Research reportSoluble interleukin-1 receptor type II levels are elevated in cerebrospinal fluid in Alzheimer's disease patients
Introduction
An increasing number of studies have shown that an inflammatory process is part of the Alzheimer's disease brain pathology. Thus, complement proteins [11]and acute phase proteins such as α1-antichymotrypsin and heparan sulphate proteoglycans 1, 35are expressed in the Alzheimer brain within or in close association with amyloid plaques. In addition, activated microglia producing proinflammatory cytokines such as interleukin-1α (IL-1α) and IL-1β, interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) have been found in areas surrounding the amyloid plaques 3, 10, 18, 29, 36.
The multipotent cytokines IL-1β, IL-6 and TNF-α are involved in the immune response, but they also exert several effects in the nervous system. In vitro studies show that IL-6 may promote survival of cholinergic neurons [19], and that IL-1β and TNF-α may inhibit long-term potentiation 22, 30. TNF-α is involved in the mechanisms of cachexia, a symptom that is common in the later stages of Alzheimer's disease. Of further interest with regard to Alzheimer's disease, are the reports on the regulation of β-amyloid precursor protein (APP) by cytokines [17]. Thus, both IL-1β 9, 13and IL-6 [9]stimulate neuronal APP mRNA synthesis. Furthermore, different molecular forms of β-amyloid peptide—a cleavage product of APP and a major component in amyloid plaques in Alzheimer's disease—have been reported to stimulate IL-1β [2], IL-6 [9]and TNF-α production 16, 25. Interestingly, β-amyloid25–35 was shown to potentiate IL-6 and TNF-α secretion by lipopolysaccharides (LPS) in astrocytes, but not in microglia [14].
The contents of cerebrospinal fluid (CSF) may reflect biochemical processes in the brain. Notably, changes in the levels of β-amyloid and tau protein have been reported to occur in CSF from Alzheimer's disease patients 4, 21, 28. There are conflicting data with regard to the levels of IL-1β and IL-6, in that elevated 5, 7, normal 20, 24, 31, and decreased [39]levels of cytokines have been reported to occur in CSF samples from Alzheimer's disease patients. To further elucidate the role of IL-1 in Alzheimer's disease, the levels of the soluble IL-1 receptor type II (sIL-1R type II), the endogenous IL-1 receptor antagonist (IL-1ra) as well as IL-1β, were analyzed in CSF samples from Alzheimer's disease patients and control subjects. In addition, the proinflammatory cytokines IL-6 and TNF-α were analyzed. The correlation of cytokine levels to cognitive decline was investigated, as well as their potential as diagnostic markers in Alzheimer's disease.
Section snippets
Subjects and collection of CSF samples
CSF samples were collected from 12 Alzheimer's disease patients (6 males and 6 females between 56 and 85 years old, mean age±S.E.M. 71±2.7 years) that had undergone an extensive investigation at the Div. of Geriatric Medicine, Dept. of Clinical Neuroscience, Occupational Therapy and Elderly Care Research, Huddinge University Hospital, Sweden, resulting in a clinical diagnosis of probable Alzheimer's disease according to NINCDS/ADRDA criteria. The cognitive status showed a mild to moderate
Results
The levels of sIL-1R type II were measured in CSF samples from Alzheimer's disease patients and from comparison subjects, and significantly higher levels were detected in the Alzheimer's disease samples (see Fig. 1). In 3 of 12 Alzheimer's disease patients, the levels of sIL-1R type II were not detectable (median level 33, range non-detectable—84 pg/ml), while the levels were measurable in 3 of 13 comparison subjects (median level non-detectable, range non-detectable—35 pg/ml, p<0.01) (Fig. 1).
Discussion
IL-1α and IL-1β bind to both IL-1 receptors, of which IL-1R type I elicits biological activity upon binding of the agonist, whereas IL-1R type II has been termed a `decoy' receptor since it binds IL-1α and IL-1β without transducing a signal 8, 33, neither in its membrane-bound nor soluble (sIL-1R type II) form. In the present study, the levels of sIL-1R type II were found to be significantly higher in CSF samples from Alzheimer's disease cases than in CSF samples from comparison cases. Notably,
Conclusion
In conclusion, the levels of sIL-1R type II were significantly increased in CSF from Alzheimer's disease patients with a mild to moderate disease state. However, experience from a larger number of samples will be necessary to evaluate whether CSF sIL-1R type II levels are suitable as a diagnostic marker in Alzheimer's disease, since there was some overlap between the values in the comparison and in the Alzheimer's disease group. In addition, further studies are necessary to establish whether
Acknowledgements
This work was supported by grants from The Bank of Sweden Tercentenary Fond, the Swedish Medical Research Council (12194), Kapten Artur Erikssons stiftelse för medicinsk forskning, Magnus Bergvalls Stiftelse, Stiftelsen för Gamla tjänarinnor, Karolinska Institute research funds, Stiftelsen Sigurd och Elsa Goljes Minne. The support from Professor Bengt Winblad, Head of the Dept. of Clinical Neuroscience, Occupational Therapy and Elderly Care Research, is gratefully acknowledged.
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