Amyloid, SeptemberDecember 2010; 17(34): 101104

Amyloid fibril protein nomenclature: 2010 recommendations from the

nomenclature committee of the International Society of Amyloidosis

JEAN D. SIPE1, MERRILL D. BENSON2, JOEL N. BUXBAUM3, SHU-ICHI IKEDA4,

GIAMPAOLO MERLINI5, MARIA J.M. SARAIVA6, & PER WESTERMARK7

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Department of Biochemistry (Emerita), Boston University School of Medicine, Boston, MA 02118, USA, 2Department of
Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA, 3Department of
Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA, 4Department of Neurology
and Rheumatology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan, 5Amyloid Research and Treatment
Center, University of Pavia, 27100 Pavia, Italy, 6Amyloid Unit, Institute of Molecular and Cellular Biology, University of
Porto, Porto, Portugal, and 7Department of Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden

Keywords: Amyloidosis, amyloid protein, amyloid fibril, inclusion body

Abstract
A system of amyloid fibril nomenclature based on the chemical identity of the amyloid fibril forming protein is recommended.
This system has been in use for approximately 40 years, but current literature remains confused with clinical and histochemical
designations used when the amyloid disease processes were poorly understood. To be designated an amyloid fibril protein, the
protein must occur in tissue deposits and exhibit affinity for Congo red and green birefringence when viewed by polarisation
microscopy. Furthermore, the protein must have been unambiguously characterised by protein sequence analysis (DNA
sequencing in the case of familial diseases). Current nomenclature lists of 27 human and nine animal fibril proteins are provided
together with a list of eight inclusion bodies that exhibit some of the properties of amyloid fibrils.

Background
The Nomenclature Committee of the International
Society of Amyloidosis met in conjunction with the
XII International Symposium on Amyloidosis
(Rome, Italy, 1821 April 2010) to formulate
recommendations on amyloid fibril protein nomenclature and to consider newly identified candidate
amyloid fibril proteins for inclusion in the nomenclature list (Table I).
The need for widespread adoption of a logical and
clearly understood nomenclature for amyloid fibril
proteins has grown more urgent as our understanding of the chemical diversity of amyloid fibril
proteins has increased. To date, there are 27 known
extracellular fibril proteins in human (Table I), at
least nine of which have been studied in animal
models (Table II). This large number of naturally
occurring amyloid fibril proteins underlies the need
for consistent use of standardised nomenclature to
facilitate the type of clear communication that will
promote advancements in our understanding of
amyloid disease processes and will hasten timely
and appropriate treatments for patients.

A large number of intracellular protein inclusions have been reported, at least one of which, the
neurofibrillary tangles, has fibrillar structure, a
cross b-sheet X-ray diffraction pattern, binds
Congo red and exhibits green birefringence when
viewed by polarisation microscopy (Table III).
The tangles are thus intracellular amyloid,
although they have not been included on the
nomenclature list. Other inclusions may have
some, but not all, of these properties, e.g. inclusion
bodies within muscle fibers of inclusion body
myositis, which are stained by Congo red, exhibit
green birefringence and are immunoreactive with
anti-amyloid-b.
Amyloid fibril protein nomenclature
The established amyloid fibril nomenclature is based
on the chemical nature of the fibril protein, which is
designated protein A and followed by a suffix that is
an abbreviated form of the parent or precursor
protein name. For example, when amyloid fibrils are
derived from immunoglobulin light chains, the amyloid fibril is AL and the disease is AL amyloidosis.

Correspondence: Jean D. Sipe, 8406 North Brook Lane, Bethesda, MD 20814. E-mail: j.d.sipe@msn.com
ISSN 1350-6129 print/ISSN 1744-2818 online 2010 Informa UK, Ltd.
DOI: 10.3109/13506129.2010.526812

102

J. D. Sipe et al.
Table I. Amyloid fibril proteins and their precursors in humans.*

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Amyloid protein

Systemic (S) or localized,

organ restricted (L)

Precursor

AL

Immunoglobulin light chain

S, L

AH

Immunoglobulin heavy chain

S, L

Ab2M

b2-microglobulin

ATTR

Transthyretin

AA
AApoAI

(Apo)serum AA
Apolipoprotein AI

AApoAII
AApoAIV
AGel
ALys
AFib
ACys
ABri
ALect2
ADan*
Ab
APrP
ACal
AIAPP

Apolipoprotein AII
Apolipoprotein AIV
Gelsolin
Lysozyme
Fibrinogen a-chain
Cystatin C
ABriPP
Leukocyte chemotactic factor 2
ADanPP
Ab protein precursor (AbPP)
Prion protein
(Pro)calcitonin
Islet amyloid polypeptide**

L?
S
S
L
S
S
S
S
S
S
S
S
L
L
L
L
L

AANF
APro

Atrial natriuretic factor

Prolactin

L
L

AIns
AMed
AKer
ALac
AOaap
ASemI

Insulin
Lactadherin
Kerato-epithelin
Lactoferrin
Odontogenic ameloblast-associated protein
Semenogelin I

L
L
L
L
L
L

Syndrome or involved tissues

Primary
Myeloma-associated
Primary
Myeloma-associated
Hemodialysis-associated
Joints
Familial
Senile systemic
Tenosynovium
Secondary, reactive
Familial
Aorta, meniscus
Familial
Sporadic, associated with aging
Familial (Finnish)
Familial
Familial
Familial
Familial dementia, British
Mainly kidney
Familial dementia, Danish
Alzheimers disease, aging
Spongioform encephalopathies
C-cell thyroid tumors
Islets of Langerhans
Insulinomas
Cardiac atria
Aging pituitary
Prolactinomas
Iatrogenic
Senile aortic, media
Cornea, familial
Cornea
Odontogenic tumors
Vesicula seminalis

S
L?
S

*Proteins are listed, when possible, according to relationship. Thus, apolipoproteins are grouped together, as are polypeptide hormones.
ADan comes from the same gene as ABri.
{
Also called amylin.
{

Table II. Amyloid fibril proteins and their precursors in animals.

Amyloid
protein

Precursor

Systemic (S) or
localized (L)

AL
AA
AApoAI
AApoAII
ATTR
Ab
AIAPP

Immunoglobulin light chain

(Apo)serum AA
Apolipoprotein AI
Apolipoprotein AII
Transthyretin*
Ab protein precursor
Islet amyloid polypeptide

S, L
S
S
S
S
L
L

AIns
ACas

Insulin
a-S2C casein

L
L

Syndrome or involved tissues

Plasmocytoma
Secondary, reactive
Age-related
Age-related
Age-related
Age-related
Islets of langerhans
Insulinoma
Islets of langerhans
Mammary gland

Species
Horse, cat
Mouse, guinea pig, cat, dog, cow, duck, etc
Dog
Mouse
Monkey
Dog, sheep, wolverine
Cats, apes, raccoon
Octodon degus
Cow

*Provisional, awaiting DNA or protein sequence analysis.

Variants are named according to the mutation in the

gene for the protein, e.g. ATTRV30M or ALysI56T
(Tables I and II). The amyloidosis is then
named after the protein, e.g. AL amyloidosis or

ATTRV30M amyloidosis. This nomenclature has

been adopted by the World Health Organization [1]
and consistently recommended by the ISA Nomenclature Committee [28].

Amyloid fibril protein nomenclature

103

Table III. Intracellular inclusions with known biochemical composition, with or without amyloid properties.
Inclusion name
Lewy bodies
Huntington bodies
Hirano bodies
Collins bodies
Not specified
Neurofibrillary tangles

Site
Neurons
Intracytoplasmic
Neurons
Intranuclear
Neurons
Neurons
Neurons, many
Different cells
Neurons
Intracytoplasmic

Protein nature

Examples of associated disease

a-synuclein*

Parkinsons disease

PolyQ expanded huntingtin

Huntingtons disease

Actin
Neuroserpin
Ferritin

Neurodegenerative disorders
Forms of familial presenile dementia
Form of familial neurodegenerative disorder

Tau

Alzheimer disease, fronto-temporal dementia,

aging, other cerebral conditions

*Simplified. Additional components may exist.

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Recommendations
The ISA Nomenclature Committee urges those
involved in amyloid research and treatment to adopt
the above standardised nomenclature, keeping in
mind the following questions:
1.

2.

3.

What is an amyloid fibril?

An insoluble protein fibril that is deposited,
mainly, in the extracellular spaces of organs and
tissues as a result of a sequence of changes in
protein folding that results in a condition known
as amyloidosis.
Is the candidate protein an amyloid fibril
protein?
An amyloid fibril protein occurs in tissue
deposits as rigid, non-branching fibrils approximately 10 nm in diameter. The fibrils bind the
dye Congo red and exhibit green birefringence
when viewed by polarisation microscopy. When
isolated and analysed by X-ray diffraction, the
fibrils exhibit a characteristic cross b diffraction
pattern.
The designation amyloid, first used in
botany, was applied by Virchow, originally to
corpora amylacea in the brain and later for the
tissue deposits of systemic amyloidosis. Subsequently, the concept of amyloid was expanded to
denote diverse localised tissue deposits (e.g. in
Alzheimers disease or type 2 diabetes) with
similar homogeneous appearance in light microscopy and with the same tinctorial and physical
properties. The definition of amyloid has now
been further widened in that it is regularly used
by biochemists for synthetic protein fibrils with
some amyloid properties. In order to avoid
confusion, the ISA Nomenclature Committee
has recommended the use of amyloid-like for
synthetic fibrils [8].
What is the chemical identity of the amyloid
fibril protein?
An amyloid fibril protein, to appear in the
official nomenclature list, must have been

unambiguously characterised by protein sequence analysis (DNA sequencing in the case

of familial diseases) and described in a peerreviewed journal.
4. Why is it important to determine the chemical
identity of an amyloid fibril protein in a patient
with systemic amyloidosis?
More than one type of amyloid fibril protein
can be deposited in a given tissue. For example,
the familial amyloidoses are chemically and
clinically heterogeneous and are associated with
nomenclature harkening back to times when the
nature of the fibril was unknown that is still in
use. An example of this early nomenclature is
familial amyloid polyneuropathy. It is important
to use the accepted nomenclature, e.g.
ATTRV30M and ATTRY78F, thus avoiding
confusion with the more frequently occurring
AL amyloidosis, for which the treatment plan
would be markedly different.
5. Why is amyloid precursor protein (APP) used
for the precursor of amyloid-b (Ab)?
The use of amyloid precursor protein (APP),
for APP, occurs widely in the neuroscience
literature. This term could, of course, refer to
any of the 27 amyloid fibril protein precursors.
The correct nomenclature is AbPP; this is
recommended by the ISA Nomenclature Committee and the journal Amyloid.
6. Why are Greek letters sometimes used for
variants of serum amyloid A (SAA), some of
which are precursors of amyloid A (AA)?
The ISA Nomenclature Committee recommended in 1999 [9] that allelic variants of human
SAA proteins should be designated as SAA1.1,
1.2, 1.3 and 1.4 instead of SAA1a, b, g and d. The
use of Greek letters should be discontinued.
7. Do amyloid fibrils serve biological function(s)?
Another nomenclature related question has
emerged with the use of the concept functional
amyloid. Structurally robust, protease resistant bsheet fibrillar assemblies are widely used in nature,
particularly in invertebrates, e.g. as bacterial

104

J. D. Sipe et al.

biofilms. In addition, it has been suggested that some

human structures, such as the p-mel framework in
melanosomes and the organisation of polypeptide
hormones when stored in secretory vesicles, have an
amyloid fibril structure [1012]. These more broadly
applied circumstances have made it increasingly
important to use clear definitions when using the
word amyloid.
Newly identified amyloid fibril protein

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The ISA Nomenclature Committee considered

candidate newly identified amyloid fibril proteins
and voted to include ALect2, first identified in renal
amyloid deposits as reported by the Benson Laboratory [13].
Declaration of interest: The authors report no
conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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