Gambi_US_Cardiology_book_temp 25/09/2009 10:27 Page 15
Neurodegenerative Diseases Alzheimer’s Disease
A Pathophysiological Role for Selective Alteration of the
Cytokine–Chemokine Network—Inflammatory Theory in Alzheimer’s Disease
Domenico Gambi, PhD
1
and Marcella Reale, PhD
2
1. Full Professor, Neurology, and Chairman, Department of Oncology and Neuroscience; 2. Physician, Unit of Immunodiagnostics,
Department of Oncology and Neuroscience, University G D’Annunzio Chieti-Pescara
Abstract
There is growing evidence that an altered metabolism of the amyloid β (Aβ) precursor protein (APP) with progressive deposition of its Aβ
fragment is a crucial event in the pathogenesis of AD. Increasing evidence suggests that inflammation and alteration of the cytokine–chemokine
network contributes to the pathophysiology of AD. Activated microglia produce multiple pro-inflammatory cytokines, chemokines, and reactive
oxygen species (ROS); additionally, Aβ itself can stimulate microglia, astrocytes, and oligodendrocytes to secrete pro-inflammatory cytokines,
chemokines, and ROS, which can lead to neuronal damage. The concomitant release of pro-inflammatory cytokines, which influence
neurodegenerative pathways, and anti-inflammatory cytokines may contribute to the chronicity of the disease. It is the balance of pro-
inflammatory products and anti-inflammatory products that may be essential in the degenerative process. Influencing this balance may help in
slowing the disease. Promising results for neurological disease treatment may be achieved by targeting cytokines and chemokines in the
development of antagonists and synthesis inhibitors.
Keywords
Alzheimer’s disease, amyloid β, cytokines, chemokines, neuroinflammation, Parkinson’s disease
Disclosure: The authors have no conflicts of interest to declare.
Received: April 16, 2009 Accepted: August 27, 2009
Correspondence: Marcella Reale, PhD, Department of Oncology and Neurosciences, University G D’Annunzio Chieti-Pescara, Via dei Vestini, 66100 Chieti, Italy.
E: mreale@unich.it
Alzheimer’s disease (AD) is the most common form of dementia, and inflammatory cytokines, chemokines, and reactive oxygen species (ROS),
worldwide affects 20–30 million individuals over 60 years of age. In 1907 which can lead to neuronal damage.
5
Alois Alzheimer first described AD following an autopsy on the brain of
a 55-year-old women who had died following progressive mental Qin et al. showed that the entry of pro-inflammatory factors such as
deterioration, increasing confusion, and memory loss. tumor necrosis factor-α (TNF-α) to the brain induced the activation of
microglia and subsequent production of more inflammatory factors,
Researchers from the Epidemiology and Prevention of Dementia group which may then cause neuronal death.
6
This has clinical implications
(EURODEM) have estimated that the prevalence increases from ~2% in the and, additionally, provides a link between peripheral inflammation and
65–69-year-old population to ~22% of those 85–89 years of age.
1
neuroinflammation. Support of the hypothesis that peripheral
Independent of the etiological agents, on a histopathological level AD is inflammation may amplify the neuroinflammation, contributing to AD
characterized by extracellular deposition of amyloid β (Aβ) protein in senile pathogenesis, and that its inhibition may slow the disease progression
plaques and intraneuronal accumulation of paired helical filaments (PHFs) can be argued from epidemiological findings indicating that prior long-
in neurofibrillary tangles, dystrophic neurites, and neuropil threads. There term non-steroidal anti-inflammatory drugs (NSAIDs) are associated
is growing evidence that altered metabolism of the Aβ precursor protein with a low risk of developing AD.
7
Increased levels of interleukin (IL)-1,
(APP) with progressive deposition of its Aβ fragment is a crucial event in IL-6, and TNF-α have been found both in autopsy specimens and in
the pathogenesis of AD.
2
The fibrillar Aβ can bind the complement factor the peripheral blood of patients with AD.
8,9
IL-6 has been implicated
C1 and activate the classic complement pathway. The activated in the transformation of diffuse neuritic plaques in the AD brain. IL-1 has
complement products play a key role in the recruitment and activation also been linked to amyloid plaque transition from the diffuse to the
of microglia at the sites of fibrillar Aβ deposits.
3
In turn, this activated dense core stage and the propagation of the inflammatory signal.
microglia produces multiple pro-inflammatory cytokines, chemokines, and
reactive oxygen species that can ultimately influence plaque and tangle Transforming growth factor-β1 (TGF-β1) has been shown to promote Aβ
formation and can lead to neuronal damage.
4
Additionally, Aβ itself can deposition in transgenic mouse models and therefore may exacerbate
stimulate microglia, astrocytes, and oligodendrocytes to secrete pro- the amyloidogenic pathology. However, TGF-β1 may also have non-
© TOUCH BRIEFINGS 2009 15
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84