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Neurodegenerative Diseases Alzheimer’s Disease
inflammatory functions and may play an important role in the growth and may delay the onset and slow the progression of the disease. The role
survival of neurons in the AD brain. The expression of the cytokine of peripheral inflammation in AD is not yet fully elucidated and remains
TNF-α is decreased in the frontal cortex, superior temporal gyrus and controversial. Thus, one hypothesis is that inflammation starts in the
entorhinal cortex of AD patients compared with non-AD controls, and CNS; a second hypothesis is that inflammation first develops in the
has both protective and destructive functions. periphery, as a result of different causes, and then contributes to brain
damage and, finally, neurodegeneration.
17
Cytokines and Chemokines in the
Alzheimer’s Disease Brain In the serum and cerebrospinal fluid (CSF) of AD patients, the
It is known that the central nervous system (CNS) has an endogenous upregulation of IL-1, IL-6, and TNF-α has been described. Chemokines
immune system in which the classic signs of inflammation such as and nitric oxide are also increased in the same clinical patterns, while
redness, swelling, heat, and pain are absent. The microglial cells, the IL-4, a modulatory cytokine, has shown a parallel downregulation.
morphological ‘delegates’ of the immune system in the brain, play a
The identification of reciprocal interactions between the brain and the
peripheral immune system permits comparison of the functions of
The activation of the peripheral
the two different districts.
18
An important finding was that cytokines
and chemokines, as well as their receptors, are endogenous to both
immune system may be both a
the brain and the immune system. These findings lead to the view that
cause and a consequence of the
the immune system and brain speak a common biochemical
language. There are both morphological and humoral pathways for
pathogenetic process of dementia,
bi-directional communication between the two systems.
19
with a self-enhancing cascade.
One mechanism by which blood-borne cytokines might affect the
functions of brain regions is by crossing the BBB for direct interaction with
significant role in the endogenous immune response. Post mortem the central nervous system tissue. A saturable transport system from the
investigations cannot easily address the inflammatory hypothesis of AD, blood to the central nervous system has been described for IL-1α, IL-1β,
in particular the question of whether inflammation is an early interleukin-1 receptor antagonist, IL-6, and TNF-α.
20
In the past decade it
component in the pathogenesis of the disease or a common final step has been demonstrated that abnormalities in both humoral and cellular
of the neurodegenerative process in AD.
10,11
immune response are supported in AD, suggesting a faulty immune
regulation in this pathological pattern. Th1 responses are increased while
Recent evidence suggests that bidirectional communication occurs Th2 activity is attenuated in AD patients, and MCP-1 is involved in the
between cells of the nervous and immune systems. The aberrant induction of polarized type Th2 responses and in the enhancement of
regulation of one system by the cells and products of the other may be IL-4 production. A possible feedback loop for Th2 activation would be the
responsible for the development of pathological conditions. After production of IL-4 and IL-13 by Th2, which stimulates MCP-1 production
activation, microglia secrete pro-inflammatory cytokines and and leads to further recruitment of Th2 cells. The impaired Th1/Th2
chemokines, followed by ROS and complement protein.
12
The function of peripheral release of cytokines could characterise the pathological state
all of these molecules is diverse, and likely regulates the intensity and of lymphocytes in AD patients.
21
duration of an inflammatory response and plays an important role in
orchestrating the behavior of immune cells that can cross the blood–brain Recent evidence suggest that systemic inflammation can induce behavioral
barrier (BBB) via their secretion of both cytokines and chemokines.
13
In changes and may induce local inflammation in the diseased brain, leading
fact, the interactions between activated T cells and microglia induce the to exaggerated synthesis of inflammatory mediators in the brain.
production of inflammatory cytokines. In the brain, IL-1 induces IL-6 and Inflammatory mediators pass from the blood to the brain via macrophage
macrophage colony-stimulating factor (M-CSF) production in astrocytes populations associated with the brain, the perivascular macrophages, and
and enhances neuronal acetylcholinesterase activity, microglial microglia. Such interactions suggest that a systemic challenge that
activation, and additional IL-1 production. IL-6 activates microglia and promotes a systemic inflammatory response may contribute to the
promotes astrogliosis. In addition to the upregulation of interleukins, an outcome or progression of a chronic neurodegenerative disease.
22
association of AD with several polymorphisms of pro-inflammatory genes,
such as IL-1, TNF-α, and IL-6, has been described.
14–16
Intracerebral The activation of the peripheral immune system may be both a cause
production of anti-inflammatory cytokines such as IL-1 receptor and a consequence of the pathogenetic process of dementia, with a self-
antagonist, IL-4, and IL-10 are consistent with induction of homeostatic enhancing cascade. This cascade includes Aβ deposit formation that
mechanisms in neuroinflammation. leads to local inflammation within the brain, resulting in the activation of
the peripheral immune system that leads to increased Aβ deposit
Peripheral Cytokines and Chemokines in formation. Recently, we have used an experimental model based on in
Alzheimer’s Disease vitro analysis of total peripheral mononuclear cells that may represent
The evidence that a systemic inflammatory reaction may contribute to the whole response among different immune cells. The results have
the pathogenesis of AD is supported by many epidemiological data, by shown that in AD there is an imbalance of cytokine and chemokine
in vitro studies, and by the hypothesis that anti-inflammatory agents expression and production that is not restricted to the brain, but also
16 US NEUROLOGY
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