Unfolding the Future - The Functional Fold: Amyloid Structures in Nature - page 163

often incurable diseases called the Amyloidoses, which include
Alzheimer's, Parkinson's, and glaucoma amongst others. These
diseases have come under increasingly intense scrutiny in
recent years due to the devastating effect they can reap on aging
populations. The detrimental effects of amyloid in the human body
would appear to take two forms, in one case the volume occupied
and mechanical stiffness associated with a high density of amyloid
fibrils in tissue, and in the other case the toxic effects on cells of
precursor oligomers, which occur on the kinetic pathway from
monomer to fibril. With regard to the latter association with disease
it has even been proposed that benefit can be derived from the
formation of amyloid fibrils because they sequester toxic oligomers
of the amyloid protein.

14
With the recent emergence of functional amyloid in the human
body (Chapter 9) it is hoped that there may be enlightening
information to be extracted from this and other forms of functional
amyloid that can be utilized in studies towards the prevention
of amyloid associated with disease. It is apparent that functional
amyloid within the human body must be highly regulated to prevent
the toxicity usually associated with amyloid formation. In the case
of the functional amyloid in skin pigmentation it has been proposed
that the rapidity of amyloidogenesis

6

could circumvent the toxicity
associated with the intermediate oligomeric stage.

15

Some functional hormone amyloids were actually found to
be moderately toxic to neuronal cells;

9

they are
encapsulated in lipid membrane which is anticipated to significantly
decrease their toxicity. This raises the question as to whether the
interaction of the functional hormone amyloids with lipid membrane
occurs specifically with an as of yet unidentified granule-recruiting
membrane protein or whether the attraction occurs spontaneously.
In either case it seems plausible that the mediation of this lipid in
any subsequent cell-amyloid interaction could serve the purpose of
decreasing toxicity. The interactions of amyloid at the membrane-
fluid interface could thus play a central role in determining
amyloid function or provide a pathogenic mechanism. Membrane
composition varies greatly between the many organisms which
utilize functional amyloid and the cholesterol rich regions of the
human body most closely connected with amyloid-based diseases
such as the brain and associated neurodegenerative diseases, such
as Alzheimer's and Parkinson's.

however, in vivo