Protein Aggregation Diseases: Toxicity of Soluble Prefibrillar Aggregates and Their Clinical Significance - Protein Misfolding and Cellular Stress in Disease and Aging - page 28

studies on Ab peptide aggregation and Ab aggregate neurotoxicity
(reviewed in ( 47 )). The idea that neuronal cells do really produce
Ab oligomers and that the latter are responsible for neuronal
impairment was first proposed over 10 years ago by the William
Klein group ( 8 ). However, one of the first evidences that Ab oli-
gomers are really produced in cultured neuronal cells impairing
cell physiology and viability was provided in 2002 by the Dennis
Selkoe group working on rat hippocampal cells overexpressing
the V717F mutant of APP ( 10 ). The Selkoe results have been
subsequently confirmed by many studies, progressively leading to
assess the nature of those Ab oligomers as spherical trimer-hexamer
to 24mer aggregates (ADDLs, amylospheroids) ( 8, 48-50 ), their
presence inside AD brains ( 51, 52 ), their formation within neu-
ronal cells ( 53-55 ), their involvement in physical degeneration of
synapses ( 56 ) and their ability to impair memory and cognitive
function ( 48, 52 ).
The idea that pre-fibrillar aggregates are the most highly toxic
species leads to consider mature fibrils as inert, harmless deposits
of the toxic precursors and hence their growth could be inter-
preted as a cell defense mechanism; it can also explain the lack of
direct correlation between density of fibrillar plaques in the brains
of Alzheimer's disease patients and the severity of their clinical
symptoms ( 57 ). However, in spite of the growing information on
the effects of amyloids on cell biochemical and functional fea-
tures, a unifying model for protein aggregation and aggregate
damage under physiological conditions has not yet been proposed
for all forms of amyloidoses; moreover, for many of these, no
information is currently available on either the identity of the
supramolecular assemblies responsible for tissue damage or the
molecular mechanism(s) of cell impairment.
A nice confirmation of the role of Ab oligomers in synapto-
toxicity has came very recently from a high resolution array
tomography study. The authors imaged a sharp reduction of den-
dritic spine density in neuronal cells surrounded by amyloid
plaques in tissue slices from AD transgenic mice and demonstrated
that such a reduction depended strictly on the gradient of Ab oli-
gomers irradiating from the plaques, strongly suggesting that the
latter can be a source of the toxic species ( 58 ). This study high-
lights the importance of amyloid fibrils in amyloid synaptotoxicity
not directly but, rather, as providers of toxic species. It also sup-
ports other considerations; in fact, recent evidence suggests that
amyloid fibrils exhibit molecular recycling with dissociation and
re-association of the monomeric and, possibly, oligomeric com-
ponents ( 59 ). In addition, fibrils of the same monomer arising
under different conditions can differ in stability and hence in
resistance against breakage ( 60 ), a process of possible importance
in fibril proliferation. Actually, a frequent breakage of the fibrils
results in increased free ends favouring not only further protein