Protein Aggregation Diseases: Toxicity of Soluble Prefibrillar Aggregates and Their Clinical Significance - Protein Misfolding and Cellular Stress in Disease and Aging - page 29

misfolding but also binding of incoming misfolded monomers, in
competition with their oligomerization into toxic assemblies.
Accordingly, fibril stability can affect the rate of progression of
systemic amyloidoses and the transmission of specific prion strains
( 60 ). Finally, it has also been reported that Ab fibrils grown
in vitro can disassemble into oligomers or protofibrils upon inter-
action with membranes ( 61 ). Taken together, these data support
the idea that amyloid fibrils, though in general harmless by them-
selves, can be a source of toxic oligomers; such a behaviour can
depend on the type and stability of the fibrils and hence on their
growth conditions, as well as on the environment where they are
settled. Even though more information on a wider population of
fibrils grown from a variety of peptides and proteins is needed to
explore the generality of these considerations, as a whole they can
provide additional clues to explain the above mentioned lack of
relation between amyloid load and severity of the clinical symp-
toms in AD ( 57 ).
The increasing knowledge supporting the cytotoxicity of
early aggregates of peptides and proteins either associated or not
associated with amyloid disease supports the idea that any amy-
loid aggregate in its pre-fibrillar organization can be intrinsically
toxic to living cells ( 33, 34 ). Moreover, it further implies that
amyloid cytotoxicity arises from shared characteristics of the
supramolecular structure of the aggregates rather than from any
specific feature of the amino acid sequences of their parent soluble
polypeptides. This concept appears in contrast to the properties
of functional proteins, whose native structures and biological func-
tions are specifically determined by their amino acid sequences.
Actually, such a remarkable result arises from the conclusion
discussed above that the structure, and hence the properties, of
conformational species other than the native state of a protein
are not directly determined by the specific interactions among
side-chains. Several reports indicate that similar aggregates of
different peptides and proteins elicit comparable biochemical
modifications in the same exposed cells, thus supporting the idea
that the cytotoxicity of amyloids grown from different peptides
and proteins relies on shared structural features of the amyloid
assemblies ( 37, 62 ).
Overall, the above considerations led to conclude that any
future design of therapeutic interventions against the differing
amyloid diseases should be primarily targeted at avoiding the
appearance of early aggregates; such a goal can be accomplished
either directly or by reducing the load of misfolded molecules
populated at equilibrium. In this view, hindering the formation of
mature fibrils without reducing protein misfolding or increasing
the efficiency of the mechanisms aimed at clearing misfolded
proteins and their oligomeric assemblies could be detrimental
rather than beneficial.