Proteins fold into energetically-favorable structures, with their hydrophobic amino acids on the inside and their charged and polar amino acids on the outside. Some proteins fold easily on their own but many are guided to fold correctly by proteins called chaperones.

Sometimes proteins fold into incorrect shapes, often referred to as misfolded proteins, which are degraded by the proteasome.

Inadequate cellular oversight, such as non-functioning chaperones or proteasomes due to aging or disease, can cause proteins to stay in abnormal shapes.

Mutations can cause protein misfolding if the original protein shape becomes less favorable.

Extrinsic factors, such as physical or chemical changes in the cytoplasm, force properly-folded proteins into new structures, suitable for the new environment. 

Whatever the mechanism, misfolding can expose short, hydrophobic segments of a protein causing it to become insoluble in water. Some of these hydrophobic segments that normally fold into alpha-helices can assemble into beta-sheets.

Hundreds of beta-sheets in identical misfolded proteins form hydrogen bonds and stack to form long filaments.  Two closely-packed stacks of beta-sheets associate to form a cross-beta filament.

In this structure, individual beta-sheets lie perpendicular to the central axis. These filaments can aggregate to form amyloid fibrils. 

Accumulation of amyloid fibrils has been observed in certain neurodegenerative conditions, such as in Alzheimer's and Parkinson's diseases. Prion diseases, such as Creutzfeldt-Jacob disease in humans and Bovine spongiform encephalopathy, commonly known as mad cow disease, also involve the formation of amyloid fibrils.

One particular prion protein, PrP, is a neural membrane protein. Misfolded PrPs can convert normal PrPs into abnormal shapes. All PrPs eventually assume the aberrant structure. 

The misfolded PrPs contain beta-sheets, and thus tend to aggregate and form amyloid fibrils. This transmissible form of amyloid formation is associated with fatal neurodegeneration.

However, not all amyloid fibrils are harmful. Some bacteria use amyloid fibrils on their surfaces to create protective biofilms. Moreover, eukaryotes build reversible amyloid fibrils to pack and store secretory proteins until the cell needs to release them. 

Understanding these reversible amyloids can help us develop treatments for irreversible amyloid aggregates.