Abstract
Amyloid-β (Aβ) can induce a chronic inflammatory immune response that is associated, amongst many others, to abnormal glycosylation, inducible nitric oxide synthase (iNOS) and nitric oxide (NO). The relation between development of Mild Cognitive Impairment (MCI) and Alzheimer’s disease progression and these serum markers has not been evaluated. Serum levels of iNOs, NO, TNF-α, IL-1β, IL-6, IL-8, IL-10, and IL-12 are determined with commercially available kits. Sialylation of albumin-free serum patterns is determined by Western blot analysis with Sambucus nigra (specific for sialic acid attached to terminal galactose in α2,6 linkage) lectin. Apolipoprotein E (ApoE) haplotype is determined by Western blot using specific anti-ApoE 2, 3 or 4 antibodies. A mini-mental state examination (MMSE) test is also performed in the 10 MCI patients, 19 Alzheimer’s disease (AD) patients and 46 healthy age-matched controls evaluated. The results show an increase of iNOS in MCI and AD but significantly higher NO concentrations are only found in MCI patients. TNF-α and IL-1β concentrations are the only significantly increased cytokines in MCI patients; no differences between control and MCI or AD patients are found in regard to the other cytokines. An abnormal MMSE test result only correlates with a decrease in serum NO concentration in MCI patients. The terminal sialic acid linkage pattern of serum proteins also shows highly significant differences between MCI and AD patient. ApoE3/4 or 4/4 haplotypes are characteristic of MCI and AD patients. Our results imply that increased serum TNF-α, IL-1β, iNOS, NO and alterations of serum proteins glycosylation patterns in adult individuals with an abnormal MMSE test may serve as an early biomarker of MCI and AD development.
Highlights
The majority of pathology alterations in Alzheimer’s disease (AD) have been associated with amyloid-β (Aβ) toxicity [1]
There was a highly significant increase in inducible nitric oxide synthase (iNOS) expression, as determined by the dpp values obtained in the western blot membranes, in the AD patients (ANOVA p = 0.0114) and a significant tendency of Mild Cognitive Impairment (MCI) patients in relation to control group (Student t p = 0.033) (Figure 1)
We found that the correlation between both was r = 0.6952, r2 = 0.4833 and p = 0.0003, which in itself is not very high, it points towards a clear tendency where increased serum nitrates values might represent damage associated with early stages of AD development, that is, mild cognitive impairment (Figure 3)
Summary
The majority of pathology alterations in Alzheimer’s disease (AD) have been associated with amyloid-β (Aβ) toxicity [1]. Aβ can activate the microglia and macrophages [2], both of which become amyloid presenting cells to T cells of extra cerebral origin [3]; this in turn favors the local liberation of pro-inflammatory interleukins and reactive oxygen species (ROS) [4], as well as modifications of the post-translation processes of proteins including glycosylation [5]. This modification is not exclusive of immune cells as in vitro activation of endothelial cells exposed to the Aβ peptide has been shown [6]. An early primary feature of AD is cognitive deficit [10] that has been associated to increased expression of IL-12 [11]; this observation remains controversial [12]
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