Gambi_Layout 1 27/10/2009 17:39 Page 22
Neurodegenerative Diseases Alzheimer’s Disease
A Pathophysiological Role for Selective Alteration of the
Cytokine–Chemokine Network – Inflammatory Theory in Alzheimer’s Disease
Domenico Gambi
1
and Marcella Reale
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: 16 April 2009 Accepted: 27 August 2009
Correspondence: Marcella Reale, 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 Qin et al. showed that the entry of pro-inflammatory factors such as
worldwide affects 20–30 million individuals over 60 years of age. In tumour necrosis factor-α (TNF-α) to the brain induced the activation
1907 Alois Alzheimer first described AD following an autopsy on the of microglia and subsequent production of more inflammatory
brain of a 55-year-old women who had died following progressive factors, which may then cause neuronal death.
6
This has clinical
mental deterioration, increasing confusion and memory loss. implications and, additionally, provides a link between peripheral
inflammation and neuroinflammation. Support of the hypothesis
Researchers from the Epidemiology and Prevention of Dementia that peripheral inflammation may amplify the neuroinflammation,
group (EURODEM) have estimated that the prevalence increases contributing to AD pathogenesis, and that its inhibition may slow the
from ~2% in the 65–69-year-old population to ~22% of those 85–89 disease progression can be argued from epidemiological findings
years of age.
1
Independent of the aetiological agents, on a indicating that prior long-term non-steroidal anti-inflammatory drugs
histopathological level AD is characterised by extracellular (NSAIDs) are associated with a low risk of developing AD.
7
Increased
deposition of amyloid β (Aβ) protein in senile plaques and levels of interleukin (IL)-1, IL-6 and TNF-α have been found both in
intraneuronal accumulation of paired helical filaments (PHFs) in autopsy specimens and in the peripheral blood of patients with AD.
8,9
neurofibrillary tangles, dystrophic neurites and neuropil threads. IL-6 has been implicated in the transformation of diffuse neuritic
There is growing evidence that altered metabolism of the plaques in the AD brain. IL-1 has also been linked to amyloid plaque
Aβ precursor protein (APP) with progressive deposition of its Aβ transition from the diffuse to the dense core stage and the
fragment is a crucial event in the pathogenesis of AD.
2
The fibrillar propagation of the inflammatory signal.
Aβ can bind the complement factor C1 and activate the classic
complement pathway. The activated complement products play a key Transforming growth factor-β1 (TGF-β1) has been shown to
role in the recruitment and activation of microglia at the sites of promote Aβ deposition in transgenic mouse models and therefore
fibrillar Aβ deposits.
3
In turn, this activated microglia produces may exacerbate the amyloidogenic pathology. However, TGF-β1 may
multiple pro-inflammatory cytokines, chemokines and reactive also have non-inflammatory functions and may play an important
oxygen species that can ultimately influence plaque and tangle role in the growth and survival of neurons in the AD brain. The
formation and can lead to neuronal damage.
4
Additionally, Aβ itself expression of the cytokine TNF-α is decreased in the frontal cortex,
can stimulate microglia, astrocytes and oligodendrocytes to secrete superior temporal gyrus and entorhinal cortex of AD patients
pro-inflammatory cytokines, chemokines and reactive oxygen compared with non-AD controls, and has both protective and
species (ROS), which can lead to neuronal damage.
5
destructive functions.
22 © TOUCH BRIEFINGS 2009