Chemistry Reference
In-Depth Information
FIGURE 21.1
Estimated rates of occurrence of Alzheimer's disease in the general population in Western societies.
(Source WHO regional
Office for southeast Asia.)
The 'metal-based neurodegeneration hypothesis' can be described by the following postulates:
1.
Redox-active metal ions (Fe, Cu), present within specific brain regions, can generate oxidative stress by
production of reactive oxygen and nitrogen species (ROS, RNS).
2.
ROS then cause peroxidation of polyunsaturated fatty acids in membrane phospholipids.
3.
This in turn leads to the formation of reactive aldehydes, such as 4-hydroxynonenal.
4.
The reactive aldehydes, together with other oxidative processes, interact with proteins to generate carbonyl
functions, which damages the proteins, which also undergo modification by reaction with RNS.
5.
The damaged, misfolded proteins aggregate, and overwhelm the ubiquitin/proteasome protein degradation
system
6.
These aggregated, ubiquinated proteins then accumulate within intracellular inclusion bodies (
Figure 21.2
)
.
7.
Such intracellular inclusion bodies are found in a great many neurodegenerative diseases.
Although both ROS and RNS are involved in physiologically relevant, and important intracellular signalling
pathways, there is considerable evidence that in particular situations of oxidative stress, they are associated with
a number of neurodegenerative pathologies. Oxidative stress refers to a situation where elevated levels of ROS are
observed, and can result from a variety of conditions that represents either increased ROS production or
a decreased level of antioxidant defence. In the case of stimulation of ROS production by macrophages during the
innate immune response to bacterial infection, the ROS so generated act in a protective manner. However, dys-
regulation of ROS levels in a variety of tissues, notably in the brain, has been linked to a growing number of
inflammatory and age-associated diseases. During oxidative stress, the oxidation of cellular components results in
the modification of DNA, proteins, lipids, and carbohydrates, and the resulting oxidative damage is frequently
associated with cell death either by necrosis or by apoptosis (
Figure 21.3
)
.
As was pointed in Chapter 13, the most reactive of the ROS is the OH radical generated from H
2
O
2
and Fe
2
þ
by
the Fenton reaction. While ROS play an important role in signal transduction and gene expression, through the
activation of nuclear transcription factors, there are some cells in the body which use the cytotoxicity of ROS to
attack and kill invading microorganisms. When macrophages and neutrophils encounter a bacterium or other
foreign particles, they ingest it and internalise it within an intracellular compartment known as a phagosome. The
multicomponent enzyme, NADPH oxidase, is then assembled within the membrane of the phagosome. This
enzyme then generates superoxide inside the phagosome, which undergoes dismutation to hydrogen peroxide, and
leads to Fe
2
þ
-catalysed hydroxyl radical formation. Reactive nitrogen species (RNS) also play an important role
as messengers in cells. The first to be discovered, nitric oxide (NO
$
), is produced by the enzyme nitric oxide
