosis and was based on polarization findings withCongo red. These researchers noted that amyloid infiltration occurs either in as-sociation with collagen fibrils or with reticulin fibrils and based a differentiationof types on this difference [179, 180]. The classification into the pericollagenform, now known to include AL amyloidosis, and the perireticulin form, partic-ularly including AA amyloidosis, did not survive for long.

1.3.4Modern Classification

The nomenclature based on the chemical nature of amyloid proteins should inprinciple replace all earlier systems. However, the original classification with pri-mary, secondary and familial systemic amyloidoses and localized amyloidosis issurprisingly difficult to eradicate. Unfortunately, this classification, although sim-ple, often leads to confusion and misunderstanding. An example is the use of “sec-ondary” amyloidosis for amyloid associated with multiple myeloma, which is che-mically identical with that in primary amyloidosis, i.e. AL amyloidosis. It can alsobe noted that none of the older classifications include familial amyloidosis as oneseparate group. We know today that the group of familial amyloidosis is a highlyheterogeneous one, containing many biochemically different amyloids.

1.3.4.1 The Present Classification of Amyloid Fibril ProteinsThe modern classification had its beginnings at the Second International Sym-posium on Amyloidosis, Helsinki (1974) [75]. Here, it was decided that the des-ignation of all amyloid forms should be based on their chemical composition.

1.3 Classification of Amyloid Diseases 15


Table 1.1 Amyloid fibril proteins and their precursors in human (from [182], slightly modified)

Amyloid Precursor protein Systemic (S)or localized (L)

Syndrome orinvolved tissues

Reference

AL immunoglobulinlight chain

S, L primarymyeloma associated

61

AH immunoglobulinheavy chain

S, L primarymyeloma associated

103

ATTR transthyretin S familialsenile systemic

110

L? tenosynoviumA�2M �2-microglobulin S hemodialysis 136

L? jointsAA (apo)serum AA S secondary, reactive 67AApoAI apolipoprotein AI S familial 127

L aorticAApoAII apolipoprotein AII S familial 128AGel gelsolin S familial 130ALys lysozyme S familial 132AFib fibrinogen � chain S familial 129ACys cystatin C S familial 126ABria ABriPP S familial dementia,

British133

L?AApoAIVc) apolipoprotein AIV S senile 184A� A� protein precursor

(A�PP)L Alzheimer’s disease,

aging144

APrP prion protein L spongioform enceph-alopathies

152

ACal (pro)calcitonin L C-cell thyroid tu-mors

64

AIAPP islet amyloid poly-peptide

L islets of Langerhansinsulinomas

165

AANF atrial natriuretic factor L cardiac atria 185APro prolactin L aging pituitary

prolactinomas186

AIns insulin L iatrogenic 187AMed lactadherin L senile aortic, media 188AKer kerato-epithelin L cornea; familial 189ALac lactoferrin L cornea; familial 190A(tbn) b, c) tbn L Pindborg tumors 191

a) ADan comes from the same gene as ABri and has an identical N-terminal sequence. ADan istherefore not included in the nomenclature as a separate protein.

b) To be named.c) Proteins that are preliminary.

The principle was created that all amyloid fibril proteins should be named “pro-tein A” with a suffix identifying the specific protein molecule. The amyloid typeand disease should then be named from the protein. Thus the term AA amyloi-dosis should replace secondary amyloidosis, and AL amyloidosis should replacethe previously used names primary and myeloma-associated amyloid. At thetime of the foundation of this classification, only the two chemical types of amy-loidosis, AA and AL, were known with certainty, although it was suspected thatthe composition of amyloid would not be as uniform as earlier often believed.However, probably no one had then imagined the enormous heterogeneity ofthe human amyloid substances that later has been found to be the case.

The first real amyloid Nomenclature Committee was founded at the Third In-ternational Symposium on Amyloidosis, Povoa de Varzim, Portugal (1979).When this meeting was held, two more amyloid fibril proteins had been de-scribed, transthyretin and (pro)calcitonin, and it was now more definitely under-stood that there were more to be discovered. In addition to protein AA and AL,preliminary terms were decided for familial amyloid proteins (AF), amyloid inendocrine tissues (AE) and amyloid associated with aging (AS; S for senile)[181]. These designations have been dropped since many of the amyloid fibrilproteins are now known. An amyloid Nomenclature Committee has been work-ing since the meeting in Povoa de Varzim and is now formally elected by theBoard of the newly formed International Society of Amyloidosis. To be acceptedas an amyloid fibril protein, the protein must be definitely shown to be the ma-jor component of a distinctive amyloid deposit and the nature of the proteinidentified by amino acid sequence. The data should also have been published ina major scientific journal. Table 1.1 lists the amyloid fibril proteins so far identi-fied [182].

1.4What is Amyloid?

We now return to the starting point: how to define amyloid? Amyloid was origi-nally described as an in vivo phenomenon and amyloidosis as a disease charac-terized by deposition of this material. With increasing knowledge of the natureof amyloid, new problems have arisen. It is possible to make Congophilic �-pleated sheet fibrils from synthetic peptides corresponding to known amyloidproteins or segments thereof. Are these fibrils amyloid? It is even possible tomake similar fibrils from normally occurring peptides never found in amyloidor from completely laboratory-designed peptides. With increasing frequency, allof these kinds of fibrils are called amyloid in the scientific literature. It shouldbe remembered that the amyloid, deposited in tissues, does not only containthe fibrils made from a single, pure protein species, but also additional proteinssuch as SAP, and glycosaminoglycans and proteoglycans. How these compo-nents are associated with the fibrils and what importance they may have inamyloidogenesis and in the persistence of the amyloid are questions that are in-

1.4 What is Amyloid? 17

sufficiently answered. The Nomenclature Committee of the International So-ciety of Amyloidosis has discussed this problem and suggests that the designa-tion “amyloid” should only be used for the abnormal, in vivo deposited material.Also, by definition, amyloid is mainly extracellular, which means that cellularinclusions, e.g. in Parkinson’s disease, are not amyloid. In vitro produced fibrilsshould be called “amyloid-like” [182] (or amylog as suggested by Buxbaum[183]).

Acknowledgments

Supported by the Swedish Research Council.


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Part I Overview of Amyloidosis and Amyloid Proteins · SAP was shown to be identical to the AP...

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