Biomedical Engineering Reference
In-Depth Information
responsible for ion homeostasis impairment in the exposed cells.
In fact, modifications of membrane permeability can occur in cells
exposed to misfolded monomers or their pre-fibrillar aggregates
with no pore-like appearance. In general, it is believed that the
interaction of the aggregates or their precursors with the cell
membranes is, by itself, able to destabilize the phospholipid
bilayer creating disordered areas allowing reduction or destruc-
tion of the ion gradients (
37, 74, 75
). The pore-or-oligomer tox-
icity dilemma can be overcome in the light of a recent study
showing that homogeneous populations of preformed annular
Ab and a-synuclein protofibrils are stable and do not permeabi-
lize phospholipid bilayers at variance with similar assemblies
grown from pre-fibrillar oligomers on the bilayer surface (
44
). It
could well be that often oligomer toxicity is mediated by their
assembly into pores at the membrane surface, similarly to what
happens with bacterial pore-forming toxins (
44
). These findings
also support the idea that annular protofibrils are off-pathway
intermediates of fibril growth and that the toxicity of amyloid
assemblies is related to their relative stabilities.
The intra- or extracellular presence of toxic aggregates can
impair a number of cell functions eventually leading to cell death
by apoptosis or necrosis (
81-83
). However, in most cases initial
alterations of fundamental cellular processes associated with mem-
brane perturbation appear to underlie subsequent cell impairment.
Increasing information points to a central role of early alterations
of the intracellular redox state and free Ca
2+
levels (see below)
following membrane permeabilization by toxic aggregates. Yet,
other causes have been proposed that are not necessarily alterna-
tive to the Ca
2+
/ROS dyshomeostasis; these include transcriptional
derangement in poly(Q) extension diseases, microtubular trans-
port alterations in poly(Q), SOD, AD and tauopathies, excitotox-
icity through deregulation of the NMDA or AMPA receptors,
and the cytotoxic effect of pro-inflammatory factors secreted by
microglia in AD (
81, 85-88
).
In general, cells exposed to toxic amyloids display a remark-
able increase in the levels of reactive oxygen and nitrogen species
(ROS, RNS); the modification of the intracellular redox state can
result in overstimulation of excitatory glutamate receptors (
89
),
lipid peroxidation, deregulation of NO metabolism, protein
nitrosylation, and up-regulation of heme oxygenase-1 (
90
). The
key role performed by the oxidative stress in amyloid aggregate
cytotoxicity is supported by many experimental data and by
the protection provided to exposed cells by antioxidants such
as tocopherol, lipoic acid, or reduced glutathione (
46, 91
). This
is also supported by data from prion-infected mice showing
that increased free radical production with reduced efficacy of
the anti-oxidant defenses in the mitochondria results in brain
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