Alzheimer’s disease (AD) is an age-related, progressive degenerative dis-order that is characterized by synapse and neuron loss in the brain and the
accumulation of protein-containing deposits (referred to as ‘senile plaques’)
and neurofibrillary tangles. Insoluble amyloid b-peptide (Ab) fibrillar
aggregates found in extracellular plaques have long been thought to cause
the neurodegenerative cascades of AD.
It is assumed that protein fibrils manifested in amyloidosis result from an
aggregation reaction involving small misfolded protein sequences being
in an ‘oligomeric’ or ‘prefibrillar’ state. This review covers recent optical
spectroscopic studies of amyloid protein misfolding, oligomerization and
amyloid fibril growth.
Prions are infectious proteins, in which self-propagating amyloid conforma-tions of proteins are transmitted. The budding yeast Saccharomyces cerevi-siae, one of the best-studied model eukaryotes, also has prions, and thus
provides a tractable model system with which to understand the mechanisms
of prion phenomena.
The accumulation of misfolded proteins in the cytosol and nucleus of
neuronal cells leads to neurodegenerative disorders. Polyglutamine diseases
are caused by polyglutamine-expanded proteins, whereas mutations in
superoxide dismutase 1 lead to amyotrophic lateral sclerosis.
A great deal must still be learnt on the structural features of amyloid
assemblies, particularly prefibrillar aggregates, and the relationship of the
latter with amyloid cytotoxicity. Presently, it is recognized that the popula-tion of unstable, heterogeneous amyloid oligomers and protofibrils is
mainly responsible for amyloid cytotoxicity.
The formation and structure of proinsulin C-peptide oligomers has been
investigated by PAGE, NMR spectroscopy and dynamic light scattering.
The results obtained show that C-peptide forms oligomers of different
sizes, and that their formation and size distribution is altered by salt and
divalent metal ions, which indicates that the aggregation process is medi-ated by electrostatic interactions.
Alzheimer’s disease (AD) is a neurological disorder characterized by the
presence of amyloidb(Ab) peptide fibrils and oligomers in the brain. It
has been suggested that soluble Ab oligomers, rather than Ab fibrils,
contribute to neurodegeneration and dementia due to their higher level of
Amyloid protein (Ab1–40) aggregation and conformation
was examined using native and sodium dodecyl sulfate/
polyacrylamide gel electrophoresis,and the results com-pared with those obtained by atomic force microscopy,
and with Congo red binding,sedimentation and turbidity
assays. The amount of Ab aggregation measured was
different,depending upon the method used. Incubation
for 15 min at pH 5.0 or in the presence of Fe
did not alter the level of Aboligomers observed on
SDS and native gels....
Protein aggregation is central to most neurodegenerative diseases, as shown
by familial case studies and by animal models. A modified ‘amyloid cas-cade’ hypothesis for Alzheimer’s disease states that prefibrillar oligomers,
also called amyloid-b-derived diffusible ligands or globular oligomers, are
the responsible toxic agent. It has been proposed that these oligomeric spe-cies, as shown for amyloid-b, b2
-microglobulin or prion fragments, exert
toxicity by forming pores in membranes, initiating a cascade of detrimental
events for the cell. ...