Abstract
Objective: The neuroprotective role of Interleukin (IL)-33 is supported in numerous pre-clinical studies but remains mostly uninvestigated in clinical studies of Alzheimer’s disease (AD). We aimed to examine the association between human blood levels of IL-33 and cognitive preservation in amnestic mild cognitive impairment (aMCI) and AD. Methods: A total of 100 participants (26 controls, 35 aMCI patients, and 39 AD patients) were completed twice Mini Mental State Examination (MMSE) over a 1-year interval. At the second MMSE, the 100 participants examined the plasma levels of IL-33, IL-β, IL-1 receptor agonist (IL-1RA), beta amyloid (Aβ), and tau and apolipoprotein E (ApoE) genotyping, and Hopkins Verbal Learning Test, Trail Making Test, forward and backward digit span, and Clinical Dementia Rating were performed as well. Results: IL-33 expression showed a positive trend among controls (1/26 = 3.8%), aMCI (9/35 = 25.7%), and AD (17/39 = 43.6%) (trend analysis: P < 0.001). The patients expressing IL-33 preserved their cognitive function compared with IL-33 non-expressing patients (1-year ΔMMSE: 0.16 ± 1.6 vs -1.5 ± 2.6; P = 0.006). The cognitive preservation was not associated with the lower levels of Aβ, tau, and AopE e4, while higher levels of AopE e4 and phosphorylated tau were indeed associated with cognitive decline. The aMCI patients with AD conversion during study period had higher proportion of IL-33(-) than non-AD converters (0.9% vs 53.3%, P = 0.04). Conclusions: IL-33 or its associated signaling pathways may represent a new treatment paradigm for aMCI and AD. Funding Statement: Supported by grants from the Ministry of Science and Technology of Taiwan (MOST 106-2314-B-016-007-MY2, MOST 108-2314-B-016-023-), Tri-Service General Hospital (TSGH-C106-068, TSGH-C108-100, TSGH-C108-216), and Beitou Branch, Tri-Service General Hospital (TSGH-BT-108-01). Declaration of Interests: All authors declare that there is no conflict of interest regarding the publication of this article. Ethics Approval Statement: The protocol was approved by the Institutional Review Board for the Protection of Human Subjects at the Tri-Service General Hospital (TSGHIRB 1-107-05-111). Informed consent was obtained from all participants.
Highlights
The neuroprotective role of Interleukin (IL)-33 is supported in numerous pre-clinical studies but remains mostly uninvestigated in clinical studies of Alzheimer’s disease (AD)
Another human study reported that compared with the mild cognitive impairment (MCI) patients with subsequent AD conversion, the MCI patients without AD conversion had higher levels of IL-33+ cells that were positively correlated with hippocampus volumes [17]
To determine whether IL-33 expression might be a protective factor for amnestic mild cognitive impairment (aMCI) and AD patients, we examined the association between IL-33 expression and 1-year change in Mini Mental State Examination (MMSE)
Summary
The neuroprotective role of Interleukin (IL)-33 is supported in numerous pre-clinical studies but remains mostly uninvestigated in clinical studies of Alzheimer’s disease (AD). An animal study showed that peripheral IL-33 administration reduced soluble Aβ levels and amyloid plaque deposition, and reversed synaptic plasticity impairment and cognitive decline in AD mouse models [15] Another animal study reported that IL-33 deficiency caused tau abnormality, neurodegeneration, and AD-like symptoms in aged mice [16]. Consistent with these findings, a human genetic study showed that IL-33 expression is reduced in the brains of AD [18] Another human study reported that compared with the mild cognitive impairment (MCI) patients with subsequent AD conversion, the MCI patients without AD conversion had higher levels of IL-33+ cells that were positively correlated with hippocampus volumes [17]. These findings suggested the potential therapeutic role of IL-33 in AD
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