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