Amyloid

Amyloid Full Name

Amyloid

Amyloid Introduction

Amyloid refers not to a specific protein, but to a specific, highly ordered insoluble aggregation state that various proteins can adopt. Irrespective of the precursor protein's original sequence or structure, all amyloids share a common core structure: rigid, unbranched fibrils approximately 10 nm in diameter. Structurally, these fibrils are characterized by a "cross-β" sheet pattern, where β-strands run perpendicular to the fibril axis. This unique architecture confers exceptional stability and resistance to degradation by proteases. Historically, amyloids were identified by their ability to bind the dye Congo Red, displaying a characteristic apple-green birefringence under polarized light.

Figure 1. Representation of the cross-b-sheet amyloid fibril fold.. (Source: Akbey Ü, et al. 2022)

The transition of a soluble protein into amyloid fibrils typically follows a nucleation-dependent polymerization pathway.
1. Misfolding: Native proteins partially unfold due to mutations, stress, or cellular aging.
2. Nucleation: These misfolded monomers aggregate to form unstable, soluble oligomers (nuclei).
3. Elongation: The nuclei act as seeds, rapidly recruiting monomers to form protofibrils and finally mature fibrils.
While the mature fibrils were originally thought to be the main culprit, current research suggests that the soluble oligomeric intermediates are often the most cytotoxic species. These oligomers can disrupt cell membranes, cause mitochondrial dysfunction, and trigger oxidative stress and inflammation, leading to cell death (proteotoxicity).

Amyloid diseases, or amyloidoses, manifest through diverse clinical profiles depending on whether the pathogenic protein deposition is localized to a specific organ or distributed systemically throughout the body. In the context of neurodegeneration, localized amyloid formation is the hallmark of conditions like Alzheimer's Disease, characterized by extracellular Amyloid-β plaques, and Parkinson's Disease, which involves α-synuclein aggregates. Conversely, systemic amyloidoses, such as AL amyloidosis (derived from immunoglobulin light chains) and ATTR amyloidosis (linked to misfolded transthyretin), can lead to multi-organ failure by affecting critical tissues like the heart and kidneys. Additionally, amyloid pathology extends to metabolic disorders; in Type 2 Diabetes, the hormone amylin (IAPP) aggregates within pancreatic islets, contributing significantly to β-cell destruction.

Alternate Names for Amyloid

PIG 4; PIG4; SAA 1; SAA 2; SAA; SAA_HUMAN; SAA1; SAA2; Serum amyloid A protein precursor; Serum amyloid A1 isoform 1; Serum amyloid A1 isoform 2; Amyloid fibril protein AA; Amyloid protein A; TP53I4; MGC111216; Tumor protein p53 inducible protein 4

• 1. Chiti F, et al. Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. Annu Rev Biochem. 2017 Jun 20;86:27-68.
  2. Akbey ü, et al. Functional amyloids from bacterial biofilms - structural properties and interaction partners. Chem Sci. 2022 May 6;13(22):6457-6477.