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The Changing Concepts of Amyloid.

Amyloidosis in humans was first recognized in the mid-19th century when Rudolf Virchow coined the term amyloid (for starch or cellulose) to describe abnormal extracellular material seen in the liver at autopsy.[1] In fact, he was mistaken about the nature of the material, since all amyloid deposits characterized to date have been shown to consist predominantly of protein not carbohydrate. However, this first became apparent almost a century later, with the advent of biochemical analysis. Nonetheless, Virchow's erroneous term has endured. The first issue of Archives of Pathology & Laboratory Medicine contained an article by Richard Jaffe[2] pertaining to studies of experimental amyloidosis induced in mice by repeated injections of casein. Before this, several articles (quoted by Jaffe) had been published at the beginning of the last century on experimental amyloidosis induced by repeated subcutaneous injections of various proteins. Jaffe's article expanded the results obtained earlier by others: his emphasis was on the twin issues of induction time and dose dependence in experimental amyloidosis.

It is currently believed that this type of experimental amyloidosis is due to the abnormal production and degradation of serum amyloid A protein (SAA).[3] Although SAA is a major acute phase reactant, its physiological role is unknown. Interestingly, SAA was first identified after the amyloid fibril protein was defined biochemically in 1971 by Benditt et al,[4] Levin et al,[5] and Husby and Natvig.[6] Jaffe confirmed that the type of stimulus is not of primary importance in this particular model of amyloidosis, since similar results could be achieved with injections of different proteins (casein, serum, etc). As is currently known, in this experimental model, injections of various proteins ultimately lead to an increase in SAA, which subsequently undergoes partial degradation and is then deposited as amyloid fibrils. Thus, Jaffe was correct in postulating an "abnormal toxic cleavage of body tissues" in experimental inflammatory amyloidosis.

It took another quarter of a century before further meaningful progress in amyloid research was seen. In the late 1950s, with the introduction of electron microscopy, the fibrillar nature of amyloid became apparent.[7] In the electron microscope, amyloid was seen to consist of randomly dispersed, nonbranching fibrils that measured 8 to 10 nm in diameter The characteristic [Beta]-pleated sheet configuration was also discovered shortly thereafter.[8] The latter is responsible for the Congo red staining properties of amyloid. Thus, the modern diagnostic criteria for amyloid were adopted. These criteria include the detection of amyloid deposits in tissues that are Congo red positive, appear birefringent when viewed under polarized light (Figure 1), and display a characteristic fibrillar ultrastructure (Figure 2).

[Figures 1-2 ILLUSTRATION OMITTED]

In the early 1970s, the first 2 amyloid fibril proteins were extracted and chemically characterized.[4,9] Thereafter, it soon became apparent that amyloid is chemically heterogeneous. Currently, 19 different proteins have been found to form amyloid fibrils in humans, and other proteins may soon be added to this group?[10-13] This diversity generated the need for a reliable nomenclature and classification. Previously, several different classifications of amyloidosis were used that were essentially based on clinical features. However, the currently accepted classification, which was first proposed in 1990 and updated in 1998, is based on the chemical structure of the amyloid fibril protein,[10,11,14] According to the currently used nomenclature, the amyloid fibril protein is designated as protein A with a suffix that identifies the specific protein. Thus, amyloid derived from the immunoglobulin monoclonal light chain is designated AL, whereas amyloid derived from protein A is designated AA.

Although distinguishing between systemic and localized amyloidoses is of clinical importance, it is increasingly apparent that several amyloid proteins may be associated with both systemic and localized forms. Thus, some amyloids that are typically systemic (AL, amyloid derived from transthyretin [ATTR]) in some patients may form only localized nodules or affect only a single organ in others. There is also a growing body of evidence to show that several localized cerebral amyloids may also be systemic. Among systemic amyloidoses there are 3 sporadic forms and several familial forms. In the former group, there is AL and amyloid derived from the immunoglobulin heavy chain (AH), AA, and amyloid derived from [[Beta].sub.2]-microglobulin (A[[Beta].sub.2]M).[1,3,15] Among the familial forms, there is ATTR and amyloid derived from apolipoprotein I (AApoAI), gelsolin (AGel), lysozyme (ALys), fibrinogen [Alpha]-chain (AFib), and cystatin C (ACys).[16-21] Among localized (or predominantly localized) forms, amyloid derived from A[Beta] protein precursor (A[Beta]PP) and prion protein (PrP) are associated with cerebral pathologic conditions, such as Alzheimer disease (AD), aging, familial cerebral amyloidosis (prototype Dutch), and spongi-form encephalopathies.[22-24] Amyloid in familial British dementia (ABrit) is associated with a novel protein with no sequence homology to known proteins.[25] Several amyloid proteins that are derived from various hormones ([pro]calcitonin, islet amyloid polypeptide, atrial natriuretic factor, prolactin, insulin, and lactoferrin) are in general associated with endocrine gland pathologic conditions.

Also known as reactive or inflammatory amyloidosis, AA is typically associated with the chronic inflammation found in tuberculosis, osteomyelitis, rheumatoid arthritis, or chronic skin infections of paraplegics and skin poppers. In addition, AA can be associated with familial Mediterranean fever, an inherited disorder. The most prevalent type of amyloid worldwide, AA occurs spontaneously in animals and some birds. It can also be experimentally induced in mice and hamsters. Control of the inflammatory process is the mainstay of treatment.[3]

On the other hand, AL is derived from the immunoglobulin light chain[1,26] However, rare examples of amyloid deposits derived from a truncated heavy chain (AH) have also been reported. Collectively, AL is the most prevalent type of systemic amyloidosis in the United States. The amyloid fibril protein is derived from the amino-terminal segment of the immunoglobulin light chain, which in most instances involves the variable region and a part of the C region. In contrast to normal or myeloma light chains, AL is more frequently derived from the [Lambda] light chains than [Kappa]. A significantly higher frequency of certain amino acid substitutions at specific positions has been associated with amyloid formation. Also, certain relatively rare subgroups, eg, [Lambda] VI,[27] appear to be preferentially associated with amyloid. It is believed that the primary structure of the light chains plays a critical role in amyloidogenesis: certain amino acid substitutions are thought to destabilize the tertiary structure and alter normal catabolism of the light chains, which then tend to accumulate and ultimately convert into a fibrillar form. By definition, AL is associated with plasma cell dyscrasia or multiple myeloma. However, in many patients, detection of light chain amyloid is the first sign of abnormal immunoglobulin production.[26] In the past, the term primary amyloid was sometimes used with reference to patients in whom no underlying plasma cell dyscrasia could be demonstrated. However, it is increasingly apparent that with more sensitive methods, plasma cell dyscrasia is detectable in virtually all patients with AL. Interestingly, only some 10% of patients with multiple myeloma develop amyloidosis. It is also noteworthy that there is a considerable spectrum of pathologic conditions associated with underlying plasma cell dyscrasia, of which amyloid is only one of many manifestations. This spectrum is particularly visible in the kidney, where, in addition to (or instead of) amyloid, a picture of light chain cast nephropathy or nonamyloidotic deposits of light chain deposition disease can often be seen[28-30] The latter deposits are nonfibrillar and are Congo red negative. Various treatment protocols targeting the underlying clonal expansion of plasma cells are currently used. Attempts have been made to reproduce AL in mice by repeated injections of human amyloidogenic light chains, with varying results. In vitro studies of AL involving human light chains and mesangial cells have shown promise.[31]

In ATTR and all other forms of familial amyloidosis, the variant structure of the amyloid precursor is the pivotal factor in amyloidogenesis,[16] TTR is a carrier protein for thyroid hormone and retinol binding protein. More than 60 single amino acid substitutions in TTR have been shown to be responsible for familial amyloidosis. A recent study showed that almost 4% of African Americans carry an abnormal TTR. ATTR is the most common form of hereditary amyloidosis. Although the age at onset and the phenotype may vary between different kinships, most include polyneuropathy, involvement of the autonomic system, or cardiomyopathy. The role of the age factor is puzzling: despite being inherited, the disease is not clinically apparent until middle or later life. Of particular interest is ATTR that occurs in elderly patients as a senile amyloidosis involving primarily the heart. This senile ATTR involves structurally normal protein and is exclusively a disease of the elderly. Since TTR is predominantly ([is greater than]95%) produced by the liver, liver transplantation in affected individuals has become an established treatment.

Other hereditary systemic amyloidoses, including AApoAI, AGel, ALys, and AFib, are relatively rare. Five variants of the apolipoprotein A-I molecule are associated with amyloid, causing nephropathy, hepatomegaly, neuropathy, and cardiomyopathy. Apolipoprotein A-I is the major protein associated with high-density lipoproteins; structural change is believed to decrease its ability to be associated with high-density lipoprotein and to increase its catabolism. Gelsotin-derived amyloid (AGel; familial, prototype Finnish) is a rare disorder, reported worldwide in kindreds carrying a gelsolin gene mutation.[32] It is characterized by cranial neuropathies, peripheral neuropathy, and corneal lattice dystrophy. Amyloid derived from a mutant fibrinogen (AFib) causes isolated renal amyloidosis, and ALys derived from a mutant lysozyme is associated with visceral involvement.

A[[Beta].sub.2]M is seen in patients undergoing long-term hemodialysis. [[Beta].sub.2]-Microglobulin, a small protein with a predominantly [Beta]-pleated sheet structure, is not effectively removed during dialysis.[15,33] Although there is no direct correlation between the absolute concentration of [[Beta].sub.2]-microglobulin and amyloidosis-related symptoms, high serum levels of this protein are believed to be the basis of amyloid deposition in tissues. Although A[[Beta].sub.2]M has a predilection for bones and joints, it has also been shown to have a truly systemic distribution. Thus, involvement of the gastrointestinal tract, kidneys, spleen, myocardium, lungs, skin, thyroid, and perineural space has been reported. Although many of these deposits may be seen predominantly in the vessel wall, bulky visceral deposits were also reported.[34] Renal transplantation generally arrests the disease process and leads to rapid relief of osteoarticular pain, but no regression of amyloid has been observed.

Cerebral amyloidoses and related disorders comprise a heterogeneous group of diseases that can be sporadic, familial and/or hereditary, and infectious. Parenchymal and/or vascular amyloid is seen in AD, familial cerebral amyloid angiopathies, and prionoses, also known as transmissible spongiform encephalopathies.[22,23,35]

Although age-related impairment in cognition and memory has been known since ancient times, the first case of memory deficits and progressive loss of cognitive abilities was reported in 1907 by Alois Alzheimer. Autopsy showed the now-recognized classic pathology of AD: numerous neurofibrillar tangles and senile plaques in the neocortex and hippocampus. Congophilic angiopathy is also a frequent feature. Alzheimer disease is a complex and genetically heterogeneous disorder.[12,22,35,36] It is also the most common type of dementia occurring in mid to late life. It is estimated that some 7% to 10% of individuals older than 65 years and as much as 40% of people older than 80 years are affected. Currently, the number of patients with AD in the United States is approximately 4 million, but it is projected that these numbers will rise with increased life expectancy of future generations. The normal function of A[Beta]PP, the precursor of A[Beta], is unknown. It may be involved in cell-to-matrix signaling. Outside the central nervous system, many cells and tissues contain A[Beta] protein precursor isoforms. Molecular genetic studies indicate a central role for A[Beta] in the pathogenesis of AD. A similar pathology has been described in primates. Attempts to reproduce AD pathology have been reported in several transgenic animal models; no treatment is currently available.

Transmissible spongiform encephalopathies occur in humans and several animal species.[23,37] In humans, transmissible spongiform encephalopathies comprise Creutzfeldt-Jakob Disease (CJD), Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, and kuru. Animal diseases comprise bovine spongiform encephalopathy (BSE, "mad cow disease"), scrapie of sheep and goats, transmissible mink encephalopathy, feline spongiform encephalopathy, and chronic wasting disease of North American mule deer and elk.[37] Recently, a variant of CJD (vCJD) has been linked to trans-species transmission of the bovine spongiform encephalopathy agent to humans.

Amyloid in prionoses is an abnormally folded isoform of the Pr[P.sup.c], termed Pr[P.sup.sc]. The term prion, an acronym for "proteinaceous infectious particle," was coined by Stanley Prusiner to describe a protein that can transform other Proteins.[38] In contrast to other infectious agents, prions elicit no specific immune response, since the infectious agent is composed of protein with a primary structure identical to the host-encoded protein. For this same reason, the "infection" also appears to be tolerated by the lymphoid system. There is a growing body of evidence that abnormalities of prion proteins may not be confined to the central nervous system. The pathologic effects of prions have also been discovered in age-related myopathy--inclusion body myositis. Myopathy is also commonly seen in scrapie of sheep, and transgenic mice overexpressing Pr[P.sup.c] develop necrotizing myopathy.

Variant CJD is a new and emerging prion disease. According to data gathered by the National Prion Disease Pathology Surveillance Center as of January 31, 2000, 51 cases of vCJD were reported in the United Kingdom and 1 in France. Epidemiologic and laboratory evidence indicates that vCJD is causally linked to bovine spongiform encephalopathy through consumption of contaminated meat or other cattle products. Also, the endemic presence of a prion disease, called chronic wasting disease, among deer and elk in parts of Colorado and Wyoming has been linked to a recent report of at least 3 young American deer and elk hunters who contracted CJD. Prionoses also have a potential impact on the future of xenotransplantation, since animal tissues have been found to contain significant levels of prions. No treatment is currently available. Of interest is a recent report on reversal of conformational changes implicated in the pathogenesis of spongiform encephalopathies using in vitro studies[39] Research on prionoses has been considerably advanced by the availability of transgenic animals overexpressing Pr[P.sup.c].

The diagnosis of amyloid is made by pathologists. As indicated earlier, the generic diagnosis of amyloid is based on its tinctorial properties (Figure 1) and ultrastructural appearance (Figure 2). However, in view of the ever-expanding heterogeneity of amyloid deposits, immunohistochemical typing of deposits is currently the standard of care. Admittedly, the typing of deposits in paraffin sections can be challenging; however, in frozen sections good results can be obtained for most patients (Figure 3). The biopsy site must target a potentially involved organ. The organ sites that are most frequently positive for amyloid deposits include the kidney, myocardium, gastrointestinal tract, and peripheral nerves. Abdominal fat aspirates have also been widely used for screening purposes (Figure 4).[40] Other related deposits, such as light chain deposition disease, fibrillary, immunotactoid, and deposits of cryoglobulins, should be considered in the differential diagnosis.[29]

[Figures 3-4 ILLUSTRATION OMITTED]

Fibrillogenesis is most likely multifactorial and differs among the various types of amyloid. Many amyloid fibril proteins are derived from a soluble precursor protein that is detectable in the circulation. Partial proteolysis of the precursor protein is consistently seen in AA and AL; significant fragmentation also occurs in TTR, amyloid derived from gelsolin, cystatin C, AD, and apolipoprotein AI. Notable exceptions include lysozyme and [[Beta].sub.2]M. In hereditary forms of amyloidosis, changes in the primary structure of the protein precursor are considered to render them amyloidogenic. Amyloid fibrils are believed to form by a common self-assembly pathway; however, why some protein sequences are more amyloidogenic than others is currently unknown. Protein aggregation has recently developed into an area of intensive research, since inhibition of aggregation has been targeted as a potentially useful approach to decreasing the amyloid burden during disease.[12]

Immunohistochemical and biochemical studies have shown that several different proteins, which are not intrinsic components of the fibril itself, are found in amyloid deposits. Several such compounds have been detected in all types of amyloid thus far examined. These compounds include amyloid P component (AP; glycoprotein related to C-reactive protein), apolipoprotein E (Apo-E; regulator of lipoprotein metabolism, Figure 5), and sulfated glycosaminoglycans (GAGs; constituents of matrix proteins)[41,42] In contrast, [Alpha]1-antichymotrypsin (a serine protease inhibitor, Figure 6) has been detected only in A[Beta], whereas the deposits present in systemic amyloidoses have been shown to be negative.[43.44] An as yet unidentified chaperone termed protein X has been postulated to be associated with prionoses.[45] Interestingly, neither amyloid P nor apolipoprotein E has been detected in the nonamyloidotic deposits derived from light chains in light chain deposition disease.[41]

[Figure 5-6 ILLUSTRATION OMITTED]

The role of these ancillary components is not clear. Several functions have been proposed, including facilitating aggregation and protein folding, leading to fibril formation, substrate adhesion, and protection from degradation. Of these theories, the function of such components as molecular chaperones that either inhibit or enhance amyloid fibril protein aggregation is gaining most interest, since it offers a possible avenue of intervention into fibrillogenesis and treatment. Rodent models have been widely used to study involvement of such components in amyloidogenesis. Thus, more recent studies using an experimental model of AA (similar to that reported by Jaffe) demonstrated coaccumulation of apolipoprotein E (Figure 5) and various basement membrane proteins with amyloid fibrils.[42]

An intriguing derivative of experimental AA is the emergence of amyloid-enhancing factor (AEF).[46-49] Essentially, AEF is a tissue extract that can be obtained from amyloid-laden organs. Such extracts have been shown to accelerate amyloidogenesis in experimental animal models of AA amyloidosis. Parenteral application of AEF together with an inflammatory stimulus, shortens the amyloid induction time from 3 to 4 weeks to 2 to 4 days. Despite numerous attempts by several laboratories, the exact composition of AEF has never been elucidated, and AEF continues to be defined by a biological assay. Interestingly, the AEF function is not related to the primary structure of the amyloid precursor and is not even species specific. Thus, it is currently believed that its function depends more directly on a macromolecular conformation common to all [Beta]-pleated sheet fibrils. In addition, AEF appears to act as a protofibril or focus of [Beta]-sheeting (the "nidus" theory). It is postulated that amyloid formation follows crystallization-type kinetics, hence the requirement for nucleus formation before the amyloid fibril can grow. To this end, in vitro fibrils have been shown to possess AEF activity.

Interestingly, AEF shows several features in common with prions. Thus, both AEF and prions contain no DNA or RNA, and both are transmissible. Of note is a recent report of dietary transmission of AEF in rodents.[48] However, AEF appears to act much faster than prions. This may be a consequence of the availability of and/or the relative distance to the target. To this end, AEF acts much faster when delivered parenterally, whereas dietary transmission is slower. Interestingly, although AEF does not appear to be a type of amyloid, nor species specific, successful transmission of prionoses seems to require a sufficient level of amino acid sequence homology between the infectious Pr[P.sup.SC] and Pr[P.sup.c] of the host.

As we enter a new millennium, the importance of amyloid and its role in human disease is not diminished. It is far from being either a rare human affliction or an item of mere intellectual interest. The association of amyloid with neurodegenerative diseases and aging makes its impact on multiple aspects of our lives quite extraordinary, and its recently demonstrated association with trans-genospecies transmissibility may portend a disturbing increase in its incidence. An important milestone in amyloid research was the recognition of the pivotal role of abnormal protein folding, leading to the formation of amyloid in general and AD and other neurodegenerative disorders in particular It seems that the evolution of the concept of amyloidogenesis has now come full circle. From what was perceived as a single entity for more than a century, through the explosion of chemical heterogeneity demonstrated during the last quarter of the previous century, a new definition of amyloid has begun to emerge. This new concept implies that amyloid is a final common pathway for protein deposition in tissues, a pathway that is associated with many disease processes, including aging and degenerative changes. Moreover, the definition of amyloid as exclusively extracellular aggregates may need to be reconsidered. For example, neurofibrillary tangles, which are intracellular, have been shown to have many of the properties of amyloid. In view of the emerging evidence that fibrillization intermediates rather than mature fibrils may have a cause-and-effect relationship to disease,[12] our current diagnostic criteria need to be revised. Thus, an updated definition of amyloid is urgently needed.

I am grateful to Roger N. Picken, PhD, for critical review of the manuscript and for helpful discussions.

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Accepted from publication August 16, 2000.

From the Department of Pathology, Loyola University Medical Center, Maywood, Ill.

Reprints: Maria M. Picken, MD, PhD, Department of Pathology, Loyola University Medical Center, 2160 S First Ave, Room 2242, Bldg 110, Maywood, IL 60153 (e-mail: mpicken@lumc.edu).
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Author:Picken, Maria M.
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Date:Jan 1, 2001
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