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The neurodegenerative inflammatory age-related disease, Alzheimer's disease (AD), is the most common cause of dementia in the elderly. It is a progressive neurological disease that results in the irreversible loss of neurons, particularly in the cortex and hippocampus. The pathological hallmarks are neuronal loss, extracellular senile plaques containing the peptide amyloid-beta (Ap) and neurofibrillary tangles; the latter are composed of a hyperphosphorylated form of the microtubular protein tau. Amyloid in senile plaques is the product of cleavage of a much larger protein, the P-amyloid precursor protein, by a series of proteases, the a-,P-,y-secretases. The y-secretase, in particular, appears to be responsible for generating the AP42 peptide, that is 42 amino acids in length and has pathogenetic importance, because it can form insoluble toxic fibrils and accumulates in the senile plaques of AD brains.70-72

Inflammation clearly occurs in pathologically vulnerable regions of the AD brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition ofhighly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble AP42 peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Senile plaques in AD brains are associated with reactive astrocytes and activated mi-croglial cells and cytokines and acute phase proteins are overexpressed in microglia and astro-cytes surrounding neuropathological lesions in AD brains. There is accumulating evidence that Ap peptide may promote or exacerbate inflammation by inducing glial cells to release immune mediators (Table 1). Moreover, microglial and astroglial cells surrounding mature plaques in AD brains have been found to express activation markers.73-76 The role of inflammation is further emphasized by a number of clinical studies demonstrating that the long-term use of nonsteroidal anti-inflammatory drugs may protect against AD.77 Enriched populations of human microglial cells isolated from mixed cell cultures prepared from embryonic human telen-cephalon tissues are able to express constitutively mRNA transcripts for cytokines and

Table 1. Markers of inflammation in the brain of patients with neuropathological diagnosis of AD

Acute Phase Proteins

Cytokines

Complement Proteins a-1-antichymotripsin IL-1

a-1-antitrypsin IL-6

a-2-macroglobulin TNF-a

C-reactive protein TGF-p1

Serum amyloid substance P IL-10

Amyloid precursor protein Chemokines

Complement activation products Membrane attack complex C1 inhibitor CD59 Clusterin Vitronectin chemokines and treatment with pro-inflammatory stimuli as lipopolysaccharide or Ap peptide led to increased expression of mRNA levels of these inflammatory molecules.

However, glial cells are also capable of producing anti-inflammatory cytokines including IL-10 and transforming growth factor (TGF)-P and balance among pro- and anti-inflammatory events may be a crucial point for development of an overt AD.79,

IL-10 is synthesized in the central nervous system (CNS) and may act to limit inflammatory responses that occur during microbial infections and immune-inflammatory diseases, including stroke and multiple sclerosis. In fact, expression of IL-10 is elevated during the course of most major diseases in the CNS promoting survival of neurons and glial cells, expressing cell survival signals and limiting inflammation in the brain. In the CNS, the anti-inflammatory mechanism of IL-10 may follow three major pathways, i.e., reducing synthesis of pro-inflammatory cytokines, suppressing cytokine receptor expression, and inhibiting receptor activation.81

Data obtained using transgenic mice that develop Ap plaques in neocortex and hippocampus of the aged brain may represent an useful tool to study such regulatory mechanisms. The Ap-induced glial responses observed in these mice were similar to those described in AD brains. Activated microglia was localized in and around plaques only, while reactive astrocytes were found in close proximity to both fibrillary and diffuse Ap deposits. The number of IL-10-positive glial cells around Ap peptide plaques seems to be increased with age indicating the development of anti-inflammatory mechanisms.82,83

Following corticectomy, local application of IL-10 has been found to decrease microglia activation and TNF-a production, while in vitro IL-10 has been shown to inhibit microglial synthesis of pro-inflammatory cytokines IL-1, IL-6 and TNF-a.81,84-86

It is more than a decade that genes responsible for familial AD have been identified. Thus, a major challenge is to identify possible genetic factors involved in the most common form of the disease, the sporadic one occurring late in life.72,7?,87,88 The most important genetic factor identified in sporadic AD is the allele e4 of apolipoprotein E (ApoE). In fact, the APOE e4 allele increases and the APOE e2 allele decreases the risk of AD.70,88 A number of associations of the disease with variant of genes other than ApoE have also been reported but remain to be confirmed and are the subject of ongoing research.70 However, a large number of studies has shown a significant association between the presence of polymorphisms linked to a high production of pro-inflammatory cytokines IL-1, IL-6 and TNF-a and acute phase proteins and the development of AD. In most studies the association between AD and polymorphisms has been shown evident (or more evident) in APOE e4 allele noncarrier or carrierpatients, suggesting a complex interaction between the genes under study and ApoE.4,5,72,74,75,87-92

These findings suggest that a genetic background leading for an excessive inflammation response may play a central role in the induction of degenerative lesions in the brain of AD patients. So, control of pro-inflammatory cytokines production may be a key mechanism in controlling and delaying disease onset. Whole blood samples from AD and controls were stimulated ex vivo with endotoxin under standard conditions and cytokine levels assessed. Patients with AD had seven- to ten-fold higher IL-1 ß production relative to the amount of IL-10. These data suggest that an absolute (or relative) reduced production of Il-10 may contribute to the development of AD.93

Recently, we have demonstrated an association between SNPs located at position —1082, -819 and —592 of the promoter region of IL-10 gene and AD. Our data demonstrate a significant increase of percentage of —1082A carrier subjects among AD patients and that this increase is mainly due to increase of the frequency at IL-10 promoter of ATA haplotype, associated to a low production of IL-10.22 So, our data strongly suggest that a genetically determined low IL-10 production may be implied in the AD susceptibility. Our findings have been recently confirmed in a study on a large cohort of North-European patients affected by AD.94 In fact, the authors published only a not-significant trend for the association between -1082A allele and AD, but a statistical analysis of their published data allows to find a strong statistically significant increase of homozygous -1082A genotype frequency in AD patient group.

The overall chance of a subject to develop AD might be profoundly affected by a "susceptibility profile" reflecting the combined influence of inheriting multiple high-risk alleles.89 IL-1 has been claimed as a key molecule in AD pathogenesis90 based on findings of an IL-1 overexpression in AD brain that is directly related to plaque progression and tangle formation, and on findings that IL-1 induces excessive synthesis, translation, and processing of neuronal amyloid precursor protein as well as synthesis of most known plaque-associated proteins. In addition, IL-1 activates astrocytes, with the important consequence of overexpression of the neuritogenic cytokine S100ß and overgrowth of dystrophic neurites in neuritic plaques. As further evidence of the importance of IL-1 in AD, several genetic studies have demonstrated that gene polymorphisms of IL-1a and IL-1 ß are associated with increased risk of AD and influence the age at onset of the disease.4,5,74,90 In Figure 2, we suggest how IL-10 can be able to counterbalance this pro-inflammatory effect of IL-1 (and of the other pro-inflammatory cytokines).

Multiple functional relationships may link these molecules and their genes influencing different but converging mechanisms involved in degeneration of the CNS might suggest novel therapeutic approach for AD.

As above reported, the deposit of Aß peptide, derived from the proteolysis of the amyloid precursor protein (APP), as deposits in senile plaques is a pathological hallmark of AD.7 In a seminal report, Schenk et al95 demonstrated that immunization of transgenic PDAPP mice with Aß led to the production ofAß antibodies and a decrease of amyloid plaque pathology. In subsequent studies, cognitive improvement was documented in experimental animals following immunization.71 High titres of IgG anti-Aß were found in immunized animals and small amounts of these antibodies crossed the blood/brain barrier. This observation, along with additional ex vivo evidence, led to one proposed mechanism for Aß42 immunization-induced reduction of Aß plaques whereby anti-Aß IgG enter the brain and opsonize Aß, thereby promoting microglia-mediated phagocytosis and clearance of Aß.95,96 A better understanding of the nature of the T helper response after Aß immunization might allow for additional therapeutic targets and/or optimisation of immunization to provide greatest therapeutic benefit. In an experimental model98 after stimulation with mitogen, primary splenocyte cultures from mice repeatedly immunized with Aß secreted less interferon(IFN)-y and IL-12, and more IL-4 and IL-10 and immunized mice showed reduced type 1 (IFN-y) and increased type 2 (IL-10) levels in blood.

These findings have implications for the use ofAß immunization as a therapy for AD. It has recently been shown that Aß immunization of mice with appreciable preexisting Aß deposits did not result in significant plaque clearance as opposed to a prophylactic regimen where mice received Aß vaccination prior to amyloid deposition.96

Apoe Inflammation

Figure 2. Schematic representation of the role of pro-inflammatory cytokines (esemplified by the key cytokine IL-1) and anti-inflammatory cytokine IL-10 on pathogenetic mechanisms of Alzheimer's disease. Astrocytes or microglial cells become activated upon contact with A|, which induces the production of inflammatory molecules. IL-1 overexpression in AD brain is directly related to excessive synthesis, translation, and processing of APP as well as synthesis of most known plaque-associated proteins. In addition, IL-1 activates astrocytes, with the important consequence of overexpression of the neuritogenic cytokine S100| and overgrowth of dystrophic neurites in neuritic plaques. The multiple inhibitory effects of IL-10 are shown.

Figure 2. Schematic representation of the role of pro-inflammatory cytokines (esemplified by the key cytokine IL-1) and anti-inflammatory cytokine IL-10 on pathogenetic mechanisms of Alzheimer's disease. Astrocytes or microglial cells become activated upon contact with A|, which induces the production of inflammatory molecules. IL-1 overexpression in AD brain is directly related to excessive synthesis, translation, and processing of APP as well as synthesis of most known plaque-associated proteins. In addition, IL-1 activates astrocytes, with the important consequence of overexpression of the neuritogenic cytokine S100| and overgrowth of dystrophic neurites in neuritic plaques. The multiple inhibitory effects of IL-10 are shown.

If A| deposition in transgenic mouse models of AD is representative of the clinical syndrome, the suggestion arises that patients with AD may be immunologically tolerant to A| vaccination, and that an A| "immune barrier" has to be overcome in order for this therapy to be effective.97 Perhaps supplementing the A| vaccine with type 2 cytokines or adjuvants known to suppress type 1 and/or evoke type 2 responses might enhance its therapeutic efficacy for AD, provided that other forms of the vaccine could be demonstrated to be safe in humans.

On the other hand, the blood/brain barrier might condition the effectiveness of this kind of approach. In a recent paper, it has been reported that IL-10 does not cross the intact barrier after intravenous peripheral delivery.98 Thus, peripheral IL-10 probably can serve as a CNS therapeutic only when the barrier is disrupted as in case of stroke but not in AD if not administered in a way or pharmacological presentation able to cross the formidable obstacle of blood/ brain barrier.

However, clinical trials on AD patients were started in 2001. Immunization with A|42 in its fibrillary form was less well tolerated by aged humans than by experimental animals. Side effects were noted during phase II of the trials, including an inflammatory reaction of the CNS in 15 of 360 vaccinated patients. These side effects were presumably due to excessive activation of the specific immune response against A|.71 So, these results have to taken into account in designing new trials.

Table 2. Potential point of attack for anti-inflammatory effect of IL-10 in atherosclerosis and AD

Atherosclerosis Alzheimer's Disease

Cells

Astrocytes

0

++

Myofibroblast

++

0

Macrophage (microglia)

+++

++

T-cell

++

?

Cytokines and Acute Phases

Mediators

CRP

+++

+

Complement proteins

+

+

Clotting factors

++

0

Cytokines: IL-1, IL-6 TNF-a

+++

+++

Cells or immune mediators: 0: absent; +: weak; ++: moderate; +++: extensive.

The inflammatory reaction may also play a role in the development of Parkinson's Disease (PD). By now there are only few and contrasting data on relationship among IL-10 production and PD development. In an animal model, two peaks of IL10 mRNA, immediately (6 h) and at the 3-day post N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induction of nigro-striatal dopamine neurodegeneration that might be linked to a protective effect of the cytokine were found.99 On the other hand, treatment with amantidine (a well known anti-PD therapy) of newly diagnosed patients seems do not affect IL-10 production by peripheral blood cells.100

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