**2. Protein constituent(s) of amyloid fibrils**

Many types of disorders are associated with amyloid deposits. Different fibril proteins underlie different pathologic contexts. **Table 1** presents examples of some types of amyloid diseases, the proteins from which their fibril proteins are derived, and their clinical associations. As will be noted below, it has become important to identify the precise molecular constituent(s) of the fibrils in order to establish the correct diagnosis and plan appropriate treatment.

In humans, the most frequently encountered pathologic amyloid fibrils are derived from fragments of immunoglobulin proteins. Some (but not all) immunoglobulin light chains (both κ and λ) have stretches of amino acids that can form the basic unit of amyloid fibrils. These are usually found in association with clonal proliferations of plasma cells which range from "monoclonal gammopathy of unknown significance" (i.e., "MGUS") to disorders such as myeloma. The fibrils themselves can cause distortion of organ microanatomy leading to cell dysfunction, disrupted cell-cell communication and, ultimately, organ failure.

Another well-studied type of amyloid fibril is derived from fragments of a small (104 amino acid) serum protein called "serum amyloid A (SAA)." Deposits of this type of amyloid are characteristic of chronic inflammatory or infectious disorders. It is likely that many of the examples of "amyloid" disease described in the pre-antibiotic era were derived from SAA (examples include tuberculosis and osteomyelitis).

Many genetic variants of transthyretin (TTR), another small, 127 amino acid serum protein, are associated with familial forms of amyloid disease. Affected individuals show progressive neurologic and/or cardiac dysfunction with concomitant amyloid deposition [6]. In addition, some individuals develop TTR amyloid disease (particularly involving the heart) in the absence of an underlying mutation in the protein.

Amyloid fibrils and plaques are characteristic of the neurodegeneration of Alzheimer disease. In this case, the parent protein is a large membrane-spanning protein referred to as β-amyloid. Only a small fragment of the primary protein is found in amyloid fibrils [7]. Specific endoproteases release this fragment from the parent molecule. As **Figure 1** shows, characteristic amyloid fibrils can be formed from Aβ(1-42) polypeptides with individual amino acid variation(s).

Parkinson disease is another disorder of the central nervous system associated with cellular depositions. In this case, α-synuclein accumulates in cells of the basal ganglia associated with loss of function. In neurons, relatively disorganized oligomers of α-synuclein appear first, and there is gradual compaction with β-sheet domains becoming prominent later [8, 9].

Considerable interest has arisen regarding prions. These are alternative conformations of proteins that can self-associate and self-propagate. First determined to be causative agents of "spongiform encephalopathy" in humans (e.g., Creutzfeldt-Jakob disease), prions also have become recognized as responsible for transmissible neuropathies in animals (e.g., "mad cow" disease). Studies of Sup35 prions in yeast have been particularly informative, and multiple strains can be isolated [10].

Another interesting category of disorders associated with amyloid fibril formation includes polypeptide hormones. Many of these are originally stored in relatively concentrated form within membrane-enclosed secretory granules. **Table 1** lists several associated types. In normal physiology dissociation of these organized structures must occur in order to release individual hormones [11]. In certain situations, however, these same hormones (or their precursors) can persist and become detected as fibrils.

**179**

their long axis.

*Pathophysiology of Amyloid Fibril Formation DOI: http://dx.doi.org/10.5772/intechopen.81965*

**3. Fibril structure**

**Table 1.**

All amyloid fibrils share a basic unit comprising a relatively short and (usually) contiguous stretch of amino acids whose three-dimensional contours can be accommodated in a β-pleated sheet conformation (both parallel and antiparallel assemblies are recognized in fibrils). Hydrogen bonds between the amide groups polarize each other. Van der Waals forces also develop between the β-sheets. Water molecules are displaced from between the faces of the sheets. These important features emphasize that protein precursors of amyloid fibrils are not in their native state—the constituent monomer is in an altered conformation, and this state may only be transient prior to nucleation. Thus, there is an array of polypeptide species that may underlie fibril formation; the most (transiently) stable and/or abundant

ACal (Pro)calcitonin Medullary thyroid carcinoma

AANF Atrial natriuretic factor Atrial amyloid AαSyn α-Synuclein Parkinson disease

**Designation Precursor protein Clinical example(s)** AL κ, λ Light chains Myeloma, MGUS AA Serum amyloid A Secondary ATTR Transthyretin Nerve/heart Aβ β-Protein precursor Alzheimer APrP Prion protein Encephalopathy Aβ2M β2-Microglobulin Dialysis related AIAPP Amylin Type II diabetes

As shown by Riek and Eisenberg [12], amyloids derived from different protein constituents may have very different β-sheet domains. In addition, these regions may be rather small in comparison with the length of the parent protein(s). This implies that only a fragment of the parent (i.e., longer) protein may be found in the ultimate amyloid fibril, and this, in turn, implies that cleavage of the parent protein is often part of the process of fibril formation. **Figure 2** presents example details of

The β-pleated sheet topology of the basic interacting region permits individual regions to stack upon one another in a highly ordered manner—thus extending into the long axis of the fibril (see **Figure 2**). The result is stabilization not only between β-sheet domains but also between stacked subunits. Fibrils often show a twist along

Once the requisite region for forming β-sheets becomes available, fibril formation begins as a nucleation event. Usually small numbers of monomers interact, but once the primordial oligomeric fibrillary unit is assembled, further extension can occur by aligning new monomers with the growing fibril surface. The kinetics of this process are consistent with this scheme, there generally being a lag in assembling the oligomer followed by more rapid extension as subunits are added.

Most amyloid fibrils share relatively common dimensions although their lengths often vary. Because the fibrils are so tightly associated within their common nuclei of β-sheet domains, they are themselves rather resistant to dissociation (substantial free energy of formation) as well as to attack by proteases (regions susceptible to

species is most likely to be captured in a stable β-sheet.

*Examples of pathologic human amyloid fibril proteins [4, 5].*

the particularly well-studied Alzheimer Aβ(1-42) fibril.

#### *Pathophysiology of Amyloid Fibril Formation DOI: http://dx.doi.org/10.5772/intechopen.81965*


**Table 1.**

*Amyloid Diseases*

osteomyelitis).

protein.

**2. Protein constituent(s) of amyloid fibrils**

correct diagnosis and plan appropriate treatment.

cell-cell communication and, ultimately, organ failure.

Many types of disorders are associated with amyloid deposits. Different fibril proteins underlie different pathologic contexts. **Table 1** presents examples of some types of amyloid diseases, the proteins from which their fibril proteins are derived, and their clinical associations. As will be noted below, it has become important to identify the precise molecular constituent(s) of the fibrils in order to establish the

In humans, the most frequently encountered pathologic amyloid fibrils are derived from fragments of immunoglobulin proteins. Some (but not all) immunoglobulin light chains (both κ and λ) have stretches of amino acids that can form the basic unit of amyloid fibrils. These are usually found in association with clonal proliferations of plasma cells which range from "monoclonal gammopathy of unknown significance" (i.e., "MGUS") to disorders such as myeloma. The fibrils themselves can cause distortion of organ microanatomy leading to cell dysfunction, disrupted

Another well-studied type of amyloid fibril is derived from fragments of a small (104 amino acid) serum protein called "serum amyloid A (SAA)." Deposits of this type of amyloid are characteristic of chronic inflammatory or infectious disorders. It is likely that many of the examples of "amyloid" disease described in the pre-antibiotic era were derived from SAA (examples include tuberculosis and

Many genetic variants of transthyretin (TTR), another small, 127 amino acid serum protein, are associated with familial forms of amyloid disease. Affected individuals show progressive neurologic and/or cardiac dysfunction with concomitant amyloid deposition [6]. In addition, some individuals develop TTR amyloid disease (particularly involving the heart) in the absence of an underlying mutation in the

Amyloid fibrils and plaques are characteristic of the neurodegeneration of Alzheimer disease. In this case, the parent protein is a large membrane-spanning protein referred to as β-amyloid. Only a small fragment of the primary protein is found in amyloid fibrils [7]. Specific endoproteases release this fragment from the parent molecule. As **Figure 1** shows, characteristic amyloid fibrils can be formed

Parkinson disease is another disorder of the central nervous system associated with cellular depositions. In this case, α-synuclein accumulates in cells of the basal ganglia associated with loss of function. In neurons, relatively disorganized oligomers of α-synuclein appear first, and there is gradual compaction with β-sheet

Considerable interest has arisen regarding prions. These are alternative conformations of proteins that can self-associate and self-propagate. First determined to be causative agents of "spongiform encephalopathy" in humans (e.g., Creutzfeldt-Jakob disease), prions also have become recognized as responsible for transmissible neuropathies in animals (e.g., "mad cow" disease). Studies of Sup35 prions in yeast have been particularly informative, and multiple strains

Another interesting category of disorders associated with amyloid fibril formation includes polypeptide hormones. Many of these are originally stored in relatively concentrated form within membrane-enclosed secretory granules. **Table 1** lists several associated types. In normal physiology dissociation of these organized structures must occur in order to release individual hormones [11]. In certain situations, however, these same hormones (or their precursors) can persist and become

from Aβ(1-42) polypeptides with individual amino acid variation(s).

domains becoming prominent later [8, 9].

**178**

can be isolated [10].

detected as fibrils.

*Examples of pathologic human amyloid fibril proteins [4, 5].*
