Review: History of the Amyloid Fibril - Biochemistry and Molecular ...

Journal of Structural Biology 130, 88–98 (2000) 

doi:10.1006/jsbi.2000.4221, available online at http://www.idealibrary.com on 

Review: History of the Amyloid Fibril 

Jean D. Sipe* ,1 and Alan S. Cohen 

*Center for Scientific Review, National Institutes of Health, Bethesda, Maryland 20892; and †Amyloid Program, 

Boston University School of Medicine, Boston, Massachusetts 02118 

Rudolph Virchow, in 1854, introduced and popularized 

the term amyloid to denote a macroscopic 

tissue abnormality that exhibited a positive iodine 

staining reaction. Subsequent light microscopic 

studies with polarizing optics demonstrated the inherent 

birefringence of amyloid deposits, a property 

that increased intensely after staining with 

Congo red dye. In 1959, electron microscopic examination 

of ultrathin sections of amyloidotic tissues 

revealed the presence of fibrils, indeterminate in 

length and, invariably, 80 to 100 Å in width. Using 

the criteria of Congophilia and fibrillar morphology, 

20 or more biochemically distinct forms of amyloid 

have been identified throughout the animal 

kingdom; each is specifically associated with a 

unique clinical syndrome. Fibrils, also 80 to 100 Å in 

width, have been isolated from tissue homogenates 

using differential sedimentation or solubility. X-ray 

diffraction analysis revealed the fibrils to be ordered 

in the beta pleated sheet conformation, with 

the direction of the polypeptide backbone perpendicular 

to the fibril axis (cross beta structure). Because 

of the similar dimensions and tinctorial properties 

of the fibrils extracted from amyloid-laden 

tissues and amyloid fibrils in tissue sections, they 

have been assumed to be identical. However, the 

spatial relationship of proteoglycans and amyloid P 

component (AP), common to all forms of amyloid, to 

the putative protein only fibrils in tissues, has been 

unclear. Recently, it has been suggested that, in 

situ, amyloid fibrils are composed of proteoglycans 

and AP as well as amyloid proteins and thus resemble 

connective tissue microfibrils. Chemical and 

physical definition of the fibrils in tissues will be 

needed to relate the in vitro properties of amyloid 

The opinions contained herein do not necessarily represent 

those of the Department of Health and Human Services or the 

National Institutes of Health. 

1 To whom correspondence should be addressed at Center for 

Scientific Review, National Institutes of Health, 6701 Rockledge 

Drive, Room 4106, MSC 7814, Bethesda, MD 20892. Fax: 301- 

480-2644. E-mail: sipej@csr.nih.gov. 

1047-8477/00 $35.00 

Copyright © 2000 by Academic Press 

All rights of reproduction in any form reserved. 

Received December 6, 1999, and in revised form January 19, 2000 

88 

protein fibrils to the pathogenesis of amyloid fibril 

formation in vivo. © 2000 Academic Press 

Key Words: amyloid fibril; amyloid protein; amyloidosis; 

electron microscopy; history 

ORIGIN OF THE TERM AMYLOID 

The term amyloid was introduced in 1854 by the 

German physician scientist Rudolph Virchow (reviewed 

by Cohen, 1986). Utilizing the best scientific 

methodology and medical knowledge of the time, 

Virchow used iodine to stain cerebral corpora amylacea 

that had an abnormal macroscopic appearance. 

The macroscopic appearance of the brain tissue 

was similar to previous descriptions of other 

tissues, perhaps as early as 1639, as lardaceous 

liver, waxy liver, and spongy and “white stone” containing 

spleens (Fig. 1). When Virchow discovered 

that the corpora amylacea stained pale blue on 

treatment with iodine, and violet upon the subsequent 

addition of sulfuric acid, he concluded that the 

substance underlying the evident macroscopic abnormality 

was cellulose and gave it the name amyloid, 

derived from the Latin amylum and the Greek 

amylon (reviewed by Cohen, 1986). At the time, the 

distinction between starch and cellulose, as related 

to the separation of the plant and animal kingdoms, 

was unclear. From subsequent literature (reviewed 

by Cohen, 1986), Virchow evidently considered the 

amyloid substance to be starch, although there was 

confusion as to whether amyloid denotes cellulose or 

starch. When, in 1859, Friedreich and Kekule (reviewed 

by Cohen, 1986) demonstrated both the presence 

of protein in a “mass” of amyloid and the apparent 

absence of carbohydrate based on the high 

nitrogen content, attention was shifted to the study 

of amyloid first as a protein and later as a class of 

proteins, with a propensity to undergo changes in 

conformation that result in fibril formation. 

During the 19th and early 20th centuries, investigations 

on the nature of amyloid evolved from the 

macroscopic observations of Virchow and contempo-

REVIEW: HISTORY OF THE AMYLOID FIBRIL 

FIG. 1. Amyloid deposits at low magnification; (a) attributed to Frerichs, 1862; (b) polarization microscopy of Congo red-stained nerve 

biopsy from patient with ATTR, V30M; original magnification, 6.3; (c) polarization microscopy of Congo red-stained heart tissue, original 

magnification, 16. 

89

90 REVIEW: SIPE AND COHEN 

raries (Fig. 1) to classifications of clinical symptoms 

(Table I). The term amyloid has been used to describe 

specific macroscopic abnormalities on autopsy 

of body organs and tissues of patients afflicted with 

a variety of clinical syndromes that were first classified 

as idiopathic (primary) or myeloma-associated, 

acquired (secondary), local, hereditary, endocrine 

associated, and amyloid associated with aging 

(Table I). While introducing the term amyloid is not 

one of Virchow’s widely known achievements, this 

distinguished scientist and advocate for public 

TABLE I 

Clinical Classification of Amyloidosis 

Systemic amyloidosis 

Primary or myeloma associated amyloidosis 

Secondary or reactive amyloidosis 

Heredofamilial amyloidosis 

Localized (organ-limited) amyloidosis 

Endocrine organ or tissue 

“Senile” plaques, brain 

Cardiovascular limited (“senile” cardiac) 

Lichen amyloidosis (skin) 

FIG. 1—Continued 

health’s use of a unifying nomenclature has led to a 

fascinating field of biomedical research. 

MICROSCOPIC STUDIES OF AMYLOID STRUCTURE 

Our understanding of amyloid structure has advanced 

with the available technology. Thus, investigators 

began to utilize, as they became available, 

light microscopy and histopathologic dyes such as 

thioflavin and Congo red. Initially, they concluded 

that amyloid of a variety of sources was structurally 

amorphous. However, subsequent polarization light 

microscopic studies (Divry and Florkin, 1927) demonstrated 

that unstained and Congo red-stained accumulations 

of amyloid in a variety of tissues exhibited 

positive birefringence with respect to the long 

axis of the deposits. Thus, Congo red staining imparts 

a marked anisotropy to the inherent birefringence 

exhibited by amyloid fibrils in situ (Missmahl 

and Hartwig, 1953). Congophilia with apple green 

birefringence was the first criterion of amyloid to be 

adopted (Fig. 2). 

The possibility of an ordered submicroscopic 

structure, as indicated by the birefringence associated 

with amyloid deposits, led Cohen and col-


FIG. 2. (a) Congo red-stained amyloidotic uterus. (b) Birefringence of section A showing the vascular amyloid and amyloid in the 

muscle wall. 

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FIG. 3. An electron micrograph of amyloid fibrils in section of human amyloidotic spleen (after Shirahama and Cohen, 1967). The 

fibrils are arranged in random array and are nonbranching. The measurements of the width of individual fibrils show moderate variation, 

with the 100-Å width most common (dark arrows), but 200–300 width also observable (open arrows). The section was stained with uranyl 

acetate and lead citrate and photographed 100 000 original magnification. Reproduced from The Journal of Cell Biology, 1967, Vol. 33, 

pp. 679–708, by copyright permission of The Rockefeller University Press. 

leagues to undertake electron microscopic studies of 

human primary and secondary amyloid tissues as 

well as experimental amyloid (Cohen and Calkins, 

1959). Their first study clearly demonstrated that 

all forms of amyloid studied exhibit a comparable 

fibrillar ultrastructure in fixed tissue sections. In 

their initial study, Cohen and Calkins analyzed sections 

of amyloidotic tissues from rabbit with caseininduced 

amyloidosis (now known to be amyloid A 

(AA)); skin biopsy from a patient with clinically defined 

primary amyloidosis (now known to be AL 

amyloid); and kidney of a patient with amyloidosis of 

parenchymal organs, i.e., spleen liver and kidney 

(now known to be AA amyloid). It has been amply 

confirmed (reviewed by Cohen et al., 1982) that amyloid 

deposits of diverse origins in humans and animals 

exhibit a similar, fibrillar submicroscopic 

structure: bundles of straight, rigid fibrils ranging in 

width from 60 to 130 Å (average 75 to 100 Å) and in 

length from 1000 to 16,000 Å (Fig. 3). The fibrillar 

morphology, upon analysis of negatively stained tissue 

sections by electron microscopy, was adopted as 

the second criterion by which amyloid is defined. 

In their original paper, Cohen and Calkins 

suggested that human and animal amyloid possess 

a beaded structure. Gueft and Ghidoni (1963) 

suggested that amyloid fibrils are double, with 

an intrafibrillar space (25 Å) approximately equal 

FIG. 4. (a) Amyloid fibrils from human amyloidotic spleen isolated by homogenization in physiological saline followed by sucrose gradient 

centrifugation. Shadowed with platinum–palladium, original magnification 70 000. (b) Sucrose gradient fraction negatively stained with 

uranyl acetate. The amyloid fibrils usually consist of two filaments aggregated side by side. The fibrils twist occasionally (arrow). The 

terminations of the fibrils are smooth and rounded (circle). Original magnification 200 000. (c) Amyloid fibril fraction prior to sucrose gradient 

centrifugation, negatively stained with phosphotungstic acid after 5 min sonication. Both amyloid fibrils (F) and amyloid P component attached 

to fibrils as stacks of pentamers (R) or as individual pentamers (P) are visible (after Shirahama and Cohen, 1967). Reproduced from The Journal 

of Cell Biology, 1967, Vol. 33, pp. 679–708, by copyright permission of The Rockefeller University Press.


93


to the diameter of each component (25 Å). Terry 

and colleagues (Terry et al., 1964), studying human 

cerebral amyloid in the senile plaque of 

Alzheimer’s disease, reported that the fibrils 

were 70–90 Å in width and had a triple density, 

indicating a hollow center. Shirahama and 

Cohen (1967) carried out extensive high-resolution 

studies of the amyloid fibril in tissues, and 

from these and other studies reviewed by Cohen et 

al. (1982), a consensus amyloid fibril structure 

was described, in which two ultrastructural features 

comprised the subunit structure of the amyloid 

fibril in vivo. A filamentous subunit structure, 

25–35 Å in diameter, longitudinally constitutes 

the 75- to 100-Å-wide amyloid fibril. Two or more 

such subunit filaments, which cross each other 

occasionally, constitute the amyloid fibril in situ 

(Fig. 3). 

IN VITRO STUDIES OF AMYLOID FIBRIL PROTEINS 

The identification of a fibril associated with the 

tinctorial properties of amyloid provided a basis 

upon which amyloid fibrils could be isolated from 

tissues. Initial isolation methods, based on a gentle 

physical separation, homogenization in saline, followed 

by low-speed centrifugation, yielded a layer of 

FIG. 4—Continued 

fibrils that was not present in sedimentation pellets 

of normal tissues (Cohen and Calkins, 1964). When 

stained with Congo red, the fibril layer demonstrated 

green birefringence with polarizing optics. 

Shadow casting or negative staining defined the diameter 

of the isolated amyloid fibril as 75–100 Å. 

Filamentous subunits of 25–35 Å are arranged along 

the long axis of the fibril in a slow twist. Amyloid 

fibrils isolated from tissues and organs by physical 

separation, using sucrose gradient centrifugation 

(Shirahama and Cohen, 1967), showed no remarkable 

differences in morphology from those tissues 

using the two criteria of Congophilia/green birefringence 

and fibrillar structure (Fig. 4). The similarities 

in dimensions and morphology between isolated 

protein fibrils and amyloid fibrils in tissues has led 

to the widely held view that the proteinaceous fibrils 

studied in vitro over the past 20 years are biochemically 

and structurally identical to the amyloid 

fibrils observed in tissues. 

However, this view has not taken into account the 

widespread immunohistochemical observation that 

other components of amyloid deposits in tissues do 

not form fibrils in vitro, but are invariably associated 

with all clinical/biochemical types of amyloid. 

These nonfibrillar components of amyloid include

TABLE II 

Proteins Associated with Amyloid Deposits in Humans 

Pathophysiology 

Fibril precursor 

(kDa) 

Immunity/ 

inflammation 

AL Immunoglobulin 

light chain (23) 

AH Immunoglobulin 

heavy chain (?) 

AA Serum amyloid A 

(12) 

Fibril protein 

(kDa) 

Variable region or 

fragment (5–23) 

(?) 

Amyloid A (5–10) 

A 2M 2-Microglobulin (12) 2-Microglobulin 

(12) 

ACys Cystatin C (13) Cystatin C 

fragment (12) 

ALys Lysozyme (14) Lysozyme (14) 

AFibA Fibrinogen (66) Fibrinogen 

fragment (11-P3) 

Endocrine 

hormones 

AIAPP Islet amyloid 

polypeptide (9) 

AANF Atrial natriuretic 

factor 

Islet amyloid 

polypeptide 

fragment (4) 

Atrial natriuretic 

factor fragment 

(4) 

ACal Procalcitonin Calcitonin 


APro Prolactin (?) 

AIns 

Transport 

molecules 

Insulin (porcine, 

iatrogenic (6) 

Insulin (6) 

ATTR Transthyretin (14) Transthyretin, 

intact/fragment 

(5–14) 

AApoAI Apolipoprotein AI Apolipoprotein AI 

(28) 


ALac 

Nervous system 

Lactoferrin (?) 

A A protein precursor 

(110–135) 

A (4–5) 

APrP Prion protein Prion protein 

Cell motility 

(30–35) 


AGel Gelsolin (80–90) Gelsolin fragment 

(9–11) 

serum amyloid P component; heparan sulfate proteoglycans; 

and apolipoprotein E, which is associated 

with a number of types of amyloid, including 

the A deposits of Alzheimer’s disease. 

Although the early isolation of amyloid fibrils 

from tissues employed differential centrifugation, 

after Pras introduced the water extraction method, 

(Pras et al., 1968), the method has been almost universally 

used for extraction of almost all biochemical 

types of amyloid, except A and APrP (Selkoe and 

Abraham, 1986; Prusiner and DeArmond, 1995). 

With the low ionic strength Pras method, amyloid 


fibrils are separated from all proteins soluble in 

physiological saline by extraction of homogenates of 

amyloid-laden tissues with physiological saline followed 

by differential centrifugation. Then, amyloid 

fibrils are separated from other saline-insoluble tissue 

proteins by suspension in water. The isolated 

protein fibrils, insoluble in physiologic saline, exhibit 

Congophilia and green birefringence and are 

80 to 100 Å in width. 

The insoluble protein fibrils, extracted from tissues 

laden with amyloid fibrils, can be solubilized 

and size fractionated by gel filtration in denaturing 

agents, such as guanidine hydrochloride. This technological 

advance made possible the biochemical era 

of amyloid studies. Amino acid sequence determination 

of solubilized, denatured amyloid fibril proteins 

quickly led to the recognition that a biochemically 

unique protein was associated with each of the clinical 

syndromes (Tables I and II). Since 1970, the 

number of biochemically distinct proteins, isolated 

from species throughout the animal kingdom, that 

satisfy the three criteria for amyloid is approaching 

20 (Table II, Sipe, 1992). 

Studies from the Benditt and Glenner laboratories 

provided the first indication of the biochemical heterogeneity 

of amyloid. Glenner and co-workers 

(1971a) reported, on the basis of amino acid sequence 

analysis, that primary amyloidosis (now 

known as AL, but initially termed amyloid B by the 

Benditt laboratory (Benditt, 1976)) is the result of 

the deposition of fragments of immunoglobulin light 

chains. Benditt and colleagues identified, on the basis 

of amino acid sequence analysis of fibrils isolated 

from tissues of patients with chronic and recurrent 

acute inflammatory diseases (secondary amyloidosis), 

a protein termed amyloid A (Benditt et al., 

1971). The existence of a third biochemical class of 

amyloid protein was revealed when Costa et al. 

(1978) and Skinner and Cohen (1981) reported that 

prealbumin, now known as transthyretin, is the 

fibril protein associated with familial amyloid polyneuropathy. 

Subsequent biochemical analyses, including 

amino acid sequencing, led to the identification 

of fragments (usually) of about 20 normally 

soluble proteins deposited in a specific anatomic pattern 

associated with specific clinical manifestation 

of disease (Table II). In some cases, only a single 

organ of the body is affected, such as the pancreas in 

diabetes or the brain in Alzheimer’s disease. In 

other cases, termed systemic amyloidoses, amyloid 

fibrils are deposited in multiple organs and tissues 

of the body and are thought to be derived from 

circulating plasma protein precursors (Sipe, 1992, 

1994). 

Today, amyloid is known to be a large biochemically 

and clinically heterogenous group of disorders 

95


of protein folding. Investigations of amyloid have led 

to the identification of previously unknown peptides 

and proteins implicated in a large number of important 

life processes. These proteins include the amyloid 

A protein and its precursor, the cytokine-regulated 

serum amyloid A (SAA); more than 70 

transthyretin (TTR) variants; the cerebral amyloid 

protein, A, and its precursor protein APP; the 

previously unrecognized diabetes-associated islet 

amyloid polypeptide (IAPP); and prion proteins that 

cause scrapie and other neurodegenerative diseases 

(APrP) (Cohen, 1967; Glenner, 1980; Sipe, 1992; 

Westermark et al., 1996; Benson and Uemechi, 

1996; Prusiner and DeArmond, 1995). 

X-ray diffraction analyses of isolated amyloid protein 

fibrils (Bonar et al., 1969; Glenner et al., 1974; 

Sunde and Blake, 1998) revealed that all proteinaceous 

amyloid fibrils were ordered in secondary 

structure, with the polypeptide backbone assuming 

the beta pleated sheet conformation and oriented 

perpendicular to the fibril axis. It is particularly 

noteworthy that, in the case of TTR, which is 

present in the vitreous fluid of FAP patients as well 

as throughout the body, the structure of the TTR 

fibril from the vitreous (for which the Pras extraction 

method would not have to be used) and the TTR 

fibril extracted from kidney (for which the Pras 

method or a modification of it would be used) are 

identical (Inouye et al., 1998). 

The association of the pentraxin SAP with tissue 

amyloid deposits was revealed by electron microscopic 

studies of fractions of tissue homogenates 

that had been separated on the basis of solubility 

and sedimentation under conditions of decreasing 

ionic strength (reviewed by Cohen et al., 1982). It 

soon became apparent that, in addition to the fibrilrich 

fraction, another, pentagonal, particle, composed 

of five identical globular subunits, was invariably 

associated with amyloid deposits in tissues. The 

pentagonal component (P component) was identified 

immunochemically by Cathcart and co-workers 

(1965) as an alpha globulin. Bladen and co-workers 

(1966), using a differential centrifugation technique, 

identified a small pentagonal structure about 90 Å 

in diameter (Fig. 4c). Subsequent studies (reviewed 

by Pepys et al., 1997) led to the identification of a 

circulating blood protein nearly if not identical to 

the tissue protein. That blood protein is now called 

serum amyloid P component or SAP. 

Despite the fact that SAP and heparan sulfate 

proteoglycans (HSPG) are always present in tissues 

with amyloid fibrils (Pepys et al., 1997; Snow and 

Wight, 1989; Magnus and Stenstad, 1997), amyloid 

fibrils can be formed in vitro in their absence from 

several natural polypeptides, including insulin, glucagon, 

calcitonin, immunoglobulin light chains, and 

2-microglobulin (reviewed in Sipe, 1994). Fibrils, 

similar in dimension and appearance to tissue-derived 

amyloid proteins, have also have been formed 

from synthetic peptides corresponding to part or all 

of AA, A, and IAPP. Amyloidogenic polypeptides 

can be influenced by heparin to assume the beta 

pleated sheet rather than the alpha helical conformation 

(McCubbin et al., 1988). Studies of synthetic 

peptides led to the identification of amyloidogenic 

sequences in some precursors, such as AA, A, and 

IAPP, but not in others, such as AL and ATTR 

(reviewed in Sipe, 1994). Some amyloidogenic precursors, 

such as TTR and immunoglobulin light 

chains, are predisposed to fibril formation by structural 

changes (amino acid substitutions) in disparate 

parts of the polypeptide, changes that promote 

unfolding. Others, such as A, AA, and AIAPP precursor, 

contain contiguous regions of amino acids 

that predispose to amyloid fibril formation. Recently, 

amyloid fibrils were generated by acid and 

heat denaturation of monellin, a sweet tasting plant 

protein (Konno et al., 1999). De novo amyloid proteins 

have been generated from designed combinatorial 

libraries, in which all sequences were designed 

to share an identical pattern of alternating 

polar and nonpolar residues, and the side chains 

were varied combinatorially (West et al., 1999). The 

resultant aggregates have fibrillar morphology, are 

Congophilic, and assume the beta pleated sheet secondary 

structure. The X-ray diffraction patterns of 

amyloid fibrils prepared in vitro and those extracted 

from tissues are similar (Glenner et al., 1974). Apparently, 

the formation of proteinaceous amyloid 

fibrils is the result of a combination of factors, including 

the primary structure of the polypeptide and 

the thermodynamic parameters of the environment 

of the polypeptide (Kelly, 1998). 

Fibrils indistinguishable from those isolated from 

tissues were created by proteolytic digestion of 

Bence-Jones immunoglobulin light chain proteins 

(Glenner et al., 1971b; Linke et al., 1973; Shirahama 

et al., 1973). The in vitro properties of fibrillar morphology, 

Congophilia, and green birefringence led to 

the conclusion that the AL fibrils were identical to 

those deposited in tissues in vivo. Thus, the in vitro 

observation of the properties of insolubility and resistance 

to proteolysis led to the assumption that 

amyloid fibrils exhibit the same properties in vivo 

and in vitro and that insolubility and resistance to 

proteolytic clearance lead to replacement and destruction 

of vital organs that are clinically affected 

with amyloidosis. 

CURRENT MODEL OF AMYLOID FIBRILS IN TISSUES 

As evidenced by other reports in this volume, we 

are currently entering a new molecular and thera-

peutic era of amyloid, one in which prevention or 

reversal of amyloid fibril formation and the ensuing 

pathology in the body may be anticipated. Future 

multidisciplinary investigations of amyloid must be 

based upon a clear understanding of how the biophysical 

properties of proteins isolated from organs 

of patients afflicted with amyloidosis relate to the 

actual secondary structure of these fibrils in tissues. 

Inoue and colleagues (Inoue et al., 1998a) have 

compared experimental mouse AA amyloid fibrils in 

situ and after isolation by the Pras method (Pras et 

al., 1968). On the basis of their observation on AA 

amyloid and on other forms, including A, 2-microglobulin, 

and ATTR (Inoue et al., 1999, 1998b, 1997), 

they have proposed an alternative to the protein 

only, beta pleated sheet, protofilament amyloid fibril 

structure. Inoue, in collaboration with Kisilevsky 

and co-workers, has suggested that the 80- to 100-Å 

fibrillar structure in tissue is different from the 

structure of isolated protein in vitro. He proposes, on 

the basis of high-resolution electron microscopic 

studies, that in tissues, the amyloid fibril core is 

composed of helically wound 30-Å chondroitin sulfate 

proteoglycan (CSPG) double tracked structures 

enclosing a pentamer of amyloid P component (AP). 

Outside the CSPG are 45- to 50-Å heparan sulfate 

proteoglycans, to which AA protein filaments are 

attached. Presumably, the filaments are ordered to 

account for Congophilia and other specific histochemical 

staining, although the molecular basis for 

Congophilia is not clearly defined. Inoue and colleagues 

have proposed that the protein only fibril is 

formed artifactually as a result of the decreased 

ionic strength employed as part of the Pras extraction 

procedure. The Inoue model would consistently 

incorporate the reported HSPG binding sites in SAA 

(reviewed by Urieli-Shoval et al., 2000) and other 

amyloid proteins as well as the consistent changes 

in proteoglycan synthesis that precede amyloidogenesis 

(Kisilevsky and Fraser, 1997). 

The structure of the amyloid fibril in tissues has 

not been as rigorously analyzed as the protein only 

model of the amyloid fibril that has been derived 

from the past 3 decades of in vitro studies. In particular, 

a revisitation of the practice of isolation of 

amyloid fibrils from tissues, using the early “gentle 

amyloid fractionation techniques,” is probably warranted. 

Future biochemical investigations will be 

more fruitful if heparan sulfate proteoglycan and AP 

content are analyzed, in addition to the major fibrilassociated 

protein. In particular, comparison of TTR 

fibrils from vitreous fluid and organs such as kidney 

from FAP patients, where the composition of extracellular 

matrix of these tissues and the fibril isolation 

procedures applied to them are distinct (Inouye 


et al., 1998), may greatly enhance our understanding 

of the nature of amyloid fibril structure in vivo. 

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