Abstract
People with Down syndrome, a frequent genetic disorder in humans, have increased risk of health problems associated with this condition. One clinical feature of Down syndrome is the increased prevalence and severity of periodontal disease in comparison with the general population. Because saliva plays an important role in maintaining oral health, in the present study the salivary proteome of Down syndrome subjects was investigated to explore modifications with respect to healthy subjects. Whole saliva of 36 Down syndrome subjects, divided in the age groups 10-17 yr and 18-50 yr, was analyzed by a top-down proteomic approach, based on the high performance liquid chromatography-electrospray ionization-MS analysis of the intact proteins and peptides, and the qualitative and quantitative profiles were compared with sex- and age-matched control groups. The results showed the following interesting features: 1) as opposed to controls, in Down syndrome subjects the concentration of the major salivary proteins of gland origin did not increase with age; as a consequence concentration of acidic proline rich proteins and S cystatins were found significantly reduced in older Down syndrome subjects with respect to matched controls; 2) levels of the antimicrobial α-defensins 1 and 2 and histatins 3 and 5 were significantly increased in whole saliva of older Down syndrome subjects with respect to controls; 3) S100A7, S100A8, and S100A12 levels were significantly increased in whole saliva of Down syndrome subjects in comparison with controls. The increased level of S100A7 and S100A12 may be of particular interest as a biomarker of early onset Alzheimer's disease, which is frequently associated with Down syndrome.
Highlights
Down syndrome (DS)1 is a frequent genetic disorder in humans characterized by premature aging [1]
The authors suggested that a possible explanation for the decline of the salivary secretion in the older subjects with DS could be the occurrence of age-related neuropathological changes, consistent with Alzheimer’s disease (AD)
It has been shown that DS is associated with early development of dementia [29], and it has been suggested that oxidative stress could play a role in the pathogenesis of the clinical features of DS [30]
Summary
All chemicals and reagents were of analytical grade and were purchased from Farmitalia-Carlo Erba, (Milan, Italy), Sigma Aldrich. The T splitter resulted in a flow-rate of 0.20 ml/min toward the diode array detector and 0.10 ml/min toward the ESI source. Cystatin C and its oxidized derivative were confirmed in the present study by high resolution HPLC-ESI-MS/MS analysis of trypsin digestion products. Semi-purified fractions of cystatin C and its derivative were collected at the T-splitter during HPLC-ESI-MS experiments and submitted to digestion using the kit “Trypsin Singles Proteomic Grade” (Sigma-Aldrich) according to the manufacturer’s instructions. The results of HPLC-ESI-MS/MS experiments (supplemental Table S1) and annotated spectra are reported in the Supplemental Material. Quantification—Quantification was based on the area of the low resolution RP-HPLC-ESI-MS eXtracted Ion Current (XIC) peaks, and considered when the S/N ratio was at least 5. 15,515 Ϯ 2 [15,514–15,515] 11,161 Ϯ 1 [11,161–11,162] 4,370.9 Ϯ 0.4 (4,370.8) 4,928.2 Ϯ 0.5 (4,928.2) 4,062.2 Ϯ 0.4 (4,062.4) 3,036.5 Ϯ 0.3 (3,036.3) 3,192.4 Ϯ 0.3 (3,192.5) 14,186 Ϯ 2 (14,185.8) 14266 Ϯ 2 (14,265.8) 14,346 Ϯ 2 (14,345.8) 14,312 Ϯ 2 (14,313.1) 14,347 Ϯ 2 (14,346.1) 22,362 Ϯ 3 (22,361.2) 11,487 Ϯ 2 (11,486.7) 13,343 Ϯ 2 (13,343.1) 13,360 Ϯ 2 (13,359.1) 5,380.0 Ϯ 0.5 (5,379.7) 5,792.9 Ϯ 0.5 (5,792.7) 4,963.7 Ϯ 0.4 (4,963.5) 3,442.1 Ϯ 0.4 (3,442.1) 3,371.0 Ϯ 0.4 (3,371.0) 3,486.1 Ϯ 0.4 (3,486.1) 11,367 Ϯ 2 (11,367.8) 10,833 Ϯ 2 (10,834.5) 12,770 Ϯ 2 (12,769.2) 12,786 Ϯ 2 (12,785.2) 12,690 Ϯ 2 (12,689.2) 12,707 Ϯ 2 (12,705.2) 13,458 Ϯ 2 (13,456.8) 10,443 Ϯ 2 (10,443.9)
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