Abstract
BackgroundAlthough the mechanisms underlying AD neurodegeneration are not fully understood, it is now recognised that inflammation could play a crucial role in the initiation and progression of AD neurodegeneration. A neuro-inflammatory network, based on the anomalous activation of microglial cells, includes the production of a number of inflammatory cytokines both locally and systemically. These may serve as diagnostic markers or therapeutic targets for AD neurodegeneration.MethodsWe have measured the levels of the inflammation-related cytokines and receptors of the IL-1 family in serum of subjects with AD, compared to mild cognitive impairment (MCI), subjective memory complaints (SMC), and normal healthy subjects (NHS). Using a custom-made multiplex ELISA array, we examined ten factors of the IL-1 family, the inflammation-related cytokines IL-1α, IL-1β, IL-18, and IL-33, the natural inhibitors IL-1Ra and IL-18BP, and the soluble receptors sIL-1R1, sIL-1R2, sIL-1R3, and sIL-1R4.ResultsThe inflammatory cytokines IL-1α and IL-1β, their antagonist IL-1Ra, and their soluble receptor sIL-1R1 were increased in AD. The decoy IL-1 receptor sIL-1R2 was only increased in MCI. IL-33 and its soluble receptor sIL-1R4 were also significantly higher in AD. The soluble form of the accessory receptor for both IL-1 and IL-33 receptor complexes, sIL-1R3, was increased in SMC and even more in AD. Total IL-18 levels were unchanged, whereas the inhibitor IL-18BP was significantly reduced in MCI and SMC, and highly increased in AD. The levels of free IL-18 were significantly higher in MCI.ConclusionsAD is characterised by a significant alteration in the circulating levels of the cytokines and receptors of the IL-1 family. The elevation of sIL-1R4 in AD is in agreement with findings in other diseases and can be considered a marker of ongoing inflammation. Increased levels of IL-1Ra, sIL-1R1, sIL-1R4, and IL-18BP distinguished AD from MCI and SMC, and from other inflammatory diseases. Importantly, sIL-1R1, sIL-1R3, sIL-1R4, and IL-18BP negatively correlated with cognitive impairment. A significant elevation of circulating sIL-1R2 and free IL-18, not present in SMC, is characteristic of MCI and disappears in AD, making them additional interesting markers for evaluating progression from MCI to AD.
Highlights
The mechanisms underlying Alzheimer’s disease (AD) neurodegeneration are not fully understood, it is recognised that inflammation could play a crucial role in the initiation and progression of AD neurodegeneration
The levels of IL-1 family cytokines and receptors were measured in serum of AD patients and compared with those of mild cognitive impairment (MCI), subjective memory complaints (SMC), and normal healthy subjects (NHS)
The levels of the inflammatory cytokines IL-1α and IL-1β were very low or undetectable in NHS (0.29 ± 1.37 pg/ml and 0.54 ± 3.31 pg/ml, respectively). Please note that these levels are below the reliable detection range of the multiplex array. These levels remained low in SMC (0.30 ± 1.12 and 0.19 ± 1.55, respectively) and MCI (0.16 ± 0.76 and 0.26 ± 1.24, respectively) and increased in the AD group (3.6 ± 16.2 pg/ml and 3.2 ± 13.5 pg/ml, respectively), reaching statistical significance in the comparison AD vs. NHS (p = 0.018) for IL-1α, and AD vs. NHS (p = 0.014), AD vs. SMC (p = 0.046), and AD vs. MCI (p = 0.012) for IL-1β (Fig. 1, upper panels)
Summary
The mechanisms underlying AD neurodegeneration are not fully understood, it is recognised that inflammation could play a crucial role in the initiation and progression of AD neurodegeneration. A neuro-inflammatory network, based on the anomalous activation of microglial cells, includes the production of a number of inflammatory cytokines both locally and systemically. These may serve as diagnostic markers or therapeutic targets for AD neurodegeneration. Alzheimer’s disease (AD) is an age-related, non-reversible brain disorder that develops over a period of years and has become a global challenge for public health. The most prominent risk factor for AD is age, and 65 years represent the benchmark for discrimination between early onset (about 10% of cases, with a likely genetic cause) and late onset (90% of cases, with multiple risk factors) [2]. Despite intensive research and drug development efforts, there are still no therapies that can stop or even slow down disease progression
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