Biomedical Engineering Reference
In-Depth Information
damage (
92
). Furthermore, recent data point to direct effects of
ageing and oxidative stress on the activity and expression levels of
the proteasome in the nervous tissue (
93
). Actually, oxidative pro-
teasome inhibition or its engulfment with oxidised or otherwise
damaged or misfolded proteins can result in the accumulation of
the latter thus reinforcing the detrimental effects of ROS.
It has been suggested that, in cells exposed to amyloid aggre-
gates, intracellular ROS elevation can be an immediate conse-
quence of the intracellular Ca
2+
increase following non-specific
membrane permeabilization or the activation of glutamate-gated
calcium channels. Increased intracellular levels of free Ca
2+
can
stimulate the oxidative metabolism by activating the dehydroge-
nases of the citric acid cycle in order to provide the ATP needed
to the ion pumps to clear the excess Ca
2+
. The resulting oxidative
stress can increase free Ca
2+
levels by modifying the physico-
chemical (lipid peroxidation) and/or functional (ion pump inac-
tivation) features of the cell membrane (
94, 95
) with further
Ca
2+
increase in a self-reinforcing loop. Such a scenario can
explain the relationship between ROS, intracellular Ca
2+
increase,
mitochondrial damage and apoptosis described in cells exposed
to toxic amyloid aggregates (
95-97
). A similar chain of events
could also occur in the old age, where cells are more susceptible
to oxidative stress and their energy load is basically reduced.
Actually, many studies support a close link between Alzheimer's,
Parkinson's, and prion diseases and calcium homeostasis deregu-
lation. Recent data show that cells exposed to early aggregates of
proteins unrelated to amyloid disease display similarly increased
ROS and free Ca
2+
levels with an apoptotic or a necrotic out-
come (
34, 45, 46, 83
) further underscoring the generality of
these effects.
It is known that different cell types in tissue are variously
affected by amyloids; for instance, AD preferentially affects neu-
rons whereas glial cells remain intact, supporting the idea that
synaptic dysfunction can be at the basis of the disease (
98
). This
and other findings strengthen the need to investigate the bio-
chemical features underlying the different vulnerability of varying
cell types to the same toxic pre-fibrillar aggregates. A recent report
shows significant correlations between cell vulnerability, aggre-
gate interaction with the plasma membrane, cholesterol content,
total antioxidant capacity and basal Ca
2+
-ATPase activity in a panel
of cultured cells (
99
). These data support the importance of the
aggregate-cell membrane interaction and the subsequent early
modifications of free Ca
2+
and redox state in triggering the chain
of events culminating with cell death; they also highlight the
importance of the cell defences against any modification of the
free Ca
2+
and ROS levels provided by the interaction with toxic
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